Scientists Explore Deficits in Processing Speed in Individuals With Spinal Cord Injury (Psychiatry)

Research team finds persons with spinal cord injury and older healthy individuals have similar brain activation during processing speed tasks. Findings support the theory of accelerated cognitive aging following spinal cord injury.

A team of rehabilitation researchers has studied processing speed deficits in individuals with spinal cord injury (SCI), comparing their brain activation patterns with those of healthy age-matched controls, and older healthy individuals. They found that the SCI group and older controls had similar activation patterns, but the SCI group differed significantly from their age-matched controls.

Dr. Wylie is director of the Rocco Ortenzio Neuroimaging Center at Kessler Foundation. © Kessler Foundation/Jody Banks

The article, “The neural mechanisms underlying processing speed deficits in individuals who have sustained a spinal cord injury: A pilot study” (doi: 10.1007/s10548-020-00798-x) was epublished on September 25, 2020 by Brain Topography. The authors are scientists with expertise in research in cognitive rehabilitation and SCI rehabilitation: Glenn Wylie, DPhil, Nancy D. Chiaravalloti, PhD, Erica Weber, PhD, Helen Genova, PhD, and Trevor Dyson-Hudson, MD, from Kessler Foundation, and Jill M. Wecht, EdD, from the James J. Peters VA Medical Center.

Individuals with chronic SCI have an increased risk for cognitive deficits that resemble the deficits associated with the aging process, giving rise to the theory of “accelerated cognitive aging.” As reported previously by this team, the deficits affect processing speed, new learning and memory, and verbal fluency, which are the domains affected during aging. This study is the first to examine the neural mechanisms of higher order cognitive tasks of individuals with SCI. The focus was on processing speed, which is known to be affected by SCI and aging, and is integral to cognitive function and everyday life activities.

The 30 participants were participants of a larger study who underwent optional neuroimaging studies at the Rocco Ortenzio Neuroimaging Center at Kessler Foundation — 10 individuals with cervical SCI, 10 age-matched controls, and 10 healthy older individuals. In addition to traditional neuropsychological testing methods, processing speed was tested in the scanner, using timed letter comparison tasks during functional magnetic resonance imaging (fMRI). This study was the first to use the modified letter comparison test.

Significant differences in brain activation were found between the SCI group and the age-matched control group, but the SCI and older groups had similar patterns, including activation of the hippocampal, frontal and parietal areas. “This suggests that individuals with SCI are compensating for deficits in processing speed by relying on the areas of the brain involved in executive control and memory,” noted Dr. Chiaravalloti, “which supports the theory of accelerated brain aging after SCI.”

Despite the limitations of sample size and level of injury, the study is an important contribution to our understanding of the impact of SCI on cognition, according to Dr. Wylie, director of the Ortenzio Center. “Our ability to observe brain activation while the individual performs specific cognitive tasks provides new information on the mechanisms that underlie the cognitive deficits that we now know affect a substantial proportion of the SCI population,” Dr. Wylie said. “Developing treatments targeted to these deficits depends on our pursuit of this line of research, which may benefit other populations affected by delayed processing speed.”

Reference: Wylie GR, Chiaravalloti ND, Weber E, Genova HM, Dyson-Hudson TA, Wecht JM. The Neural Mechanisms Underlying Processing Speed Deficits in Individuals Who Have Sustained a Spinal Cord Injury: A Pilot Study. Brain Topogr. 2020 Nov;33(6):776-784. doi: 10.1007/s10548-020-00798-x. Epub 2020 Sep 25. PMID: 32978697. https://pubmed.ncbi.nlm.nih.gov/32978697/

Provided by Kessler Foundation

New Research May Explain Severe Virus Attacks on the Lungs (Medicine)

In some cases, immune cells in the lungs can contribute to worsening a virus attack. In a new study, researchers at Karolinska Institutet in Sweden describe how different kinds of immune cells, called macrophages, develop in the lungs and which of them may be behind severe lung diseases. The study, which was published in Immunity, may contribute to future treatments for COVID-19, among other diseases.

The development of human macrophages. © The research team.

The structure of the lungs exposes them to viruses and bacteria from both the air and the blood. Macrophages are immune cells that, among other things, protect the lungs from such attacks. But under certain conditions, lung macrophages can also contribute to severe lung diseases, such as chronic obstructive pulmonary disease (COPD) and COVID-19.

To date, research on the development of human lung macrophages has been limited.

Macrophages can have different origins and develop, among other things, from white blood cells, monocytes, that are divided into different genetically determined main types. In humans, two of these are “classical” CD14+ monocytes and “non-classical” CD16+ monocytes.

In a new study at Karolinska Institutet, researchers have used a model to study the development of lung macrophages directly in a living lung. This has been combined with a method to study gene activity in individual cells, RNA sequencing, and thereby discovered how blood monocytes become human lung macrophages.

“In our study, we show that classical monocytes migrate into airways and lung tissue and are converted into macrophages that protect the health and function of the lungs. We have also identified a special kind of monocyte, HLA-DRhi, which is an intermediate immune cell between a blood monocyte and an airway macrophage. These HLA-DRhi monocytes can leave the blood circulation and migrate into the lung tissue,” says Tim Willinger, Associate Professor at the Department of Medicine, Huddinge, Karolinska Institutet, who led the study.

