CSIC Scientific Challenges: Towards 2030. Volume 4. Challenges in Biomedicine and Health
Abstract
A lesson that we have learned from the pandemia caused by coronavirus is that solutions in health require coordinated actions. Beside this and other emerging and re-emerging infectious diseases, millions of Europeans are suffering a plethora of disorders that are currently acquiring epidemic dimensions, including cancer, rare diseases, pain and food allergies, among others. New tools for prevention, diagnosis and treatment need to be urgently designed and implemented using new holistic and multidisciplinary approaches at three different levels (basic research, translational/clinical and public/social levels) and involving researchers, clinicians, industry and all stakeholders in the health system. The CSIC is excellently positioned to lead and coordinate these challenges in Biomedicine and Health.
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Corneal biomechanics plays a fundamental role in the genesis and progression of corneal pathologies, such as keratoconus, in corneal remodeling after corneal surgery, and in affecting the measurement accuracy of glaucoma biomarkers, such as the intraocular pressure (IOP). Air-puff induced corneal deformation imaging reveals information highlighting normal and pathological corneal response to a non contact mechanical excitation. However, current commercial systems are limited to monitoring corneal deformation only on one corneal meridian. Here, we present a novel custom developed swept-source optical coherence tomography (SSOCT) system, coupled with a collinear air-puff excitation, capable of acquiring dynamic corneal deformation on multiple meridians. Backed by numerical simulations of corneal deformations, we propose two different scan patterns, aided by low coil impedance galvanometric scan mirrors that permit an appropriate compromise between temporal and spatial sampling of the corneal deformation profiles. We customized the air puff module to provide an unobstructed SSOCT field of view and different peak pressures, air puff durations, and distances to the eye. We acquired multi meridian corneal deformation profiles (a) in healthy human eyes in vivo, (b) in porcine eyes ex vivo under varying controlled IOP, and (c) in a keratoconus mimicking porcine eye ex vivo. We detected deformation asymmetries, as predicted by numerical simulations, otherwise missed on a single meridian that will substantially aid in corneal biomechanics diagnostics and pathology screening.
The amount of data collected and managed in (bio)medicine is ever-increasing. Thus, there is a need to rapidly and efficiently collect, analyze, and characterize all this information. Artificial intelligence (AI), with an emphasis on deep learning, holds great promise in this area and is already being successfully applied to basic research, diagnosis, drug discovery, and clinical trials. Rare diseases (RDs), which are severely underrepresented in basic and clinical research, can particularly benefit from AI technologies. Of the more than 7000 RDs described worldwide, only 5% have a treatment. The ability of AI technologies to integrate and analyze data from different sources (e.g., multi-omics, patient registries, and so on) can be used to overcome RDs’ challenges (e.g., low diagnostic rates, reduced number of patients, geographical dispersion, and so on). Ultimately, RDs’ AI-mediated knowledge could significantly boost therapy development. Presently, there are AI approaches being used in RDs and this review aims to collect and summarize these advances. A section dedicated to congenital disorders of glycosylation (CDG), a particular group of orphan RDs that can serve as a potential study model for other common diseases and RDs, has also been included.
The development of high-resolution, label-free, noninvasive, and subsurface microscopy methods of living cells remains a formidable problem. Force-microscopy-based stiffness measurements contribute to our understanding of single-cell nanomechanics. The elastic properties of the cell's outer structures, such as the plasma membrane and actin cytoskeleton, dominate stiffness measurements, which in turns prevents the imaging of intracellular structures. We propose that the above limitation could be overcome by combining 2D sections of the cell's viscoelastic properties. We show the simultaneous imaging of the outer cell's cytoskeleton and the organelles inside the nucleus. The elastic component of interaction force carries information on the cell's outer elements as the cortex and the actin cytoskeleton. The inelastic component is sensitive to the hydrodynamic drag of the inner structures such the nucleoli.
