The mechanism of the most commonly used antimalarial drugs unveiled

For centuries, quinoline has been an effective compound in antimalarial drugs, although no one knew its mode of action in vivo.

Today, a team led by the Weizmann Institute has discovered its mechanism in infected red blood cells in near-native conditions, by using the ESRF, Alba Synchrotron and BESSY. They publish their results in PNAS.

Malaria remains one of the biggest killers in low-income countries. Estimates of the number of deaths each year range from 450,000 to 720,000, with the majority of deaths happening in Africa. In the last two decades, the malaria parasite has evolved into drug-resistant strains. “Recently, the increasing geographical spread of the species, as well as resistant strains has concerned the scientific community, and in order to improve antimalarial drugs we need to know how they work precisely”, explains Sergey Kapishnikov, from the University of Copenhagen, in Denmark, and the Weizmann Institute, in Israel, and leader of the study.

Plasmodium parasite, when infecting a human, invades a red blood cell, where it ingests hemoglobin to grow and multiply. Hemoglobin releases then iron-containing heme molecules, which are toxic to the parasite. However, these molecules crystallise into hemozoin, a disposal product formed from the digestion of blood by the parasite that makes the molecules inert. For the parasite to survive, the rate at which the heme molecules are liberated must be slower or the same as the rate of hemozoin crystallization. Otherwise there would be an accumulation of the toxic heme within the parasite.

>Read more on the ESRF website

Image (taken from BESSY II article): The image shows details such as the vacuole of the parasites (colored in blue and green) inside an infected blood cell.
Credit:
S. Kapishnikov

Two other institutes, BESSY II at HZB and ALBA Synchrotron, have participated in this research. Please find here their published articles:

> X-ray microscopy at BESSY II reveal how antimalaria-drugs might work

> The mechanism of the most commonly used antimlalarial drugs in near- native conditions unveiled

Gene encapsulation with MOFs for new delivery vectors in gene therapy

A research team from RMIT University, CSIRO Manufacturing, University of New South Wales, Graz University of Technology and the University of Adelaide, in Australia, have demonstrated an easy and efficient method to use nano MOFs for carrying large-size intact gene sets to be applied in gene therapy. Their study reports encapsulation of a complete gene-set in zeolitic imidazolate framework-8 (ZIF-8) MOFs and cellular expression of the gene delivered by the nano MOF composites, with data obtained at the MISTRAL beamline at the ALBA Synchrotron showing intracellular presence of the biocomposite particles.

MOFs (metal-organic frameworks) are porous materials with well-defined geometry and high loading capacity. For biological applications, their high porosity makes these composites an effective strategy for loading and protection of proteins; however, their use for other biomacromolecules such as nucleic acids is still in their infancy. Now, a research team lead by RMIT University from Melbourne has been studying the use of ZIF-8 MOFs as possible gene delivery vectors. The results show encapsulation of a gene-set in ZIF-8 MOFs and its cellular expression, proving that MOFs do not damage the structural and functional activity of the cargo nucleic acid, essential for possible applications in gene therapy as disease treatments.

>Read more on the ALBA website

Image: Left: Confocal laser scanning microscope images of plGFP@ZIF-8 transfected into human prostate cancer epithelial cells. See the entire image here.

A research, led by the ALBA Synchrotron and funded by the European project NANOCANCER, has analysed the impact of nanoparticles in radiotherapy of glioma tumour cells.

Combining radiotherapy with nanoparticles can increase the efficacy of cancer treatments. The experiment has been carried out at the MIRAS beamline of ALBA, devoted to infrared microspectroscopy.

The use of nanotechnology in medicine is nothing short of revolutionary. Nanosensors for diagnosis, nanoparticles for drug delivery or nanodevices that can regenerate damaged tissue are changing the way we face and treat several diseases.