Associate Professor Tim Willinger and Doctoral Student Elza Evren, Department of Medicine Huddinge at Karolinska Institutet. © Tiphaine Parrot

The non-classical monocytes, however, develop into macrophages in the many blood vessels of the lungs and do not migrate into the lung tissue.

“Certain macrophages in the lungs probably have a connection to a number of severe lung diseases. In respiratory infections, for example, monocytes in the lungs develop into macrophages, which combat viruses and bacteria. But a certain type of macrophage may also contribute to severe inflammation and infections,” says the study’s first author Elza Evren, a doctoral student in Tim Willinger’s research team.

In an infection with the novel coronavirus, SARS-COV-2, which causes COVID-19, researchers believe that protective, anti-inflammatory macrophages are replaced by pro-inflammatory lung macrophages from blood monocytes.

“The existence of these blood monocyte-derived macrophages has been shown in other studies to correlate with how severely ill a person becomes in COVID-19 and how extensive the damage to the lungs is. Patients with severe COVID-19 also have fewer HLA-DRhi monocytes in their blood, probably because they move away from the blood into the lungs. Given their important role in rapid inflammatory responses, our results indicate that future treatments should focus on inflammatory macrophages and monocytes to reduce lung damage and mortality from severe COVID-19,” says Tim Willinger.

The research is financed by the Swedish Research Council, Karolinska Institutet, Centre for Innovative Medicine (CIMED)/Region Stockholm, the Swedish Heart-Lung Foundation, and the Swedish Cancer Foundation. There are no reported conflicts of interest.

Reference: Elza Evren, Emma Ringqvist, Kumar Parijat Tripathi, Natalie Sleiers, Ines Co Rives, Arlisa Alisjahbana, Yu Gao, Dhifaf Sarhan, Tor Halle, Chiara Sorini, Rico Lepzien, Nicole Marquardt, Jakob Michaelsson, Anna Smed-Sorensen, Johan Botling, Mikael C. I. Karlsson, Eduardo J. Villablanca, Tim Willinger, “Distinct developmental pathways from blood monocytes generate human lung macrophage diversity”, Immunity, online 30 December 2020, doi: 10.1016/j.immuni.2020.12.003. https://www.cell.com/immunity/ppt/S1074-7613(20)30531-8.ppt

Provided by Karolinska Institutet

Binding Pathway Determines Norepinephrine Selectivity For The Human β1AR Over β2AR (Neuroscience)

Liu Xiangyu’s group in the School of Pharmaceutical Sciences, Tsinghua University, in collaboration with researchers from Stanford University, Friedrich-Alexander-Universität Erlangen-Nürnberg , and the University of California San Diego, recently reported on the crystal structures of the human β1AR bound to an antagonist carazolol and different agonists including norepinephrine, epinephrine and BI-167107, elucidatinghow the extracellular vestibule serves as a ‘selectivity filter’ to determine ligand subtype selectivity.

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors with more than 800 family members in the human genome. GPCRs play important roles in physiology and they are the targets of approximately 30% of clinical drugs.The beta-adrenergic receptors (βARs) belong to the GPCR family.As part of the sympathetic nervous system, βARs mediate physiological responses to the catecholamines norepinephrine and epinephrine to regulate cardiovascular, respiratory and metabolic functions.

Norepinephrine is a neurotransmitter released from sympathetic nerves, while epinephrine is a hormone primarily released from the adrenal medulla into the systemic circulation. While epinephrine binds β1AR and β2AR with similar affinities, the smaller norepinephrine is approximately tenfold-times as selective for the β1AR. Under physiological conditions, β2AR activationshould be minimized to avoid opposing β1AR-mediated cardiac regulation. Thus, the lower affinity of the β2AR for norepinephrine appears to play an important role in cardiac physiology. This difference is surprising given that norepinephrine and epinephrine are very similar, except that epinephrine contains an additional methyl group, and the amino acids that form the orthosteric binding pocket are identical for β1AR and β2AR. The molecular mechanism of norepinephrine’sselectivity for β1AR over β2ARhas been a puzzle for decades.

To understand the molecular mechanism for this physiologically important phenomenon, the research group measured the binding kinetics of norepinephrine to both human β1AR and β2AR, as well as two chimeric constructs that switch the extracellular vestibules of β1AR and β2AR (named β1ARin/ β2ARoutand β2ARin/ β1ARout). The results suggest that the association rate rather than the dissociation rate determines the selectivity of norepinephrine to the receptors,andthe extracellular vestibules of the β1AR and β2AR are the key determinants of these different association rates (Figure1).

Figure 1. Kinetic studies of norepinephrine binding to the β1AR, β2AR and β1ARin/ β2ARout, β2ARin/ β1ARoutchimeras.

