Drug Combination Increases Susceptibility to Chemotherapy in Cases of Severe Neuroblastoma (Medicine)

Researchers at the University of Gothenburg now suggest a possible cure for children with hard-to-treat forms of neuroblastoma using a new combination of drugs. In a new study in the journal Cancer Research, they describe how a two small molecule-based drug combination likely inhibit the tumor’s growth.

Chandrasekahr Kanduri, Sahlgrenska Academy, University of Gothenburg. © Photo by Margareta G. Kubista

Neuroblastoma is the most common form of childhood cancer, derived from the peripheral nervous system, i.e., the part of the nervous system that is not the brain or spinal cord. The disease can occur in the chest, neck, abdomen and adrenal glands and can also spread to the spine. Symptoms include general aches, anemia and skeletal pain.

The average age of children at diagnosis is 17 months, and it is rarely diagnosed over the age of five. The milder form of neuroblastoma can, in some cases, self-heal, while the more aggressive form is the deadliest form of childhood cancer. Treatment is successful in less than half of these cases.

Central molecule in the study is the p53 gene. The p53 gene is often mutated in other cancer forms but rarely in neuroblastoma. When it is not mutated, p53 codes for a protein that inhibit the growth of cancer. This study shows that how the expression levels of a long non-coding RNA molecule influences the function of p53 protein. “Interestingly, this long non-coding RNA increases p53 function in the nucleus to make tumor cells more susceptible to cytostatic treatment,” says Chandrasekhar Kanduri, professor of medical genetics specialized in RNA epigenetics at the University of Gothenburg.

The RNA molecule NBAT1 changes the function of the protein CRM1, which transports p53 from nucleus to cytoplasm. NBAT1 also helps in keeping the p53 protein in the nucleus to increase p53 controlled gene expression. Based on these findings, the research group tested a new treatment that combines the drugs Selinexor and Nutlin-3a. Both drugs are currently undergoing clinical trials for cancer treatments but not for neuroblastoma. Selinexor restores p53’s ability to inhibit cancer growth and Nutlin-3a inhibits the breakdown of p53.

“The combination treatment blocks the protein export function of CRM1, which leads to p53 accumulation in the cell nucleus. This treatment increases p53 dependent functions, such as DNA damage and cell death. We think that combining these two drugs with current treatment strategies may allow us to cure hard-to-treat neuroblastomas.”

The results are promising, but they are based on preclinical studies of cancer cell lines and mouse models (xenografts) and more research is needed before the findings can be translated into treatment. These laboratory results have been partly validated with the neuroblastoma patient data, obtained in collaboration with the researchers at Karolinska Institutet. Thus, this study has clearly opened the way for a potential new treatment strategy for high-risk neuroblastoma patients.

Reference: http://dx.doi.org/10.1158/0008-5472.CAN-19-3499

Provided by University of Gothenburg

A Brain Mechanism Underlying “Vision” in the Blind is Revealed (Neuroscience)

Researchers observed slow spontaneous fluctuations in the brain’s visual centers that preceded visual hallucinations in blind people.

Some people have lost their eyesight, but they continue to “see.” This phenomenon, a kind of vivid visual hallucination, is named after the Swiss doctor, Charles Bonnet, who described in 1769 how his completely blind grandfather experienced vivid, detailed visions of people, animals and objects. Charles Bonnet syndrome, which appears in those who have lost their eyesight, was investigated in a study led by scientists at the Weizmann Institute of Science. The findings, published today in Brain, suggest a mechanism by which normal, spontaneous activity in the visual centers of the brain can trigger visual hallucinations in the blind.

Prof. Rafi Malach and his group members of the Institute’s Neurobiology Department research the phenomenon of spontaneous “resting-state” fluctuations in the brain. These mysterious slow fluctuations, which occur all over the brain, take place well below the threshold of consciousness. Despite a fair amount of research into these spontaneous fluctuations, their function is still largely unknown. The research group hypothesized that these fluctuations underlie spontaneous behaviors. However, it is typically difficult to investigate truly unprompted behaviors in a scientific manner for two reasons, since, for one, instructing people to behave spontaneously is usually a spontaneity-killer. Secondly, it is difficult to separate the brain’s spontaneous fluctuations from other, task-related brain activity. The question was: How could they isolate a case of a truly spontaneous, unprompted, behavior in which the role of spontaneous brain activity could be tested?