The diagnostic yield of exome and genome sequencing remains low (8-70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show that this unbiased method, which does not rely upon specific knowledge on individual genes, is effective in both identifying previously unknown disease gene associations, and flagging genes that have previously been incorrectly implicated in disease. GADO can be run on www.genenetwork.nl by supplying HPO-terms and a list of genes that contain candidate variants. Finally, applying GADO to a cohort of 61 patients for whom exome-sequencing analysis had not resulted in a genetic diagnosis, yields likely causative genes for ten cases.
This work presents an affordable and easily customizable methodology for phantom manufacturing, which can be used to mimic different anatomic organs and structures. This methodology is based on the use of polyvinyl alcohol–based cryogels as a physical substitute for biologic soft tissues and of 3-D printed polymers for hard tissues, moulding and supporting elements. Thin and durable soft-tissue mimicking layers and multilayer arrangements can be obtained using these materials. Special attention was paid to the acoustic properties (sound speed, attenuation coefficient and mechanical impedance) of the materials developed to simulate soft tissues. These properties were characterized as a function of the additives concentration (propylene-glycol and alumina particles). The polyvinyl alcohol formulation proposed in this work is stable over several freeze-thaw cycles, allowing the manufacturing of multilayer materials with controlled properties. The manufacturing methodology presented was applied to the development of a phantom for high-frequency cranial ultrasonography in infants. This phantom was able to reproduce the main characteristics of the ultrasound images obtained in neonates through the anterior fontanel, down to 8-mm depth.
Importance
Although the detrimental effects of alcohol on the brain are widely acknowledged, observed structural changes are highly heterogeneous, and diagnostic markers for characterizing alcohol-induced brain damage, especially in early abstinence, are lacking. This heterogeneity, likely contributed to by comorbidity factors in patients with alcohol use disorder (AUD), challenges a direct link of brain alterations to the pathophysiology of alcohol misuse. Translational studies in animal models may help bridge this causal gap.
Objective
To compare microstructural properties extracted using advanced diffusion tensor imaging (DTI) in the brains of patients with AUD and a well-controlled rat model of excessive alcohol consumption and monitor the progression of these properties during early abstinence.
Design, Setting, and Participants
This prospective observational study included 2 cohorts of hospitalized patients with AUD (n = 91) and Marchigian Sardinian alcohol-preferring (msP) rats (n = 27). In humans cross-sectional comparison were performed with control participants (healthy men [n = 36]) and longitudinal comparisons between different points after alcohol withdrawal. In rats, longitudinal comparisons were performed in alcohol-exposed (n = 27) and alcohol-naive msP rats (n = 9). Human data were collected from March 7, 2013, to August 3, 2016, and analyzed from June 14, 2017, to May 31, 2018; rat data were collected from January 15, 2017, to May 12, 2017, and analyzed from October 11, 2017, to May 28, 2018.
Main Outcomes and Measures
Fractional anisotropy and other DTI measures of white matter properties after long-term alcohol exposure and during early abstinence in both species and clinical and demographic variables and time of abstinence after discharge from hospital in patients.
Results
The analysis included 91 men with AUD (mean [SD] age, 46.1 [9.6] years) and 27 male rats in the AUD groups and 36 male controls (mean [SD] age, 41.7 [9.3] years) and 9 male control rats. Comparable DTI alterations were found between alcohol and control groups in both species, with a preferential involvement of the corpus callosum (fractional anisotropy Cohen d = −0.84 [P < .01] corrected in humans and Cohen d = −1.17 [P < .001] corrected in rats) and the fornix/fimbria (fractional anisotropy Cohen d = −0.92 [P < .001] corrected in humans and d = −1.24 [P < .001] corrected in rats). Changes in DTI were associated with preadmission consumption patterns in patients and progress in humans and rats during 6 weeks of abstinence. Mathematical modeling shows this process to be compatible with a sustained demyelination and/or a glial reaction.
Conclusions and Relevance
Using a translational DTI approach, comparable white matter alterations were found in patients with AUD and rats with long-term alcohol consumption. In humans and rats, a progression of DTI alterations into early abstinence (2-6 weeks) suggests an underlying process that evolves soon after cessation of alcohol use.