Delineating structural information on the extracellular vestibules is the key to understanding the molecular mechanism of norepinephrine selectivity. The structures of the human β1AR in both inactive and active conformations were determined, including the structures of the human β1AR bound to two endogenous ligands norepinephrine and epinephrine. Structural comparison revealed that the catecholamine-binding pockets are identical between β1AR and β2AR, but the extracellular vestibules have different shapes and electrostatic properties. Metadynamic simulations indicated that β1AR and β2AR have different ligand entrance pathways that account for the association rate difference. Interrogation of the entrance pathway through site-directed mutagenesis suggests that residues within the extracellular vestibule may serve as “selectivity filter” for norepinephrine. Metadynamic simulations revealed that epinephrine also takes different paths to bind to human β1AR and β2AR. However, the additional methyl group at its nitrogen alters the electron distribution on the catecholamine. Consequently, epinephrine does not show a preference for the extracellular vestibule of the β1AR or β2AR (Figure 2).

Figure 2. The ligand entrance pathways of the β1AR and the β2AR have different electrostatic properties.

This work addresses an interesting and physiologically important difference in the binding affinity of norepinephrine for the human β1AR and β2AR.The results also have a broader implication for drug development where receptors with identical orthosteric pockets could have different selectivity filters that define the pharmacology. Identifying subtype-selective drugs is a major goal in the development of safer and more efficacious therapeutics that target GPCRs. This work suggests that efforts to develop subtype-selective ligands using structure-based drug design should consider the extracellular vestibule not only in the context of allosteric modulators or bitopic ligands, which bridge both the orthosteric site and the vestibule, but also for smaller orthosteric ligands.

The work recently published in Cell Research, entitled “Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR”. Itis the result of a collaboration between Professor Xiangyu Liu’s group at Tsinghua University, Professor Brian Kobilka’s group at Stanford University, Professor Peter Gmeiner’s group at Friedrich-Alexander-Universität Erlangen-Nürnberg and Professor Roger Sunahara’s group at University of California San Diego. Professor Xiangyu Liu, Professor Peter Gmetiner and Professor Roger Sunahara are corresponding authors of the paper. Dr. Xinyu Xu from School of Life Science, Tsinghua University, Dr. Jonas Kaindl from School of Medicinal Chemistry, Friedrich-Alexander-Universität University and Dr. Mary J. Clark from School of Medicine, University of California San Diego are co-first authors of the paper. The work is supported by grants from Beijing Advanced Innovation Center for Structural Biology and Tsinghua-Peking Joint Center for Life Sciences. Crystal diffraction and data collection was supported by Spring-8 synchrotron radiation facility, Japan.

Reference: Xu, X., Kaindl, J., Clark, M.J. et al. Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR. Cell Res (2020). https://www.nature.com/articles/s41422-020-00424-2 https://doi.org/10.1038/s41422-020-00424-2

Provided by Tsinghua University

LSU Health New Orleans Discovers Potential New Rx Strategy for Stroke (Medicine)

Research conducted at LSU Health New Orleans Neuroscience Center of Excellence reports that a combination of an LSU Health-patented drug and selected DHA derivatives is more effective in protecting brain cells and increasing recovery after stroke than a single drug. The findings are published in Brain Circulation, available here.

Αmyloid β peptide–mediated damage © LSU health

Nicolas Bazan, MD, PhD, Boyd Professor, Professor of Neurology and Director of the Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine, and Ludmila Belayev, MD, LSU Health New Orleans Professor of Neuroscience, Neurology, and Neurosurgery, discovered this novel therapeutic strategy for ischemic stroke using an experimental model.

During an ischemic stroke, signals are produced from arriving blood white cells and primary brain immune cells called microglia that cause neuroinflammation leading to a buildup of chemicals that harm the brain. Platelet-activating factor (PAF) accumulates, and inhibition of this process plays a critical role in neuronal survival. Dr. Bazan’s earlier studies also showed that in addition to its anti-inflammatory properties, DHA, an essential omega-3 fatty acid, stimulates the production of Neuroprotectin D1 (NPD1), a molecule that protects brain cells and promotes their survival. One complicating factor in developing neuroprotective strategies for stroke are the multiple routes and events that occur in the brain during a stroke, which has been approached mainly by monotherapeutic agents that were mostly unsuccessful.

Because no single therapy has proven effective in treating the complexity of stroke, the team aimed at two different events – blocking pro-inflammatory platelet-activating factor receptors (PAF-R) and activating cell-survival pathways. They found that treatment with LAU-0901, a synthetic molecule discovered in the Bazan lab that blocks pro-inflammatory platelet-activating factor, plus aspirin-triggered NPD1 (AT-NPD1) reduced the size of the damaged area in the brain, initiated repair mechanisms, and remarkably improved behavioral recovery.

Total lesion volumes were reduced with LAU‑0901 plus NPD1 by 62% and LAU‑0901 plus AT‑NPD1 by 90%. Combinatory treatment with LAU‑0901 plus AT‑NPD1 improved the behavioral score up to 54% on day three. LAU‑0901 and LAU‑0901 plus DHA decreased the production of 12‑hydroxyeicosatetraenoic acid, a pro‑inflammatory mediator.

“The biological activity of LAU-0901 and AT-NPD1 is due to specific activation or modulation of signaling pathways associated with the immune system, inflammation, cell survival, and cell-cell interactions,” notes Dr. Bazan. “These findings provide a major conceptual advance of broad therapeutic relevance for cell survival, brain function and, particularly, stroke and neurodegenerative diseases.”

“We discovered that these novel molecules promote neuronal cell survival with important anti-inflammatory activity,” explains Dr. Belayev. “This combinatorial therapy may hold promise for future therapeutic development against ischemic stroke.”