The same visual system is active when we see the world outside of us, when we imagine it, when we hallucinate, and probably also when we dream

Individuals experiencing Charles Bonnet visual hallucinations presented the group with a rare opportunity to investigate their hypothesis.  This is because in Charles Bonnet syndrome, the hallucinations appear at random, in a truly unprompted fashion, and the visual centers of the brain do not process outside stimuli (because these individuals are blind), and are thus activated spontaneously. In a study led by Dr. Avital Hahamy, a former research student in Malach’s lab who is now a postdoctoral research fellow at University College London, the relation between these hallucinations and the spontaneous brain activity has indeed been unveiled.

The researchers first invited to their lab five people who had lost their sight and reported occasionally experiencing clear visual hallucinations. These participants’ brain activity was measured using an fMRI scanner while they described their hallucinations as these occurred. The scientists then created movies based on the participants’ verbal descriptions, and they showed these movies to a sighted control group, also inside the fMRI scanner. A second control group consisted of blind people who had lost their sight but did not experience visual hallucinations. These were asked to imagine similar visual images while in the scanner.

The same visual areas in the brain were active in all three groups – those that hallucinated, those that watched the films and those creating imagery in their minds’ eye. But the researchers noted a difference in the timing of the neural activity between these groups. In both the sighted participants and those in the imagery group, the activity was seen to take place in response either to visual input or to the instructions set in the task. But in the group with Charles Bonnet syndrome, the scientists observed a gradually increasing wave of activity, reminiscent of the slow spontaneous fluctuations, that emerged just before the onset of the hallucinations. In other words, the hallucinations were not the result of external stimuli (eg., sensory images or instructions to imagine specific things), but were rather evoked internally by the slow, spontaneous, brain activity fluctuations.

The  visual centers in those seeing a film or imagining as instructed had similar timing in their brain activity, while those experiencing spontaneous hallucinations showed a gradual increase in slow fluctuations © Weizmann Institute of Science

“Our research clearly shows that the same visual system is active when we see the world outside of us, when we imagine it, when we hallucinate, and probably also when we dream,” says Malach. “It also exemplifies the creative power of vision and the contribution of spontaneous brain activity to unprompted and creative behaviors,” he adds.

In addition to the scientific value of the work, Hahamy hopes it may raise awareness of Charles Bonnet syndrome, which can be frightening to those who experience it. “These individuals may keep their visual hallucinations a secret – even from doctors and family – and we want them to understand that these visions are a natural product of a healthy brain, in which the visual centers remain intact, even if the eyes have ceased to send them sensory input,” she says.

Also participating in this research were Dr. Meytal Wilf, formerly in Malach’s lab, of Lausanne University Hospital, Switzerland; Dr. Boris Rosin, of the Ophthalmology Departments of Hadassah-Hebrew University Medical Center, Jerusalem, and University of of Pittsburgh Medical Center; and Prof. Marlene Behrmann of Carnegie Mellon University, Pittsburgh, Pennsylvania.

Provided by Weizmann Institute of Science

When Galaxies Collide: Hubble Showcases 6 Beautiful Galaxy Mergers (Astronomy)

To celebrate a new year, the NASA/ESA Hubble Space Telescope has published a montage of six beautiful galaxy mergers. Each of these merging systems was studied as part of the recent HiPEEC survey to investigate the rate of new star formation within such systems. These interactions are a key aspect of galaxy evolution and are among the most spectacular events in the lifetime of a galaxy.