Background
The western Gironès is a district located in NE Catalonia (NE Iberian Peninsula). This area comprising 186.55 km² and 10,659 inhabitants is composed of 5 municipalities encompassing 29 villages, located in the hydrographic basins of the Ter and Llémena rivers.
Methods
Following the methodology based on the semi-structured interviews, we carried out 40 interviews with 57 informants, 31 were women and the remaining 26 were men, with an average age of 78.6 years.
Results
In the present study, data from 316 taxa (301 angiosperms, 8 gymnosperms, and 7 pteridophytes) belonging to 89 botanical families were collected. The interviewed informants referred 3776 UR of 298 taxa, 1933 (51.19%) of them corresponding to the food category, 949 (25.13%) to the medicinal ones, and 894 (23.68%) to other uses. In addition, 581 vernacular names for 306 species, subspecies, and varieties have also been collected.
Conclusions
These results reveal the validity of traditional knowledge in the studied area, which can be seriously threatened by the loss of its rural condition and its proximity to industrialized areas.
Uncertainties in the proton range in tissue during proton therapy limit the precision in treatment delivery. These uncertainties result in expanded treatment margins, thereby increasing radiation dose to healthy tissue. Real-time range verification techniques aim to reduce these uncertainties in order to take full advantage of the finite range of the primary protons. In this paper, we propose a novel concept for real-time range verification based on detection of secondary neutrons produced in nuclear interactions during proton therapy. The proposed detector concept is simple; consisting of a hydrogen-rich converter material followed by two charged particle tracking detectors, mimicking a proton recoil telescopic arrangement. Neutrons incident on the converter material are converted into protons through elastic and inelastic (n,p) interactions. The protons are subsequently detected in the tracking detectors. The information on the direction and position of these protons is then utilized in a new reconstruction algorithm to estimate the depth distribution of neutron production by the proton beam, which in turn is correlated with the primary proton range. In this paper, we present the results of a Monte Carlo feasibility study and show that the proposed concept could be used for real-time range verification with millimetric precision in proton therapy.
High-throughput sequencing has ushered in a diversity of approaches for identifying genetic variants and understanding genome structure and function. When applied to individuals with rare genetic diseases, these approaches have greatly accelerated gene discovery and patient diagnosis. Over the past decade, exome sequencing has emerged as a comprehensive and cost-effective approach to identify pathogenic variants in the protein-coding regions of the genome. However, for individuals in whom exome-sequencing fails to identify a pathogenic variant, we discuss recent advances that are helping to reduce the diagnostic gap. © 2018 Frésard and Montgomery; Published by Cold Spring Harbor Laboratory Press.
Hospitals worldwide are facing an increasing incidence of hard-to-treat infections. Limiting infections and providing patients with optimal drug regimens require timely strain identification as well as virulence and drug-resistance profiling. Additionally, prophylactic interventions based on the identification of environmental sources of recurrent infections (e.g., contaminated sinks) and reconstruction of transmission chains (i.e., who infected whom) could help to reduce the incidence of nosocomial infections. WGS could hold the key to solving these issues. However, uptake in the clinic has been slow. Some major scientific and logistical challenges need to be solved before WGS fulfils its potential in clinical microbial diagnostics. In this review we identify major bottlenecks that need to be resolved for WGS to routinely inform clinical intervention and discuss possible solutions.
Ethnopharmacological relevance:
The discovery of the antimalarial agent artemisinin is considered one of the most significant success stories of ethnopharmacological research in recent times. The isolation of artemisinin was inspired by the use of Artemisia annua in traditional Chinese medicine (TCM) and was awarded a Nobel Prize in 2015. Antimalarial activity has since been demonstrated for a range of other Artemisia species, suggesting that the genus could provide alternative sources of antimalarial treatments. Given the stunning diversity of the genus (c. 500 species), a prioritisation of taxa to be investigated for their likely antimalarial properties is required.
Materials and methods:
Here we use a phylogenetic approach to explore the potential for identifying species more likely to possess antimalarial properties. Ethnobotanical data from literature reports is recorded for 117 species. Subsequent phylogenetically informed analysis was used to identify lineages in which there is an overrepresentation of species used to treat malarial symptoms, and which could therefore be high priority for further investigation of antimalarial activity.