According to the Centers for Disease Control and Prevention, someone in the United States has a stroke every 40 seconds. Every 4 minutes, someone dies of stroke. Every year, more than 795,000 people in the United States have a stroke. About 87% of all strokes are ischemic strokes, in which blood flow to the brain is blocked. Stroke-related costs in the United States came to nearly $46 billion between 2014 and 2015. This total includes the cost of health care services, medicines to treat stroke, and missed days of work. Stroke is a leading cause of serious long-term disability. Stroke reduces mobility in more than half of stroke survivors age 65 and over.

Other LSU Health authors include Drs. Pranab K. Mukherjee, Eric J. Knott and Reinaldo B. Oria, along with Larissa Khoutorova and graduate students Madigan M. Reid and Cassia R. Roque. Dr. Andre Obenaus, Lawrence Nguyen, and Jeong Bin Lee from the University of California Irvine School of Medicine, and Dr. Nicos A. Petasis of the University of Southern California, are also co-authors.

This research was supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and Brazilian CAPES.

Reference: Belayev L, Obenaus A, Mukherjee PK, Knott EJ, Khoutorova L, Reid MM, Roque CR, Nguyen L, Lee JB, Petasis NA, Oria RB, Bazan NG. Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke. Brain Circ [serial online] 2020 [cited 2020 Dec 30];6:260-8. Available from: http://www.braincirculation.org/text.asp?2020/6/4/260/305408

Provided by LSU Health

LSU Health Sciences Center New Orleans (LSU Health New Orleans) educates Louisiana’s health care professionals. The state’s health sciences university leader, LSU Health New Orleans includes a School of Medicine with branch campuses in Baton Rouge and Lafayette, the state’s only School of Dentistry, Louisiana’s only public School of Public Health, and Schools of Allied Health Professions, Nursing, and Graduate Studies. LSU Health New Orleans faculty take care of patients in public and private hospitals and clinics throughout the region. In the vanguard of biosciences research, the LSU Health New Orleans research enterprise generates jobs and enormous annual economic impact. LSU Health New Orleans faculty have made lifesaving discoveries and continue to work to prevent, advance treatment or cure disease. To learn more, visit http://www.lsuhsc.edu, http://www.twitter.com/LSUHealthNO, or http://www.facebook.com/LSUHSC.

The Map of Nuclear Deformation Takes the Form of a Mountain Landscape (Chemistry)

Until recently, scientists believed that only very massive nuclei could have excited zero-spin states of increased stability with a significantly deformed shape. Meanwhile, an international team of researchers from Romania, France, Italy, the USA and Poland showed in their latest article that such states also exist in much lighter nickel nuclei. Positive verification of the theoretical model used in these experiments allows describing the properties of nuclei unavailable in Earth laboratories.

Deformation landscape of the nickel-64 nucleus. Prolate, oblate local minima and main spherical minimum are indicated by red, green and blue ellipsoids, respectively. (Source: IFJ PAN)

More than 99.9 per cent of the mass of an atom comes from the atomic nucleus, the volume of which is over a trillion times smaller than the volume of the entire atom. Hence, the atomic nucleus has an amazing density of about 150 million tons per cubic centimetre. This means that one tablespoon of nuclear matter weighs almost as much as a cubic kilometre of water. Despite their very small size and incredible density, atomic nuclei are complex structures made of protons and neutrons. One may expect that such extremely dense objects would always take spherical form. In reality, however, the situation is quite different: most nuclei are deformed – they exhibit shape flattened or elongated along one or even two axes, simultaneously. To find the favourite form of a given nucleus, it is customary to construct a landscape of the potential energy as a function of deformation. One may visualize such landscape by drawing a map on which the plane coordinates are the deformation parameters, i.e. degrees of elongation or flattening along the two axes, while the colour indicates the amount of energy needed to bring the nucleus to a given shape. Such a map is a full analogy to a geographical map of mountain terrain.

If a nucleus is formed in the nuclear reaction, it appears at a given point of the landscape – it takes specific deformation. It then starts to slide (change deformation) towards the lowest energy point (stable deformation). In some cases, however, before reaching the ground state, it may be stopped for a while in some local minimum, a trap, which corresponds to metastable deformation. This is very similar to water that springs in a particular location in the mountain area and flows downward. Before it reaches the lowest valley, it may be trapped in local depressions for some time. If a stream connects the local depression to the lowest point of the landscape, water will flow down. If the depression is well isolated, the water will stay there for a very long time.

Experiments have shown that local minima in the nuclear deformation landscape at spin zero exist only in massive nuclei with atomic numbers larger than 89 (actinium) and a total number of protons and neutrons well above 200. Such nuclei can be trapped in these secondary minima at metastable deformation for a period even tens of millions of times longer than the time needed to reach the ground state without being slowed down by the trap. Until a few years ago, an excited zero-spin state associated with metastable deformation had never been observed among nuclei of lighter elements. The situation changed a few years ago when a state with sizeable deformation characterized by increased stability was found in nickel-66, the nucleus with 28 protons and 38 neutrons. This identification was stimulated by calculations performed with the sophisticated Monte Carlo shell model developed by Tokyo University theorists, which predicted this deformation trap.