To celebrate a new year, the NASA/ESA Space Telescope has published a montage of six beautiful galaxy mergers. Each of these merging systems was studied as part of the recent HiPEEC survey to investigate the rate of new star formation within such systems. These interactions are a key aspect of galaxy evolution and are among the most spectacular events in the lifetime of a galaxy.
Top left: NGC 3256
This image of NGC 3256 was taken with the Wide Field Camera 3 (WFC3) and the Advanced Camera for Surveys (ACS), both installed on the NASA/ESA Hubble Space Telescope. The galaxy is about 100 million light-years from Earth and provides an ideal target in which to investigate starbursts that have been triggered by galaxy mergers.
Credit: ESA/Hubble, NASA
Top Middle: NGC 1614
The galaxy system NGC 1614 has a bright optical centre and two clear inner spiral arms that are fairly symmetrical. It also has a spectacular outer structure that consists principally of a large one-sided curved extension of one of these arms to the lower right, and a long, almost straight tail that emerges from the nucleus and crosses the extended arm to the upper right. 
Credit: NASA, ESA, the Hubble Heritage Team (STScI/AURA)-ESA/Hubble Collaboration and A. Evans (University of Virginia, Charlottesville/NRAO/Stony Brook University)
Top Right: NGC 4194
NGC 4194 is also known as the Medusa merger.  An early galaxy consumed a smaller gas-rich system, throwing out streams of stars and dust out into space. These streams, seen rising from the top of the merger galaxy, resemble the writhing snakes that Medusa, a monster in ancient Greek mythology, famously had on her head in place of hair, lending the object its intriguing name. The Medusa merger is located about 130 million light-years away in the constellation of Ursa Major (The Great Bear). 
Credit: ESA/Hubble & NASA, A. Adamo
Bottom Left: NGC 3690
This system consists of a pair of galaxies, dubbed IC 694 and NGC 3690, which made a close pass some 700 million years ago. As a result of this interaction, the system underwent a fierce burst of star formation. In the last fifteen years or so six supernovae have popped off in the outer reaches of the galaxy, making this system a distinguished supernova factory. 
Credit: NASA, ESA, the Hubble Heritage Team (STScI/AURA)-ESA/Hubble Collaboration and A. Evans (University of Virginia, Charlottesville/NRAO/Stony Brook University)
Bottom Middle: NGC 6052
Located in the constellation of Hercules, about 230 million light-years away, NGC 6052 is a pair of colliding galaxies. They were first discovered in 1784 by William Herschel and were originally classified as a single irregular galaxy because of their odd shape. However, we now know that NGC 6052 actually consists of two galaxies that are in the process of colliding. This particular image of NGC 6052 was taken using Hubble’s Wide Field Camera 3.
Credit: ESA/Hubble & NASA, A. Adamo et al.
Bottom Right: NGC 34
Lying in the constellation Cetus (The Sea Monster), NGC 34’s outer region appears almost translucent, pin pricked with stars and strange wispy tendrils. This image shows the galaxy’s bright centre, a result of this merging event that has created a burst of new star formation and lit up the surrounding gas. As the galaxies continue to intertwine and become one, NGC 34’s shape will become more like that of a peculiar galaxy, devoid of any distinct shape.
Credit: ESA/Hubble & NASA, A. Adamo et al.

Credit:NASA & ESA

It is during rare merging events that galaxies undergo dramatic changes in their appearance and in their stellar content. These systems are excellent laboratories to trace the formation of star clusters under extreme physical conditions.

The Milky Way typically forms star clusters with masses that are 10 thousand times the mass of our Sun. This doesn’t compare to the masses of the star clusters forming in colliding galaxies, which can reach millions of times the mass of our Sun.

These dense stellar systems are also very luminous. Even after the collision, when the resulting galactic system begins to fade into a more quiescent phase, these very massive star clusters will shine throughout their host galaxy, as long-lasting witnesses of past merging events.

By studying the six galaxy mergers shown here, the Hubble imaging Probe of Extreme Environments and Clusters (HiPEEC) survey has investigated how star clusters are affected during collisions by the rapid changes that drastically increase the rate at which new stars are formed in these galaxies. Hubble’s capabilities have made it possible to resolve large star-forming “knots” into numerous compact young star clusters. Hubble’s ultraviolet and near-infrared observations of these systems have been used to derive star cluster ages, masses, and extinctions and to analyse the star formation rate within these six merging galaxies. The HiPEEC study reveals that the star cluster populations undergo large and rapid variations in their properties, with the most massive clusters formed towards the end of the merger phase.

Each of the merging systems shown here has been previously published  by Hubble, as early as 2008 and as recently as October 2020. To celebrate it’s 18th anniversary in 2008, the Hubble Space Telescope released a collection of 59 images of merging galaxies, which can be explored here.

More information

The Hubble Space Telescope is a project of international cooperation between ESA and NASA.

The HiPEEC survey was completed as part of the Hubble Space Telescope program GO 14066 (PI: A. Adamo). A repository with the study’s final data and catalogues is available here in the MAST Archive.

The international team of astronomers in this study consists of A. Adamo, K. Hollyhead, M. Messa, J. E. Ryon, V. Bajaj, A. Runholm, A. Aalto, D. Calzeti, J. S. Gallagher, M. J. Hayes, J. M. D. Kruijssen, S. König, S. S. Larsen, J. Melinder, E. Sabbi, L. J. Smith, and G. Östlin.

Reference: A Adamo, K Hollyhead, M Messa, J E Ryon, V Bajaj, A Runnholm, S Aalto, D Calzetti, J S Gallagher, M J Hayes, J M D Kruijssen, S König, S S Larsen, J Melinder, E Sabbi, L J Smith, G Östlin, Star cluster formation in the most extreme environments: insights from the HiPEEC survey, Monthly Notices of the Royal Astronomical Society, Volume 499, Issue 3, December 2020, Pages 3267–3294, https://doi.org/10.1093/mnras/staa2380 https://academic.oup.com/mnras/article-abstract/499/3/3267/5900984

Provided by ESA/HUBBLE

Focused Ultrasound Shows Promise for Parkinson’s Disease (Neuroscience)

A scalpel-free alternative to brain surgery has the potential to benefit people with Parkinson’s disease symptoms that are much more severe on one side of the body, new research suggests.