Combining radiotherapy with nanoparticles is a promising strategy to increase the efficacy of cancer treatments. High-atomic number nanoparticles are used as tumour radiosensitizers: tumour cells previously loaded with nanoparticles enhance the radiation effects when exposed to radiotherapy. “It’s a kind of knock-on effect; the interaction of the radiation with the nanoparticles generates short-range secondary radiation that induces a local dose enhancement in the tumour cells. However, the mechanisms underlying the synergistic effects involved in these techniques are not clearly understood’, says Immaculada Martínez-Rovira, Marie Curie scientist of ALBA and expert in the development of innovative radiotherapy approaches.

>Read more on the ALBA website

Image: Researcher Imma Martínez-Rovira, Marie Curie scientist of ALBA and expert in the development of innovative radiotherapy approaches.

Synchrotron light for deciphering Friedreich’s Ataxia

A team from the Germans Trias i Pujol Research Institute (IGTP) in Badalona is performing an experiment at the ALBA Synchrotron to obtain for the first time 3D images of cells with this disease.

Friedreich’s ataxia affects more than 3,000 people in Spain, causing serious mobility problems and other severe illnesses such as heart disease. At present there is no treatment to prevent or cure the disease.

Friedreich’s ataxia is a rare neurodegenerative disease that progressively damages mobility, balance and coordination. It is an inherited disease, caused by a genetic mutation, that can appear when both parents are carriers. A research group from the Germans Trias i Pujol Research Institute (IGTP), at the Can Ruti Campus in Badalona, led by Dr. Antoni Matilla, is looking into the causes and possible treatments for this disease that results in high disability and an important decrease in the patients’ quality of life.

“Today there is no treatment or cure for Friedreich’s ataxia. It is necessary to try to understand how the disease develops in order to propose therapeutic solutions”, says Dr. Ivelisse Sánchez, co-Principal Investigator of this project at the Neurogenetics Unit of the IGTP. Researchers are now analysing donors’ cells in the ALBA Synchrotron to see the changes caused by the disease.

>Read more on the ALBA website

Image: Dr. Ivelisse Sánchez, co-Principal Investigator of the project, and pre-doctoral researcher Eudald Balagué at the MISTRAL beamline.

New method to get stable perovskite-based material for more efficient solar cells

Perovskites materials are promising candidates for next generation solar cells. However, their use is still limited by their instability within ambient conditions. Instead of absorbing all visible light and appearing black, some of these super materials preferentially form another structure which is yellow. Since only the black form is optically active, the current challenge is achieving stable black perovskites thin films suitable for real world optoelectronic devices. An international team of scientists, led by a group from KU Leuven in Belgium, have shone a light on this problem developing a new method to stabilize the black form introducing strain into the perovskite thin film using the glass substrate on which it sits. Synchrotron-based techniques at the ALBA Synchrotron and the European Synchrotron Radiation Facility were crucial for obtaining these results, published today in Science.

>Read more on the ALBA website

A step closer to smart catalysts for fuel generation

Researchers at the Universidade Federal do Rio Grande do Sul in Brazil in collaboration with the ALBA Synchrotron have performed the first detailed measurement of the strong metal-support interaction (SMSI) effect in Cu-Ni nanoparticles supported on cerium oxide.

A better understanding of this effect is essential for developing smart catalysts that are more selective, stable and sustainable. The quest for the best catalysts in industry has been a long one, but a new study by Universidade Federal do Rio Grande do Sul in Brazil, in collaboration with the ALBA Synchrotron, has come a step closer. For the first time, researchers have found evidence of what could be the origin of the SMSI effect in catalysts supported on cerium oxide.

Catalysts are used to increase the reaction rate of a given chemical reaction, and have applications in a wide variety of fields. In heterogeneous catalysis, the catalyst is usually composed of metal nanoparticles supported on metal oxides. Among them, CeO2-based catalysts have unique structural and atomic properties that make them suitable in the cutting-edge environmental industry of fuel cells and hydrogen. In this field, they are being explored as high-end photocatalytic reactors for the thermal splitting of water and carbon dioxide. However, what has been termed as the SMSI effect can undermine their desired properties.