“The calculations performed by our Japanese colleagues also provided another unexpected result,” says Prof. Bogdan Fornal (IFJ PAN). “They showed that a deep, local depression (trap) associated with sizeable deformation should be present also in the potential energy landscape of nickel-64, the nucleus with two neutrons less than nickel-66, which until now was considered to have only one main minimum with a spherical shape. The problem was that in nickel-64 the depression was predicted at high excitation energy – at high altitude in the mountain terrain analogy – and it was extremely difficult to find an experimental method to place the nucleus in this trap.”

A tour de force took place involving four complementary experiments, jointly conducted by a collaboration lead by experimentalists from Romania (IFIN-HH in Bucharest), France (Institut Laue-Langevin, Grenoble), Italy (University of Milan), USA (the University of North Carolina and TUNL) and Poland (IFJ PAN, Krakow). Measurements were performed at four different laboratories in Europe and the USA: Institut Laue-Langevin (Grenoble, France), IFIN-HH Tandem Laboratory (Romania), Argonne National Laboratory (Chicago, USA) and the Triangle Universities Nuclear Laboratory (TUNL, North Carolina, USA). Different reaction mechanisms were employed including proton and neutron transfer, thermal-neutron capture, Coulomb excitation and nuclear-resonance fluorescence, in combination with state-of-the-art gamma-ray detection techniques.

All the data taken together allowed to establish the existence of two secondary minima in the potential energy landscape of nickel-64, corresponding to oblate (flattened) and prolate (elongated) ellipsoidal shapes, with the prolate one being deep and well isolated as indicated by the significantly retarded transition to the main spherical minimum.

“The extension of time which the nucleus spends when trapped in the prolate minimum of the Ni-64 nucleus is not as spectacular as that of the heavy nuclei, where it reaches tens of millions of times. We recorded the increase of only a few tens of times; yet the fact that this increase is close to the one provided by the new theoretical model, is a great achievement,” states Prof. Fornal.

A particularly valuable outcome of the study is identifying a previously unconsidered component of the force acting between nucleons in complex nuclear systems, the so-called tensor monopole, which is responsible for the multifaceted landscape of deformation in the nickel isotopes. Scientists expect that this interaction is accountable to a large extent for shaping the structure of many nuclei that have not yet been discovered.

In a broader perspective, the presented investigation indicates that the theoretical approach applied here, being able to adequately predict the unique characteristics of the nickel nuclei, has great potential in describing the properties of hundreds of nuclear systems which are not accessible in the laboratory on the Earth today, but continually produced in stars.

Reference: N. Mărginean, D. Little, Y. Tsunoda, S. Leoni, R. V. F. Janssens, B. Fornal, T. Otsuka, C. Michelagnoli, L. Stan, F. C. L. Crespi, C. Costache, R. Lica, M. Sferrazza, A. Turturica, A. D. Ayangeakaa, K. Auranen, M. Barani, P. C. Bender, S. Bottoni, M. Boromiza, A. Bracco, S. Călinescu, C. M. Campbell, M. P. Carpenter, P. Chowdhury, M. Ciemała, N. Cieplicka-Oryńczak, D. Cline, C. Clisu, H. L. Crawford, I. E. Dinescu, J. Dudouet, D. Filipescu, N. Florea, A. M. Forney, S. Fracassetti, A. Gade, I. Gheorghe, A. B. Hayes, I. Harca, J. Henderson, A. Ionescu, Ł. W. Iskra, M. Jentschel, F. Kandzia, Y. H. Kim, F. G. Kondev, G. Korschinek, U. Köster, Krishichayan, M. Krzysiek, T. Lauritsen, J. Li, R. Mărginean, E. A. Maugeri, C. Mihai, R. E. Mihai, A. Mitu, P. Mutti, A. Negret, C. R. Niţă, A. Olăcel, A. Oprea, S. Pascu, C. Petrone, C. Porzio, D. Rhodes, D. Seweryniak, D. Schumann, C. Sotty, S. M. Stolze, R. Şuvăilă, S. Toma, S. Ujeniuc, W. B. Walters, C. Y. Wu, J. Wu, S. Zhu, and S. Ziliani
„Shape Coexistence at Zero Spin in 64Ni Driven by the Monopole Tensor Interaction”
Phys. Rev. Lett. 125, 102502;
DOI: 10.1103/PhysRevLett.125.102502

Provided by IFJ PAN

Cannabis Extract As A Remedy for Dying Bees (Biology)

Bees are not able to protect themselves against pesticides and at huge chemical concentrations they die. Danel Załuski, Dr. habil. NCU professor from Collegium Medicum is a member of a team whose aim is to search for specimens of natural origin which protect insects.

“Help bees”, “Save bees”, “Save our bees”, “Be like Bee” are only some of online actions which are to protects our buzzing friends. What is all the fuss about? Albert Einstein was the one who already warned that “if bees disappear, human kind will soon follow their fate”, as the production of 75% of food in the world depends on the insects which pollinate flowers. And they are massively dying out. The reason is not only nosemosis or varroosis caused by excessive multiplications of the parasite Varroa destructor. Beekeepers are also concerned with the collapse of bee families outside beehives. Scientists have proved that the massive extinction of bees happens due to the use of insecticides on farm lands and in forests – insect-killing neonicotinoids, i.e., neuroactive substances from a pesticide group which disrupt bees’ orientation and communication.