Jeff Elias, MD, is a neurosurgeon at UVA Health and a pioneer in the field of focused ultrasound. © UVA Health

More testing is needed, but the approach, which uses a technology called focused ultrasound, could offer a new option for patients whose symptoms are poorly controlled by medications and those who cannot or do not wish to undergo traditional brain surgery.

“This small brain region, the subthalamic nucleus, had a very strong and potent effect on Parkinsonian symptoms when we targeted it with precise, focused ultrasound energy,” said researcher Jeff Elias, MD, a neurosurgeon at UVA Health and a pioneer in the field of focused ultrasound. “The key for the ultimate adoption of this new procedure will be further refinements of the technology to ensure reliability and safety.”


Focused ultrasound offers a minimally invasive alternative to traditional surgery approaches. The technology focuses sound waves inside the body, much like a magnifying glass focuses light. This allows doctors to interrupt faulty brain circuits or destroy unwanted tissue. Magnetic-resonance imaging (MRI) allows doctors to monitor the procedure in real time – and to make adjustments as needed to obtain the best patient outcomes.

To determine if the technology could benefit patients with “asymmetrical” Parkinson’s symptoms, Elias and Binit Shah, MD, from UVA’s Department of Neurology, collaborated with Spain’s Centro Intregral de Neurociencias to evaluate the approach in 40 volunteers in a randomized, double-blinded study. Twenty-seven study participants received treatment with focused ultrasound, while 13 others received a simulated treatment, so that the researchers could compare the results between the real procedure and the placebo. The average age of study participants was 57.

The volunteers’ symptoms before and after the procedure were assessed on a scale of 1-44. Those who received the focused ultrasound procedure saw an improvement of 10 points, while those who received the sham treatment saw a difference of less than two points.

The study also looked at the safety of the procedure. Side effects included unwanted movements, muscle weakness, speech disturbances and difficulty walking. In most cases, these were temporary, but some effects persisted in six patients a year later.

The results warrant additional studies in larger numbers of volunteers conducted over longer periods of time, the researchers conclude.

“Parkinson’s disease affects patients in more ways than just tremor,” Shah said. “The current FDA approval for focused ultrasound in Parkinson’s disease treats only tremor. Targeting this new area allows us to improve tremor but also get more overall benefit for our patients than we previously were able to achieve.”


UVA has been at the leading edge of research into the technology’s potential to treat disease. For example, the federal Food and Drug Administration approved focused ultrasound for the treatment of essential tremor, a common movement disorder, based on Elias’ pioneering research. His work also paved the way for the FDA to authorize the technology to treat tremors caused by Parkinson’s disease.

Other researchers at UVA are investigating the technology’s potential to treat a wide variety of conditions, including epilepsy and breast cancer.


Elias and his colleagues have published their latest findings in the prestigious New England Journal of Medicine. The research team consisted of Raúl Martínez-Fernández, Jorge U. Máñez-Miró, Rafael Rodríguez-Rojas, Marta del Álamo, Binit B. Shah, Frida Hernández-Fernández, Jose A. Pineda-Pardo, Mariana H.G. Monje, Beatriz Fernández-Rodríguez, Scott A. Sperling, David Mata-Marín, Pasqualina Guida, Fernando Alonso-Frech, Ignacio Obeso, Carmen Gasca-Salas, Lydia Vela-Desojo, Elias and Jose A. Obeso.

The research was supported by InSightec, the manufacturer of the focused ultrasound technology; Charlottesville’s Focused Ultrasound Foundation, a longtime supporter of UVA’s focused ultrasound research; Fundación MAPFRE in Madrid; Fundación Hospitales de Madrid; and a University of Virginia Center of Excellence grant. Elias disclosed that his department at UVA has received research funding from InSightec, but the company had no role in the study design or analysis. A full list of author disclosures is included in the paper in the New England Journal of Medicine.

Reference: Raúl Martínez-Fernández, Jorge U. Máñez-Miró, Rafael Rodríguez-Rojas, Marta del Álamo, et al., “Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson’s Disease”, N Engl J Med 2020; 383:2501-2513. https://www.nejm.org/doi/10.1056/NEJMoa2016311
DOI: 10.1056/NEJMoa2016311

Provided by University of Virginia Health System

Researchers Synthesize Bio-based Methylcyclopentadiene with 3-Methylcyclopent-2-enone (Chemistry)

Methylcyclopentadiene (MCPD) is an important monomer in the production of RJ-4 fuel, a high-energy-density rocket fuel, and various valuable products.