>Read more on the ALBA website

Image: (extract, full picture here) Near Ambient Pressure – X-ray Photoemission Spectroscopy allowed the identification of the chemical components of the nanoparticles in situ.

X-rays find key insights in metal-oxide thin film interfaces

Researchers from the Institut de Ciència de Materials de Barcelona (ICMAB-CSIC) and ALBA Synchrotron have led a collaborative research, together with the Institut Català de Nanociència i Nanotecnologia (ICN2), the Dept. of Electronics and Biomedical Engineering (University of Barcelona) and CIC nanoGUNE (Donostia), where they have exploited X-ray absorption spectroscopy at the BOREAS beamline of ALBA for unveiling the optical and spin transport properties of transition metal oxides for photovoltaics and spintronics applications.
There is an urgent need of metallic and transparent electrodes for applications in advanced technologies such as flat panel displays or electrodes for photovoltaics, that may substitute the ubiquitous and exceedingly expensive and scarce Indium-Tin oxide (ITO). The AMO3 perovskites (being A an alkaline earth and M an early 3d transition metal, e.g. SrVO3) are driving attention because their intrinsic metallic character combines with the strong electron correlation within the narrow 3d band, to produce a material having its plasma frequency down to infrared and thus transparent at visible range.

>Read more on the ALBA website

Image: Illustration of different phenomena occurring at the interface between a ferromagnetic insulator and a heavy metal.

The interaction between two proteins involved in skin mechanical strength

A research team from the Centro de Investigación del Cáncer of the Universidad de Salamanca has obtained a detailed 3D image of the union between two hemidesmosomal proteins.

The structure of this complex has been unveiled using XALOC beamline techniques, at the ALBA Synchrotron. The results, published in “Structure”, provide insights to understand how these epithelial adhesion structures are formed. Researchers from Centro de Investigación del Cáncer – Instituto de Biología Molecular y Celular del Cáncer of Salamanca, from Centro Universitario de la Defensa in Zaragoza, and from the Netherlands Cancer Institute in Amsterdam have described how two essential proteins interact to each other in order to join epidermis and dermis together. This study reveals at atomic scale how the binding between two hemidesmosomal proteins called integrin α6β4 and BP230 takes place.
Epithelial tissues, such as epidermis, settle on fibrous sheets called basement membrane, formed by extracellular matrix proteins. The junction between epithelia and basement membrane happens through hemidesmosomes, multi-protein complexes located at the membrane of epithelial cells. Integrin α6β4 is an essential protein of the hemidesmosomes, which adheres to proteins of the basement membrane. Inside the cell cytoplasm, plectin and BP230 proteins bind to α6β4 and connect it to the intermediate filaments of the cytoskeleton. Genetic or autoimmune alterations that affect the hemidesmosomal proteins reduce skin resistance and cause diseases such as bullous pemphigoid and various types of epidermolysis bullosa.

>Read more on the ALBA website

Image: Structure of β4(WT)-BP230 complex.

Coherent scattering imaging of skyrmions

Profiting from the coherence of synchrotron light, scientists have performed both reciprocal and real-space observations of magnetic skyrmion lattice deformation in a chiral magnet Co8Zn8Mn4.

The study of these materials is key for developing futures spintronic applications such as racetrack memory and logic devices.
The interplay between exchange interaction, antisymmetric Dzyaloshinskii-Moriya interaction, and magnetocrystalline anisotropy may cause incommensurate spin phases such as helical, conical, and Bloch-type skyrmion lattice states. The typical size of a magnetic skyrmion varies in a range from a few to a few hundred nanometers which makes them promising candidates for future spintronic applications such as skyrmion racetrack memory – with storage density higher than solid-state memory devices- and logic devices.
Coherent soft X-ray scattering and imaging are powerful tools to study the spin ordering in multicomponent magnetic compounds with element selectivity.
In this experiment, a skyrmion-hosting compound Co8Zn8Mn4 was investigated at cryogenic temperatures and applied high magnetic fields by a group of researchers from the Japanese RIKEN Center of Emergent Matter Science, National Institute for Materials Science, the Science and Technology Agency, University of Tokyo, the Institute of Materials Structure Science and Photon Factory, as well as from the ALBA Synchrotron.
 