Cannabis extract as a remedy for dying bees
fot. Nadesłane

Pesticides are chemical compounds, for instance derivatives of phenoxyacetic acid, organochlorine or organophosphate compounds, which are used mainly in agriculture and gardening, but also in forestry, veterinary sciences and textile materials impregnation. Apart from active substances, pesticides also contain emulsifiers, preservatives or other auxiliary substances which, for certain, are not indifferent to the environment. Spraying seeds with nicotinoids makes these compounds penetrate the whole plant, including flowers and pollen. Therefore, by collecting pollen and carrying it into the beehive, bees transport poison, which affects not only the insects working outside the beehive but also those which stay inside including the queen. – Pesticides usually affect bees’ nervous system, they change their behavior and decrease immunity – explains Daniel Załuski, Dr. habil, NCU professor, from the Department of Pharmaceutical Botany and Pharmacology of Collegium Medicum. – I have not heard of any substances which would protect bees against the negative influence of insecticides from the group of nicotinoids. Therefore, our research team have begun research on developing such substances of natural origin.

Dr hab. Daniel Załuski, prof. UMK fot. Nadesłane

There is a lot to protect bees against as pesticides may affect them on different layers. Contact substances affect their nervous system This may cause even chemicals which are considered to be nontoxic to poison a bee though direct contact. Pesticides may enter the bee’ organism with contaminated food, for example nectar, pollen, honeydew or water. Depending on the degree of toxicity of the formulation, bees may die instantly or in the beehive. Death in the beehive triggers off other consequences as the contaminated material poisons young bees and further contaminates honey with the pesticide. Bees do not have protective mechanisms against pesticides. At high concentration, they are defenseless.

Dr hab. Aneta Ptaszyńska, prof. UMCS fot. Archiwum NAWA/Alicja Szulc

Apart from professor Daniel Załuski, there are in the research team Aneta Ptaszyńska, Dr. habil, prof. of University of Maria Skłodowska-Curie in Lublin, and Rafał Kuźniewski, Dr., from the Department Pharmaceutical Botany and pharmacology of CM NCU. The problem of massive extinction of bees has been within the scientists’ interest since 2012. – As it often happens in science, the actions undertaken and commercialized initiatives came into life by accident – says professor Załuski. The main subject of my scientific activity are vegetable raw materials with adaptogenic affect, which increases the efficiency of a human organism through the influence on the immune, endocrine or nervous systems. Yet, professor Ptaszyńska has begun her research to seek natural substances which fight against nosemosis in honeybees. – Once, she told me about a tragic situation of bees and the possibility of their extinction, which causes my anxiety. We both agreed that it was worth looking for natural substances of plant origin which could stimulate the immune system of bees. The effect of many years of research is developing a formulation which fights against nosemosis in bees, and which has been on the market since 2018.

Dr Rafał Kuźniewski fot. Nadesłane

The cooperation has not ended with only one project. Scientists have begun research on plants like cannabis, which is the main subject of interest of doctor Kuźniewski. Unexpectedly it turned out that aquatic and ethanolic extracts increase survival of bees in conditions exposed to the presence of pesticides. The scientists obtained the essences from the leaf, stem and roots though the method of extraction supported with ultrasounds, and with application of water and water solutions of alcohols as solvents. Next, the extracts were lyophilizated and used in the tests which examined the survivability of bees in conditions stimulated with the extract and pesticide. The scientists solved the essence of cannabis in food, that is in high fructose corn syrup or a mixture of honey and powdered sugar.

The research model comprised 30 standard cages, each containing 40 bees. The bees were being given the extract for eight days, on the seventh day they were contaminated with imidacloprid or acetamiprid, and for two days they were given food with the extract. Survivability of the bees in particular cages was compared to survivability in the control sample, which was not stimulated with the formulation. It was also there that the bigger number of dead bees was recorded – arithmetic means calculated upon the three cages in the end of the experiment were respectively five and seven alive bees. The lowest number of dead bees was recorded in the groups which were provided with ethanolic or aquatic extract of cannabis leaves (Cannabis sativa L.) – the number of living bees in the end was 19 and 16.

Scientists find it relatively difficult to unequivocally answer the question if the cannabis extract may protect bees against a harmful impact of all pesticides or only selected ones.

Chemical differentiation of pesticides is huge, therefore environmental research should be done in the areas with highly developed agricultural production based on polycultures, which require application of various pesticides. – explains professor Załuski. – Such research usually takes two or three years, and it requires seasonal application of the mixture of food and extract to the bees. In our experiments, we usually used two most often applied pesticides from the group of neonicotinoids: imidacloprid and acetamiprid.

It turned out unexpectedly that the extracts of roots, leaves or stems of cannabis, which were obtained with aquatic solution of ethanol, both prolong the life of bees exposed to pesticides of nicotinoid group, and also decrease the amount of pathogenic spore of Nosema spp. This considerably limits nosemosis in bees.

In April 2020, the scientists made two patent applications, and currently they are preparing an application for an international patent. If they find a licensee, the product should enter the market in two or three years.