Results:
We show that these lineages indeed include several species with documented antimalarial activity. To further inform our approach, we use LC-MS/MS analysis to explore artemisinin content in fifteen species from both highlighted and not highlighted lineages. We detected artemisinin in nine species, in eight of them for the first time, doubling the number of Artemisia taxa known to content this molecule.
Conclusions:
Our findings indicate that artemisinin may be widespread across the genus, providing an accessible local resource outside the distribution area of Artemisia annua.
Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.
Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers1,2,3,4. Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells5, and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy.
Este trabajo aborda el proceso de morir y la muerte como un hecho
social de primer orden. Sobre dicho proceso y lo que sería una buena
muerte existe un ideal socialmente compartido que, en la actualidad, se
está en condiciones de alcanzar y del que, sin embargo, la realidad
política y jurídica se aleja. En este contexto nos planteamos como
objetivos, en primer lugar, medir el apoyo que tienen dos prácticas, como
son la eutanasia y el suicidio médico asistido (SMA). En segundo lugar,
contrastar si hay diferencias significativas en las opiniones y actitudes de
los españoles respecto a su regulación y cuáles son las características
sociodemográficas y contextuales que pudieran ayudarnos a explicarlas
y, por último, interpretar y discutir los resultados desde una perspectiva
sociológica que bebe del republicanismo cívico y la bioética.
The rise of genomics engendered intense struggle over the control of knowledge. In Reordering Life, Stephen Hilgartner examines the “genomics revolution” and develops a novel approach to studying the dynamics of change in knowledge and control. Hilgartner focuses on the Human Genome Project (HGP)—the symbolic and scientific centerpiece of the emerging field—showing how problems of governance arose in concert with new knowledge and technology. Using a theoretical framework that analyzes “knowledge control regimes,” Hilgartner investigates change in how control was secured, contested, allocated, resisted, justified, and reshaped as biological knowledge was transformed. Beyond illuminating genomics, Reordering Life sheds new light on broader issues about secrecy and openness in science, data access and ownership, and the politics of research communities.
Drawing on real-time interviews and observations made during the HGP, Reordering Life describes the sociotechnical challenges and contentious issues that the genomics community faced throughout the project. Hilgartner analyzes how laboratories control access to data, biomaterials, plans, preliminary results, and rumors; compares conflicting visions of how to impose coordinating mechanisms; examines the repeated destabilization and restabilization of the regimes governing genome databases; and examines the fierce competition between the publicly funded HGP and the private company Celera Genomics. The result is at once a path-breaking study of a self-consciously revolutionary science, and a provocative analysis of how knowledge and control are reconfigured during transformative scientific change.
https://mitpress.mit.edu/books/reordering-life
Atomic force microscopy (AFM) is a powerful, multifunctional imaging platform that allows biological samples, from single molecules to living cells, to be visualized and manipulated. Soon after the instrument was invented, it was recognized that in order to maximize the opportunities of AFM imaging in biology, various technological developments would be required to address certain limitations of the method. This has led to the creation of a range of new imaging modes, which continue to push the capabilities of the technique today. Here, we review the basic principles, advantages and limitations of the most common AFM bioimaging modes, including the popular contact and dynamic modes, as well as recently developed modes such as multiparametric, molecular recognition, multifrequency and high-speed imaging. For each of these modes, we discuss recent experiments that highlight their unique capabilities.
This paper examines some of the main elements that shaped eugenic discourse and practices during the first decades of the Franco regime. It primarily addresses the ideological basis of racial hygiene stemming from Francoist medicine and psychiatry, examining its relationship with the concept of Spanishness (Hispanidad). It shows that Francoist eugenics had punitive and coercive aspects and outlines the role it played in the brutal repression unleashed against the regime’s political enemies, constructing its anti-Spanish identity. The paper also explores how the Catholic Church accepted eugenics as long as it was not linked to neo-Malthusianism and did not propagate sterilization, contraception, and abortion. In this respect, the paper examines the Catholic Church’s position on the premarital certificate and counseling.