Image: Coherent soft x-ray speckle patterns measured for Co8Zn8Mn4 sample at L3 absorption edge of Co at different temperatures 150 K, 120 K, 25 K (top panel, left to right) and applied field of 70 mT. White scale bar corresponds to 0.05 nm−1. Bottom panel shows micromagnetic simulations of the corresponding skyrmionic spin textures.

 

A new study explains the inefficacy of some diabetes drugs

Synchrotron light has been used for the first time to simulate damages due to oxidative stress on the aldose reductase protein with the aim of obtaining its activated form.

This form of the protein, related with some several diabetic complications, is insensitive to the drugs being developed, which hinders the treatment. ALBA researchers have shown that chemical changes suffered by the protein under oxidative stress are the cause of drugs inefficacy in the attempt to block aldose reductase. The team of the Synchrotron suggests a new method for drugs design considering the changes in proteins under oxidative stress, like the ones involved in diseases such as cancer, Parkinson or Alzheimer.
The protein aldose reductase has been explored as a drug target since the 1980s for its implication in diabetic complications. Now, the team of the ALBA Synchrotron, in collaboration with the Autonomous University of Barcelona, has shown the reason why some drugs against the effects of diabetes under development do not work in the attempt to block aldose reductase.
This protein has mainly detoxifying functions inside the cell but it can also transform glucose into a molecule called sorbitol. Under hyperglycemic conditions (high level of glucose in blood), this reaction increases much more and sorbitol accumulates, consuming antioxidant defenses. So, if hyperglycemia situation becomes chronic – like in diabetes -, there are unbalanced conditions inside the cell that lead to harmful oxidative stress environment.

Image: Isidro Crespo, Judith Juanhuix and Albert Castellví, at the biolaboratoy of the ALBA Synchrotron.

ALBA collaborates in the discovery of a new muscular disease: myoglobinopathy

An international collaboration led by IDIBELL identifies the first disease caused by a mutation in myoglobin.

At the MIRAS beamline of the ALBA Synchrotron they could demonstrate the presence of oxidized lipids in the damaged muscle cells.
Researchers of the Bellvitge Biomedical Research Institute (IDIBELL) led by Dr. Montse Olivé have described in Nature Communications a new muscular disease caused by a mutation in the myoglobin gene. The study has been possible thanks to a collaboration with a group of geneticists from the University of Western Australia (UWA), led by Prof. Nigel Laing, and researchers from the Karolinska Institute (Stockholm, Sweden).

Myoglobin, the protein that gives muscles their red colour, has as its main function the transportation and intracellular storage of oxygen, acting as an oxygen reservoir when there are low levels (hypoxia) or a total lack thereof (anoxia). It also acts as scavenger of free radicals and other reactive oxygen species, avoiding cell damage due to oxidative stress.

>Read more on the ALBA website

Image: Left, Typical μFTIR spectra and their second derivative of the muscle tissue where the lipid region has been highlighted in orange and the protein region in blue; the inset shows the lipid/protein ratio (calculated from the Infrared spectra) on an optical image of a tissue section with sarcoplasmic bodies. The color bar represents intensity of the ratio: blue and red mean low and high lipid content, respectively. The scale bar is 4 microns. Right,  Infrared second derivative spectrum of the amide region of one sarcoplasmic body (green) showing an increase of β-sheet structures indicating protein aggregation. Second derivative of the amide region corresponding to the tissue surrounding the sarcoplasmic bodies (black).