Provided by NCU in Torun

Gum Disease-causing Bacteria Borrow Growth Molecules From Neighbors to Thrive (Medicine)

The human body is filled with friendly bacteria. However, some of these microorganisms, such as Veillonella parvula, may be too nice. These peaceful bacteria engage in a one-sided relationship with pathogen Porphyromonas gingivalis, helping the germ multiply and cause gum disease, according to a new University at Buffalo-led study.

Patricia Diaz, DDS, PhD, Professor of Empire Innovation in the UB School of Dental Medicine and director of the UB Microbiome Center. © University at Buffalo

The research sought to understand how P. gingivalis colonizes the mouth. The pathogen is unable to produce its own growth molecules until it achieves a large population in the oral microbiome (the community of microorganisms that live on and inside the body).

The answer: It borrows growth molecules from V. parvula, a common yet harmless bacteria in the mouth whose growth is not population dependent.

In a healthy mouth, P. gingivalis makes up a miniscule amount of the bacteria in the oral microbiome and cannot replicate. But if dental plaque is allowed to grow unchecked due to poor oral hygiene, V. parvula will multiply and eventually produce enough growth molecules to also spur the reproduction of P. gingivalis.

More than 47% of adults 30 and older have some form of periodontitis (also known as gum disease), according to the Centers for Disease Control and Prevention. Understanding the relationship between P. gingivalis and V. parvula will help researchers create targeted therapies for periodontitis, says Patricia Diaz, DDS, PhD, lead investigator on the study and Professor of Empire Innovation in the UB School of Dental Medicine.

“Having worked with P. gingivalis for nearly two decades, we knew it needed a large population size to grow, but the specific processes that drive this phenomenon were not completely understood,” says Diaz, also director of the UB Microbiome Center. “Successfully targeting the accessory pathogen V. parvula should prevent P. gingivalis from expanding within the oral microbial community to pathogenic levels.”

The study, which was published on Dec. 28 in the ISME Journal, tested the effects of growth molecules exuded by microorganisms in the mouth on P. gingivalis, including molecules from five species of bacteria that are prevalent in gingivitis, a condition that precedes periodontitis.

Of the bacteria examined, only growth molecules secreted by V. parvula enabled the replication of P. gingivalis, regardless of the strain of either microbe. When V. parvula was removed from the microbiome, growth of P. gingivalis halted. However, the mere presence of any V. parvula was not enough to stimulate P. gingivalis, as the pathogen was only incited by a large population of V. parvula.

Data suggest that the relationship is one-directional as V. parvula received no obvious benefit from sharing its growth molecules, says Diaz.

“P. gingivalis and V. parvula interact at many levels, but the beneficiary is P. gingivalis,” says Diaz, noting that V. parvula also produces heme, which is the preferred iron source for P. gingivalis.

“This relationship that allows growth of P. gingivalis was not only confirmed in a preclinical model of periodontitis, but also, in the presence of V. parvula, P. gingivalis could amplify periodontal bone loss, which is the hallmark of the disease,” says George Hajishengallis, DDS, PhD, co-investigator on the study and Thomas W. Evans Centennial Professor in the University of Pennsylvania School of Dental Medicine.

“It is not clear whether the growth-promoting cues produced by P. gingivalis and V. parvula are chemically identical,” says Diaz. “Far more work is needed to uncover the identity of these molecules.”

Additional investigators include Anilei Hoare, PhD, assistant professor, University of Chile; Hui Wang, PhD, postdoctoral researcher, University of Pennsylvania; Archana Meethil, resident, University of Connecticut; Loreto Abusleme, PhD, assistant professor, University of Chile; Bo-Young Hong, PhD, associate research scientist, Jackson Laboratory for Genomic Medicine; Niki Moutsopoulos, DDS, PhD, senior investigator, National Institute of Dental and Craniofacial Research; and Philip Marsh, PhD, professor, University of Leeds.

The research was funded by the National Institute of Dental and Craniofacial Research of the National Institutes of Health.

Reference: Hoare, A., Wang, H., Meethil, A. et al. A cross-species interaction with a symbiotic commensal enables cell-density-dependent growth and in vivo virulence of an oral pathogen. ISME J (2020). https://www.nature.com/articles/s41396-020-00865-y https://doi.org/10.1038/s41396-020-00865-y

Provided by University at Buffalo

Can Visually Impaired People Perceive Images? (Science and Technology)

Images are considered as the main source for people to perceive the world, however, not suitable for visually impaired people (e.g. blind, or low-vision). Traditional way attempts to solve this by training them to activating their visual cortex using auditory messages, which is still not practical as it’s time-consuming.

Fig. 1. The schematic diagram of the image-to – audio-description task (Image by XIOPM)

Recently, Prof. LU Xiaoqiang from the Xi’an Institute of Optics and Precision Mechanics (XIOPM) of the Chinese Academy of Sciences(CAS) proposed a new method to achieve the image-to-audio-description (I2AD) task using cross-modal generation.

Different from the current cross-modal retrieval task which only needs to retrieve samples that exist in a database, the I2AD task requires learning a complex generative function that produces meaningful outputs. In other words, the I2AD task is not only to understand the content of the input image but also to translate the information contained in the image as an intelligible natural language in audio form (audio description).