Background
Wild food plants (WFP) have always been consumed by humans, first as the main basis of their food and, since the origins of agriculture, as ingredients of normal diets or as an alternative during situations of scarcity. In contemporary industrialized societies their use is for the most part being abandoned, but they may still play an important role. With the purpose of advancing in the ethnobotanical knowledge of one region of the Catalan Pyrenees, the present study reports the findings of a research project conducted in the Ripollès district (Catalonia, Iberian Peninsula), concerning ethnobotanical knowledge and use of wild and semi-wild vascular plants as foods, along with minor crops. Methods
From August 2004 to July 2014, we performed 104 interviews (93 of which yielded data on food plants) with 163 informants, using the method of semi-structured ethnobotanical interview. We identified the plants quoted and kept herbarium vouchers. ResultsWe detected 967 use reports for 80 wild or naturalized taxa, which are or have been consumed in the Ripollès district, the most cited being Taraxacum dissectum, Cynara cardunculus and Origanum vulgare. Certain frequently reported species such as Molopospermum peloponnesiacum and Taraxacum dissectum have only been rarely cited previously or indicated as food plant in very restricted geographical areas. Most cited families included Asteraceae and Lamiaceae, followed by Rosaceae and Apiaceae. Preferred consumed plant parts included leaves, followed by aerial parts, along with fruits and infructescences, while most wild food plants are eaten raw or used as condiments. Demographic factors such as age and locality of informants seem to be more relevant to wild food plant knowledge than gender. Middle-aged people and inhabitants from the Higher Freser River Valley seem to have a greater knowledge of WFP, both in relation to the number of species elicited, as well as the diversity of uses and preparations. To a lesser degree, women seem to have a slightly higher WFP knowledge than men. The consumption of these resources is still fairly alive amongst the populace, yet changes affecting younger generations–in most cases abandonment–have been reported by various participants. Conclusion
The information provided by this kind of research permits the detection of those traditional species that could constitute the basis for the future development and management of wild edible plant resources along with minor crops. It also helps to determine the factors affecting their use, as well as the distinct target groups that such programmes could be addressed to.
Introduction:
. Thermo transient receptor potential (thermoTRP) channels are some of the most intensely pursued therapeutic targets of the past decade. They are considered promising targets of numerous diseases including chronic pain and cancer. Modulators of these proteins, in particular TRPV1-4, TRPM8 and TRPA1, have reached clinical development, but none have been approved for clinical practice yet.
Areas covered:
. The therapeutic potential of targeting thermoTRP channels is discussed. The discussion is centered on our experience and on available data found in SciFinder, PubMed and ClinicalTrials.gov database from the past decade. This review focuses on the therapeutic progress concerning this family of channels, including strategies to improve their therapeutic index for overcoming adverse effects.
Expert opinion:
. Although thermoTRPs are pivotal drug targets, translation to the clinic has faced two key problems, (i) unforeseen side effects in Phase I trials and, (ii) poor clinical efficacy in Phase II trials. Thus, there is a need for (i) an enhanced understanding of the physiological role of these channels in tissues and organs and (ii) the development of human-based pre-clinical models with higher clinical translation. Furthermore, progress in nanotechnology-based delivery strategies will positively impact thermoTRP human pharmacology.
In vitro-transcribed, messenger RNA-based infectious disease vaccines have the potential to successfully address many of the weaknesses of traditional vaccine platforms, such as the lack of potency and/or durability of vaccine protection, time-consuming, and expensive manufacturing, and, in some cases, safety issues. This optimism is fueled by a great deal of impressive recent data demonstrating that mRNA vaccines have many of the attributes that are necessary for a viable new vaccine class for human use. This review briefly describes mRNA vaccine types, discusses the most relevant and recent publications on infectious disease mRNA vaccines, and highlights the hurdles that need to be overcome to bring this promising novel vaccine modality to the clinic.
Este trabajo aborda el proceso de creación colectiva de una nueva categoría científica surgida a partir de las innovaciones tecnológicas producidas en el campo de la imagen médica computacional: el caso de los “Imaging Biomarkers”. Su creación supone tanto un avance en el diagnóstico, evaluación y tratamiento de enfermedades de alto impacto económico y social, como una auténtica revolución conceptual en el campo emergente de la medicina de precisión.