Urea susbstitutes noble metal catalysts

… for the photodegradation of organic polluants.

A new laser-based technique developed by the Institute of Materials Science (ICMAB-CSIC) uses urea, a common substance in the chemical industry and a low-cost alternative to noble metal co-catalyst, to enable a more efficient, one-step production of hybrid graphene-based organic-inorganic composite layers for environmental remediation, photodegradation of antibiotic contaminants from wastewater. The composition and chemical bonds of the urea-enriched thin layers were studied in detail using synchrotron light at the ALBA Synchrotron.
Human activity is increasing the amount of pollutants in water and air, as well as in all sorts of materials at home and work place. The existence of antibiotic contamination is undeniably one of the most threatening challenges to date, at a time when antibiotic-resistant bacteria has already been flagged as the next world-wide pandemic crisis.
Semiconductor photocatalysts have long been investigated for environmental remediation because they can degrade or mineralize a wide range of organic contaminants as well as pathogens. Research focuses on addressing some drawbacks that prevent their use on a large scale. On the one hand, many photocatalysts are activated only by UV radiation which represents solely a small fraction of the total available solar emission. On the other hand, the recombination of the photogenerated  electron-hole pairs that enable the decomposition of the pollutant is usually faster than the oxidation reactions that cause the degradation of organic molecules. As a consequence, noble metal co-catalysts acting as electron scavengers, such as gold or platinum, are needed in the process.

Image: Researchers Ángel Pérez  del Pino and Enikö György from the ICMAB-CSIC together with Ibraheem Yousef, scientists responsible of MIRAS beamline at ALBA.

Mine tailings dumped into the sea analysed with synchrotron light

The case of Portmán Bay, at the Spanish Mediterranean coast, is one of the most extreme cases in Europe causing great impact on the marine ecosystem by disposal of mine tailings.

For more than 40 years, 60 million tonnes of mine waste were dumped directly into the sea, resulting from the open pit mining that took place in Sierra Minera in Cartagena. As a consequence, the Bay was literally filled with metal-rich artificial soil. Since 2014, a research group from the University of Barcelona (UB) has been studying Portmán Bay. Now, they have analysed samples of these sediments at ALBA because with synchrotron light they can obtain unprecedented information about the heavy metals contamination, such as arsenic.

Very few people know about Portmán Bay, where took place one of the most extreme cases of coastal ecological impact by mine activity in Europe. Figures speak for itself: the mining company Peñarroya dumped more than 60 million tonnes of mine waste into the sea through a 2km-long pipeline located at the west part of the bay. Over the years, the bay became totally filled with a mountain of artificial sediment. The shoreline moved 600m seaward and the trace of the pollution reached 12km out to sea.

>Read more on the ALBA website

Image: Miquel Canals putting sample supports, which were specifically designed and printed with 3D technology at ALBA, at the CLAESS beamline to be analysed with synchrotron light; with Carlo Marini, beamline scientist and Andrea Baza, PhD student from UB.

The ALBA synchrotron and Portugal boost their scientific collaboration

Science ministers from Portugal and Spain have visited ALBA, motivated by a collaboration agreement that promotes the Portuguese scientific community using the ALBA Synchrotron and also includes a training program for Portuguese postdoctoral researchers at ALBA.

On 11th February 2019, at the ALBA Synchrotron facility, an agreement has been signed to promote scientific collaboration between Spain and Portugal. The agreement has been signed by Caterina Biscari, director of ALBA, and Paulo Ferrão, president of the Fundação para a Ciência e a Tecnologia (FCT), under the auspices of Pedro Duque, minister of Science, Innovation and Universities of the Spanish Government, Manuel Heitor, minister of Science Technology and Higher Education of Portugal, and Àngels Chacón, regional minister of Business and Knowledge of the Catalan Government and current chair of the ALBA Rector Council.