To solve the problem, the researchers proposed a modal translation network (MT-Net) which includes three progressive sub-networks: feature learning, cross-modal mapping, and audio generation. The feature learning step aims to learn the feature of image and audio respectively, then the cross-modal mapping step transforms the image feature into a cross-modal representation that accounts for the audio feature. Finally, the audio generation step generates the audio waveform from the cross-modal representation.

As this is the first attempt to study the I2AD task, three large-scale datasets are built as test datasets, and the results verified the feasibility and the effectiveness of the proposed method.

The results were published in a paper in Neurocomputing entitled “Audio description from image by modal translation network”.

Fig. 2 The proposed network (Image by XIOPM)
Fig. 3 The qualitative results of the proposed MT-Net. (Image by XIOPM)

Reference: Hailong Ning, Xiangtao Zheng, Yuan Yuan, Xiaoqiang Lu, “Audio description from image by modal translation network”, Neurocomputing, Volume 423, 2021, Pages 124-134, ISSN 0925-2312,
https://doi.org/10.1016/j.neucom.2020.10.053.
http://www.sciencedirect.com/science/article/pii/S0925231220316283

Provided by Chinese Academy of Sciences

Reversible Stickiness is Something to Smile About (Medicine)

Tokyo Medical and Dental University (TMDU) researchers report a cross-linker for dental cement that breaks down under UV light, making treatments easier to reverse.

Everyone who has had tooth cavities filled knows that the best dental materials stay where the dentist puts them. The adhesion of currently available dental materials to tooth surfaces continues to improve, but what about short-term treatments that are not supposed to adhere indefinitely? TMDU researchers have developed a method of making dental materials easier to remove; their findings are published in ACS Applied Polymer Materials.

UV light-embrittled dental resin cement containing photodegradable polyrotaxane cross-linkers. To facilitate the debonding of dental restorative materials adhered on tooth surfaces, UV light-embrittled dental resin cement containing photodegradable polyrotacane (PRX) cross-linkers was developed. PRX is a supramolecular interlocked polymer composed of α-cyclodextrin threaded on a linear polymer chain capped with bulky stopper molecules. The photodegradable PRXs containing photolabile o-nitrobenzyl ester was newly designed and used as a cross-linker of dental resin cements. The UV irradiation cleaves o-nitrobenzyl ester and the PRXs are dissociated, leading to decreasing the adhesive force of the dental resin cements. The plastic block was adhered on to the surface of bovine dentin using adhesive resin cement cross-linked with photodegradable PRXs, and the adhesive strength between plastic and dentin was clinically acceptable value. By contrast, the adhesive force was decreased by approximately 60% through the irradiation of UV light for 2 min, due to the photodegradation of PRX cross-linkers. This result suggests that the adhesive resin cement containing photodegradable PRX cross-linkers is a promising candidate for facilitating the debonding of dental materials from tooth surfaces via UV light irradiation. © TMDU

The continual improvement of long-lasting caries treatments can be regarded a triumph of dental material research. However, there are dental procedures that require non-permanent adhesion to the tooth surface, such as the fixing of orthodontic brackets. Removing adhered materials after such procedures generally requires mechanical detachment that can damage tooth enamel.

Efforts to improve removal processes have produced materials that are weakened by triggers, such as heat or electric currents. However, approved sources of these stimuli are not readily available in standard dental clinics. The researchers therefore focused on UV light-responsive materials that can be triggered by the UV sources widely used by dentists to cure resin cements and composites.

The toughness of many dental cements is a result of mixing them with a cross-linker that locks the cement molecules to each other to form a stable network. The researchers have introduced a chemical ‘switch’ into a new cross-linker that opens when UV light is shined on it.

“The cross-linker structure resembles rings threaded onto a piece of string with bulky stoppers at each end,” study lead author Atsushi Tamura explains. “We have added a section to the string—an o-nitrobenzyl ester group—that breaks under UV light causing the rings to slide off. This has a significant effect on the stability of the cement material the cross-linker is holding in place.”

The researchers used their cross-linker to stabilize a commercially available resin cement that was used to stick two polymer blocks together, or to attach a polymer block to a bovine tooth. After shining UV light on the cross-linked cement for just 2 minutes, the cement showed a significant reduction in adhesion strength in both tests, meaning separation of the bonded materials was easier following UV treatment.

“We are very encouraged by the initial findings using our cross-linker,” study corresponding author Nobuhiko Yui explains. “Although the UV wavelength used to disrupt the material was not clinically appropriate in this case, we intend to develop the chemistry of our internal switch so that it can provide a facile and readily accessible method of removing adhesives in the clinic.”

References: Satomi Matsunaga, Atsushi Tamura, Mayu Fushimi, Hokuto Santa, Yoshinori Arisaka, Toru Nikaido, Junji Tagami, & Nobuhiko Yui, “Light-Embrittled Dental Resin Cements Containing Photodegradable Polyrotaxane Cross-Linkers for Attenuating Debonding Strength”, ACS Appl. Polym. Mater. 2020, 2, 12, 5756–5766. https://pubs.acs.org/doi/10.1021/acsapm.0c01024 DOI: https://doi.org/10.1021/acsapm.0c01024

Provided by Tokyo Medical and Dental University