Direct hydrodeoxygenation of MCP to MCPD on the partially reduced Zn-Mo oxide catalyst. © DICP

Currently, MCPD is mainly obtained from the by-products of petroleum cracking tar at a very low yield of ~ 0.7 kg ton-1 and high price of ~10,000 USD ton-1. The exploration of highly efficient processes to convert renewable biomass to MCPD is stimulated by the energy and environment problems.

Recently, a group led by Prof. LI Ning and Prof. ZHANG Tao from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS) synthesized bio-based MCPD via direct hydrodeoxygenation of 3-methylcyclopent-2-enone (MCP) derived from cellulose.

Their study was published in Nature Communications on Jan. 4.

The researchers found that selective hydrodeoxygenation of MCP to MCPD could be achieved on the partially reduced Zn-Mo oxide catalyst.

The Zn-Mo oxide catalyst formed ZnMoO3 species during the reduction of ZnMoO4, which might preferentially adsorb C=O bond in the presence of C=C bond in vapor phase hydrodeoxygenation of MCP led to highly selective formations of MCPD with a carbon yield of 70%.

“This is a following work of our previous report about the synthesis of 2,5-hexanedione by the direct hydrogenolysis of cellulose and the intramolecular aldol condensation of 2,5-hexanedione to MCP,” said Prof. Li.

This study opens up a horizon for the production of dienes with unsaturated ketone by a direct hydrodeoxygenation process.

Reference: Liu, Y., Wang, R., Qi, H. et al. Synthesis of bio-based methylcyclopentadiene via direct hydrodeoxygenation of 3-methylcyclopent-2-enone derived from cellulose. Nat Commun 12, 46 (2021). https://www.nature.com/articles/s41467-020-20264-3 https://doi.org/10.1038/s41467-020-20264-3

Provided by Dalian Institute of Chemical Physics, China Academy of Sciences

Want to Diagnose Brain Diseases? A Mass Spectrometry Imaging May One Day Help You (Psychiatry)

Researchers from Osaka University developed a new method for brain tissue analysis in high spatial resolution that requires no sample preparation.

Medical professionals all want to be able to quickly and correctly diagnose diseases. Their future ability to do so will depend on identifying what biochemicals are present in tissue sections, where the biomolecules are, and at what concentrations. For this purpose, mass spectrometry imaging–which can identify multiple biochemicals in a single experiment–will be useful. However, the stability of biomolecular sampling needs improvement to obtain the chemical distribution information with high spatial resolution.

(a) Schematic of the measurement system developed in this study. By using this technology, extraction and ionization of picoliter volumes can be performed without disruptions caused by surface roughness. In addition, one can measure the height of the sample from the change in vibration amplitude. (b) Relationship between the length of the capillary probe and the resonance frequency of the probe. (c) Correlation between the input voltage to the piezoelectric actuator used to vibrate the probe and the probe vibration amplitude. (d) Correlation between the height of the sample and the feedback control signal. © Reproduced with permission. Copyright (2021) American Chemical Society.

In the recent study published in Analytical Chemistry, researchers from Osaka University used mass spectrometry to image the distribution of fat molecules in mouse brain tissue. They acquired data at a spatial resolution of 6.5 micrometers, enabling analysis on a cellular level.

The researchers used a very small capillary to gently extract lipid molecules from a tissue section, and a carefully designed setup for fine 3D directional control. Although biological tissue may often seem smooth to the naked eye, on an ultrasmall scale it’s rather rough. The ability to account for this ultrasmall-scale roughness is central to obtaining reproducible biochemical data at high spatial resolution.

(a) Optical microscopy image of a mouse brain tissue section. (b,c) Mass spectrometry imaging of two regions of the optical microscopy image in positive ion mode and negative ion mode, respectively. (d,e) Score plots obtained by principal component analysis of mass spectra included in the selected regions in (b) and (c), respectively. (f,g) Intra-tissue distribution of the score values of the second and third principal components obtained by principal component analysis. We obtained feature images from differences in the structure of the brain tissue. © Reproduced with permission. Copyright (2021) American Chemical Society. https://pubs.acs.org/doi/abs/10.1021/acs.analchem.0c04144

“In our experiments, the probe’s vibration amplitude is constant even when the sample height changes,” says Yoichi Otsuka, first author. “We can also measure changes in sample height up to 20 micrometers, and it can be increased up to 180 micrometers.”