A lo largo de la historia, el dolor ha sido conceptualizado de ma,neras diferentes, aunque su interpretación ha estado vinculada mayoritariamente al modelo biomédico, según el cual los aspectos morfológicos del cuerpo son los factores principales en su explicación. Esta interpretación se ha visto modificada por un cambio de paradigma que evidencia el impacto que producen los aspectos sociales y las condiciones de vida de las personas sobre aspectos generales y específicos de la salud. Tomando el dolor del parto como objeto de estudio, y desarrollando un análisis sociológico del discurso, se ha podido observar que la percepción y la interpretación de este dolor están influidas por las condiciones sociales y materiales de vida de las mujeres y por las características de sus contextos, por ser este el espacio en el
que se construye la propia subjetividad a través del desempeño del rol maternal. Es por esto que el dolor del parto es muy diferente según el habitusde las mujeres, a causa del significado y del sentido que para ellas tiene este dolor. Asimismo, el sistema sanitario también condiciona la experiencia del dolor, aunque en este caso el elemento diferenciador entre unas y otras mujeres es la posibilidad de comprender la lógica del sistema y de participar en los procesos en los que están inmersas. Dada la naturaleza multidimensional del dolor y la influencia que tienen sobre él los aspectos biopsicosociales, entendemos que es un campo de análisis enriquecedor para la investigación sociológica
During aging, human white matter (WM) is subject to dynamic structural changes which have a deep impact on healthy and pathological evolution of the brain through the lifespan; characterizing this pattern is of key importance for understanding brain development, maturation, and aging as well as for studying its pathological alterations. Diffusion magnetic resonance imaging (MRI) can provide a quantitative assessment of the white-matter microstructural organization that characterizes these trajectories. Here, we use both conventional and advanced diffusion MRI in a cohort of 91 individuals (age range: 13-62 years) to study region- and sex-specific features of WM microstructural integrity in healthy aging. We focus on the age at which microstructural imaging parameters invert their development trend as the time point which marks the onset of microstructural decline in WM. Importantly, our results indicate that age-related brain changes begin earlier in males than females and affect more frontal regions-in accordance with evolutionary theories and numerous evidences across non-MRI domains. Advanced diffusion MRI reveals age-related WM modification patterns which cannot be detected using conventional diffusion tensor imaging.
In this paper two theoretical methodologies, the Schwinger multichannel (SMC) method and the independent atom model with the screening corrected additivity rule (IAM-SCAR), were employed to study positron scattering by benzene over a broad impact energy range. The SMC calculations were carried out in the static plus polarization approximation, accounting for the elastic channel, for impact energies up to 20 eV. The IAM-SCAR method covered energies up to 1000 eV to provide total, elastic, ionization, excitation, and positronium formation cross sections. In the low-energy region we discuss how the description of the polarization effects affects the cross sections. In particular, our calculations support the existence of a bound state in the positron scattering by benzene, in agreement with previous predictions by Young and Surko [Phys. Rev. A 77, 052704 (2008)].
Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases. Antisense drugs are currently in development for the treatment of amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease, and multiple research programs are underway for additional neurodegenerative diseases. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. Importantly, nusinersen improves disease symptoms when administered to symptomatic patients rather than just slowing the progression of the disease. In addition to the benefit to spinal muscular atrophy patients, there are discoveries from nusinersen that can be applied to other neurological diseases, including method of delivery, doses, tolerability of intrathecally delivered antisense drugs, and the biodistribution of intrathecal dosed antisense drugs. Based in part on the early success of nusinersen, antisense drugs hold great promise as a therapeutic platform for the treatment of neurological diseases.