The Portuguese scientific community has been using the ALBA Synchrotron since the beginning of its operation in 2012. Nowadays, Portugal is the 5th country that performs more experiments at ALBA, after Germany, France, Italy and the United Kingdom. They have obtained 60% of requested beamtime and have carried out experiments mainly in biology, protein crystallography and materials science.

>Read more on the ALBA website

Image: Images of the signing agreement ceremony, held at the ALBA Synchrotron. From left to right, Caterina Biscari, director of the ALBA Synchrotron, Àngels Chacón, regional minister of Business and Knowledge of the Catalan government, Pedro Duque, minister of Science, Innovation and Universities of the Spanish Government, Manuel Heitor, minister of Science Technology and Higher Education of Portugal, and Paulo Ferrão, president of the Fundação para a Ciência e a Tecnologia (FCT). In the last picture, members of the ALBA Synchrotron management, Joan Gómez Pallarés, General director of Research from the Catalan government, and Ramon Pascual, honorary president of ALBA.

Synchrotron light unveils new insights about amytrophic lateral sclerosis

Synergetic combination of different imaging and spectroscopic synchrotron techniques performed in ALBA and APS (USA) has discovered new aspects about astrocytes cells of this neurodegenerative disease.

Results, published in Analytical Chemistry, show significant differences between ALS and control astrocytes, including structural, chemical and macromolecular anomalies. Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that causes the degeneration and death of neurons that control voluntary muscles. Still today the causes of this disease are unknown in 90% of the cases. However, some of them are caused by the mutation of sod1 gene. This gene encodes an enzyme (SOD1) that is involved in cellular protection against oxidative stress. Mutations dramatically alter the biochemical properties of SOD1, in particular its metal binding affinity and its anti-oxidative activity levels. But it is still unknown how these mutations block the normal cell function and lead to death of motor neurons. The ALBA Synchrotron, in collaboration with researchers from the University of Belgrade Pavle Andjus and Stefan Stamenković (who accomplished his PhD thesis using these results) and Vladan Lučić from Max Planck Institute of Biochemistry (Germany), has studied with synchrotron light techniques and classical biochemical laboratory approaches the cellular structural and biochemical changes of this gene mutation in a transgenic animal model of ALS. In particular, scientists have analysed astrocytes, one kind of brain cells that are key players in pathological processes of this disease.

>Read more on the ALBA website

Image: Researcher Tanja Dučić during the experiment performed at ALBA, at the MIRAS beamline.

From Pakistan to Barcelona, from scientists to friends

Shamila Imtiaz and Sidra Ibadat happily describe their experience during their research internship at ALBA within the framework of the Open Sesame European project.

Shamila Imtiaz (31 years old, PhD candidate and Chemistry junior scientist at PINSTECH Islamabad) and Sidra Ibadat (25 years old, MS Physics Student at the International Islamic University Islamabad) happily describe their experience during their research internship at ALBA. They come from Pakistan and have been granted by the H2020 Open Sesame project to spend 8 weeks at our facility in order to widen their expertise in synchrotron-based Fourier Transform Infrared Microspectroscopy SR-FTIRM at the infrared beamline MIRAS. For both of them, this is their first experience in Europe and, apart from their scientific activity, they are enjoying their walks, their talks and taking care of Shamila’s 9-month old baby. Additionally, ALBA is “proud to help in the development of the scientific careers of young mothers here and elsewhere”, says Miguel Ángel García Aranda, ALBA Scientific Director

“The situation in Pakistan has greatly changed in the past years, there are more women than men in science studies but it’s not easy to find funding opportunities to continue with the studies”, says Sidra. “The Open Sesame project has been a great opportunity for us for visiting and seeing how a synchrotron light source works and bring back all this knowledge to our country”, according to Shamila. “Having access to more sophisticated tools that those in Pakistan can boost our research projects”, continues Sidra.

>Read more on the ALBA website