The researchers’ first experiments were to measure irregular distributions of molecules across an uneven surface: microwells filled with various concentrations of a dye. The measured concentrations correlated with the known concentrations, and the measured surface topography was close to the actual microwell diameter. Experiments with mouse brain sections yielded a multi-dimensional data of multiple molecules such as the distribution of certain hexosylceramides–lipids that are important in aging.

Results of multi-imaging of mouse brain tissue. Cross-sectional profiles of the vertical white line in the figure are shown below each image. (a) Topography showing the roughness of the sample surface. (b) Amplitude image showing the change in vibration amplitude of the probe, which is suppressed in uneven tissue. (c) Phase image showing the change in vibration phase of the probe. The oscillation phase of the probe differs between the brain tissue and glass substrate. Scale bar, 1 mm. © Reproduced with permission. Copyright (2021) American Chemical Society. https://pubs.acs.org/doi/abs/10.1021/acs.analchem.0c04144

“Principle component analysis helped us integrate our wide-ranging data,” explains Takuya Matsumoto, senior author. “For example, we could assign the classes of lipids that are primarily present in the cortex and brainstem.”

Correlating such data with disease progression will require further study and perhaps additional development of the researchers’ biomolecule extraction setup. The researchers anticipate that their approach will be useful for quantitatively imaging the myriad neural networks in brain tissue. Ultimately, they hope to help medical practitioners reliably diagnose diseases such as brain cancer in a tissue section with the support of molecular information in high spatial resolution.

The article, “High-spatial-resolution multimodal imaging by tapping-mode scanning probe electrospray ionization with feedback control,” was published in Analytical Chemistry at DOI: https://doi.org/10.1021/acs.analchem.0c04144

Provided by Osaka University

A Subtle Change in the DNA May Predispose to Polyneuropathy After Gut Infection (Biology)

Researchers from Tokyo Medical and Dental University (TMDU) identify a novel genetic variant associated with Guillain-Barré syndrome.

Guillain-Barré syndrome is an infamous autoimmune neuropathy, yet genetic variants predisposing individuals to this disease have yet to be described. In a new study, researchers from Tokyo Medical and Dental University (TMDU) discovered two novel genetic variants in a protein made by antibody-forming immune cells, providing a mechanism for the development of the disease.

The body’s immune system is supposed to fight off invaders; however, in autoimmune diseases this defense goes rogue and attacks the host instead through the production of autoantibodies. Guillain-Barré syndrome (GBS) is an acutely developing, autoimmune peripheral neuropathy that leads to muscle weakness and numbness. It is based on the production of autoantibodies against gangliosides, a specific type of lipid molecules on the membranes of cells of the nervous system, which in turn damage those neurons and result in polyneuropathy. That is, damage to multiple peripheral nerves that may cause muscle weakness and numbness. GBS is often preceded by an immune stimulation such as an infection. Indeed, infection with the bacterium Campylobacter jejuni, causing a diarrheal illness, is the most common event before GBS develops. However, as not all patients with this bacterial illness then develop GBS, it has long been thought that genetic variants (small differences in the DNA between individuals) may be what predisposes patients with GBS to the polyneuropathy.

“GBS remains somewhat of a medical mystery. We do not fully understand why patients develop this disease,” says corresponding author of the study Professor Takeshi Tsubata. “The goal of our study was to identify genetic variants in patients with GBS and provide a potential mechanism for the production of autoantibodies that lead to the development of polyneuropathy in these patients.”

To achieve their goal, the researchers focused on the protein Siglec-10. Siglec-10 is produced by B lymphocytes, a specific type of immune cell that produces antibodies, and binds to gangliosides. The researchers hypothesized that Siglec-10 may play an inhibitory role in the production of antibodies against gangliosides, and in turn that genetic variants in Siglec-10 may diminish this inhibitory role and thus facilitate the development of GBS. By analyzing the DNA sequence encoding for the protein Siglec-10 in patients with GBS, the researchers identified two rare variants that change the amino acid sequence in the protein in GBS patients. There were no patients with only one of the two variants probably because these two variants are located very closely in the Siglec-10 gene.

The researchers then made the GBS-specific Siglec-10 protein in the lab to understand how it differs from the normal Siglec-10 protein at the molecular level. They found that only one of the two variants was responsible for the deleterious effects of the alternate protein, causing a marked alteration in the molecular structure of the protein and in turn a significant impairment of the protein to bind gangliosides.

Identification of a gene associated with Guillain–Barré syndrome (GBS) suggests pathogenesis of the disease. Patients with GBS characteristically produce autoantibodies to sialic acid-containing glycolipids called gangliosides present in neuronal cells. These autoantibodies are thought to bind to gangliosides present on the surface of neurons, and cause paralysis and sensory disturbance by damaging neurons. Here we demonstrate that a rare variant of the molecule called Siglec-10 accumulates in patients with GBS. Siglec-10 is a cell surface molecule present in various immune cells including antibody-producing cells. Siglec-10 recognizes sialic acid-containing molecules including gangliosides as ligands, and is known to inhibit activation of antibody-producing cells upon interaction with the ligands. Normal Siglec-10 may inhibit activation of anti-ganglioside antibody-producing cells when these cells interact with gangliosides present in neurons. In contrast, the Siglec-10 variant accumulated in patients with GBS shows impaired binding to gangliosides. Therefore, this Siglec-10 variant may fail to inhibit activation of anti-ganglioside antibody-producing cells, thereby allowing production of anti-ganglioside autoantibodies. ©TMDU

“These are striking results that show how Siglec-10 suppresses antibody production of gangliosides, and in turn how a variant protein may predispose to the development of Guillain-Barré syndrome. These findings help us understand the pathophysiology of the disease,” says first author of the study Amin Alborzian Deh Sheikh.

The article, “A Guillain-Barré syndrome-associated SIGLEC10 rare variant impairs its recognition of gangliosides” was published in Journal of Autoimmunity at DOI: 10.1016/j.jaut.2020.102571

Provided by Tokyo Medical and Dental University

Oldest Hominins of Olduvai Gorge Persisted Across Changing Environments (Archeology)

~2.0 to 1.8 million year-old archaeological site demonstrates that early humans had the skills and tools to cope with ecological change.

Olduvai (now Oldupai) Gorge, known as the Cradle of Humankind, is a UNESCO World Heritage site in Tanzania, made famous by Louis and Mary Leakey. New interdisciplinary field work has led to the discovery of the oldest archaeological site in Oldupai Gorge as reported in Nature Communications, which shows that early human used a wide diversity of habitats amidst environmental changes across a 200,000 year-long period.

Olduvai (now Oldupai) Gorge, known as the Cradle of Humankind, is a UNESCO World Heritage site in Tanzania. New interdisciplinary field work has led to the discovery of the oldest archaeological site in Oldupai Gorge, which shows that early human used a wide diversity of habitats amidst environmental changes across a 200,000 year-long period. © Michael Petraglia

Located in the heart of eastern Africa, the Rift System is a prime region for human origins research, boasting extraordinary records of extinct human species and environmental records spanning several million years. For more than a century, archaeologists and human palaeontologists have been exploring the East African Rift outcrops and unearthing hominin fossils in surveys and excavations. However, understanding of the environmental contexts in which these hominins lived has remained elusive due to a dearth of ecological studies in direct association with the cultural remains.

In the new study, published in Nature Communications, researchers from the Max Planck Institute for for the Science of Human History teamed up with lead partners from the University of Calgary, Canada, and the University of Dar es Salaam, Tanzania, to excavate the site of ‘Ewass Oldupa’ (meaning on ‘the way to the Gorge’ in the local Maa language, as the site straddles the path that links the canyon’s rim with its bottom). The excavations uncovered the oldest Oldowan stone tools ever found at Oldupai Gorge, dating to ~2 million years ago. Excavations in long sequences of stratified sediments and dated volcanic horizons indicated hominin presence at Ewass Oldupai from 2.0 to 1.8 million years ago.

The excavations uncovered the oldest Oldowan stone tools ever found at Oldupai Gorge, dating to ~2 million years ago. Excavations in long sequences of stratified sediments and dated volcanic horizons indicated hominin presence at Ewass Oldupai from 2.0 to 1.8 million years ago. © Michael Petraglia

Fossils of mammals (wild cattle and pigs, hippos, panthers, lions, hyena, primates), reptiles and birds, together with a range of multidisciplinary scientific studies, revealed habitat changes over 200,000 years in riverine and lake systems, including fern meadows, woodland mosaics, naturally burned landscapes, lakeside palm groves and dry steppe habitats. The uncovered evidence shows periodic but recurrent land use across a subset of environments, punctuated with times when there is an absence of hominin activity.

Dr. Pastory Bushozi of Dar es Salaam University, Tanzania, notes, “the occupation of varied and unstable environments, including after volcanic activity, is one of the earliest examples of adaptation to major ecological transformations.”

Hominin occupation of fluctuating and disturbed environments is unique for this early time period and shows complex behavioural adaptations among early human groups. In the face of changing habitats, early humans did not substantially alter their toolkits, but instead their technology remained stable over time. Indicative of their versatility, typical Oldowan stone tools, consisting of pebble and cobble cores and sharp-edged flakes and polyhedral cobbles, continued to be used even as habitats changed. The implication is that by two million years ago, early humans had the behavioural capacity to continually and consistently exploit a multitude of habitats, using reliable stone toolkits, to likely process plants and butcher animals over the long term.

Excavation at Ewass Oldupa uncovered the oldest Oldowan stone tools ever found at Oldupai Gorge, dating to ~2 million years ago and fossils of mammals, reptiles and birds. © Michael Petralia

Though no hominin fossils have yet been recovered from Ewass Oldupa, hominin fossils of Homo habilis were found just 350 metres away, in deposits dating to 1.82 million years ago. While it is difficult to know if Homo habilis was present at Ewass Oldupa, Professor Julio Mercader of the University of Calgary asserts that “these early humans were surely ranging widely over the landscape and along shores of the ancient lake.” Mercader further notes that this does not discount the possibility that other hominin species, such as the australopithecines, were also using and making stone tools at Ewass Oldupa, as we know that the genus Paranthropus was present in Oldupai Gorge at this time.

The findings uncovered at Oldupai Gorge and across eastern Africa indicate that early human movements across and out of Africa were possible by 2 million years ago, as hominins possessed the behavioural ability to expand into novel ecosystems. Professor Michael Petraglia of the Max Planck Institute notes, “This behavioural flexibility arose in the context of the dawn of the evolution of our own genus, Homo, and it set the stage for the eventual global, invasive spread of Homo sapiens.”


Researchers involved in this study include scholars from the Universities of Calgary, Manitoba, McMaster, and Toronto (Canada), the University of Dar es Salaam and Iringa as well as the Ministry of Natural Resources and Tourism (Tanzania), the Max Planck Institute for the Science of Human History (Germany), the Institut Català de Paleoecologia Humana i Evolució Social, and the Madrid Institute for Advanced Study (Spain). All institutions work closely with the Tanzania Commission for Science and Technology, the Division of Antiquities (MNRT), and under the sponsorship of the Canadian Social Sciences and Humanities Research Council (Partnership program).

Reference: Mercader, J., Akuku, P., Boivin, N. et al. Earliest Olduvai hominins exploited unstable environments ~ 2 million years ago. Nat Commun 12, 3 (2021). https://www.nature.com/articles/s41467-020-20176-2 https://doi.org/10.1038/s41467-020-20176-2

Provided by Max Planck Institute for Science of Human

Bedside EEG Test Can Aid Prognosis in Unresponsive Brain Injury Patients (Neuroscience)

Assessing the ability of unresponsive patients with severe brain injury to understand what is being said to them could yield important insights into how they might recover, according to new research.

A team at the University of Birmingham has shown that responses to speech can be measured using electroencephalography, a non-invasive technique used to record electrical signals in the brain. The strength of these responses can be used to provide an accurate prognosis that can help clinicians make the most effective treatment decisions.

Significantly the assessments can be made while the patient is still in intensive care and does not require any conscious response from the patient – they do not have to ‘do’ anything.

In the study, published in Annals of Neurology, the team assessed 28 patients with acute traumatic brain injury (TBI) who were not under sedation, and who failed to obey commands. The patients were assessed within just a few days of their injury. They were played streams of sentences and phrases made up of monosyllabic words while their brain activity was monitored using EEG.

In healthy individuals, EEG activity only synchronises with the rhythm of phrases and sentence when listeners consciously comprehend the speech. The researchers assessed the level of the unresponsive patients’ comprehension by measuring the strength of this synchronicity.

The researchers were able to follow up 17 of the patients three months following their injury, and 16 of the patients after six months. They found the outcomes significantly correlated with the strength of the patients’ response to speech measured by the EEG.

Patients with traumatic brain injury are commonly assessed by their behaviour or by a CT scan, but some patients who remain unresponsive pose a significant challenge. Recent studies have shown that TBI patients can be shown to ‘imagine’ themselves following commands. This activity can also be tracked using EEG. However, this approach requires a fairly sophisticated response from the patient, so patients with lower brain capabilities may be overlooked.

Lead author Dr Damian Cruse is based at the University of Birmingham’s School of Psychology and Centre for Human Brain Health. He explains: “The strength of our approach is that we can measure a scale of comprehension without needing any other sort of response from the patient. This insight could significantly reduce prognostic uncertainty at a critical point. It could help clinicians make more appropriate decisions about whether or not to continue life-sustaining therapy – and also ensure rehabilitation resources are allocated to patients who are most likely to benefit.”

Reference: Cruse et al (2020). ‘Covert speech comprehension predicts recovery from acute post-traumatic unresponsive states.’ Annals of Neurology.

Provided by University of Birmingham