This work presents the experimental spectra obtained with different gold absorbers for incident electron and photon radiation induced by Tl-204. The energy spectra of beta and X-rays after penetrating gold of various thicknesses were obtained simultaneously by using a beta-X Si(Li) spectrometer without a beryllium window. Gold was chosen as the absorbent material since in recent studies an enhancement of radiation effects on biological systems has been demonstrated in the presence of gold nanoparticles, and thus the detailed microscopic description and understanding of radiation transport in this medium is becoming of high importance. This study also applied Monte Carlo codes GEANT4 and TRAX to simulate primary and secondary particle interactions in gold. Comparisons between the simulations and our corresponding experimental studies are then presented and discussed.
Technologically useful and robust graphene-based interfaces for devices require the introduction of highly selective, stable and covalently bonded functionalities on the graphene surface, whilst essentially retaining the electronic properties of the pristine layer. This work demonstrates that highly-controlled, ultra-high vacuum covalent chemical functionalization of graphene sheets with a thiol-terminated molecule provides a robust and tunable platform for the development of hybrid nanostructures in different environments. We employ this facile strategy to covalently couple two representative systems of broad interest: metal nanoparticles, via S-metal bonds, and thiol-modified DNA aptamers, via disulfide bridges. Both systems, which have been characterized by a multi technique approach, remain firmly anchored to the graphene surface even after several washing cycles. Atomic force microscopy images demonstrate that the conjugated aptamer retains the functionality required to recognize a target protein. This methodology opens a new route to the integration of high-quality graphene layers into diverse technological platforms, including plasmonics, optoelectronics or biosensing. With respect to the latter, the viability of a thiol-functionalized CVD graphene-based solution‐gated field‐effect transistor array was assessed.
This paper is based on a 16-year-long ethnography of mass grave exhumations in contemporary Spain and deals with the tortuous, painful, much-disputed, and incomplete unmaking of a concrete and massive militaristic inscription of Spain: that related to its last internal war (1936–1939) and subsequent dictatorship (1939–1975). To understand this process and its historical roots, the paper first dissects the formation of a “funerary apartheid” in the country since the end of the war. Second, it analyzes the impact on the social fabric of the mass grave exhumations of Republican civilians that started in the year 2000. Third, it traces how these disinterments have intersected with Spain’s most prominent Francoist stronghold, the Valley of the Fallen, and threaten the dictator’s burial place. Finally, it discusses the parallel dismantling of the dictatorship’s official statuary that once presided over prominent public spaces in many cities and some military quarters. It argues that rolling back militarization by dismantling war-derived cartographies of death, challenging military burial arrangements, or degrading statues of generals necessarily involves a certain level of remilitarizing by other means. I call this mirroring and deeply embodied memorial backfiring “phantom militarism.”. © 2019 by The Wenner-Gren Foundation for Anthropological Research. All rights reserved.
In the final years of the Franco dictatorship and during the period known as the democratic transition, there were a significant number of protests in the sphere of mental health in Spain. This article analyses the origins and functioning of the Psychiatric Network, which emerged in 1971, its connection to the formation of professional organizations and its role in the reception of anti-psychiatry ideas in Spain. We reach the conclusion that, although the Network's activities took place within a left-wing political and ideological framework, and at such an important time of social change as the end of the dictatorship, its discourse and practices always demonstrated a marked professional approach.
Pain is a prevalent complex medical problem, characterized by physically debilitating and mentally destabilizing conditions. Current pain therapeutics mainly include non-steroidal anti-inflammatory drugs and narcotics (opioids), but they exhibit limitations in efficacy, unwanted side effects and the problem of drug abuse. To overcome these issues, the discovery of different molecular players within pain pathways could lead to new opportunities for therapeutic intervention. Among other strategies, peptides could be powerful pharmaceutical agents for effective opioid-free medications for pain treatment. This review is a compendium of representative non-opioid analgesic peptides acting directly or indirectly at different ion channels and receptors distributed in nociceptive pathways. They include peptides targeting Ca²⁺, Na⁺ and K⁺ voltage-gated ion channels, the neuronal nicotinic receptors (nAChR), transient receptor potential channels (TRP), and different non-opioid G-protein coupled receptors (GPCRs), like the calcitonin gen-related peptide (CGRP), cannabinoid, bradykinin and neurotensin receptors, among others. Peptides engineered from protein-protein interactions among pain-related receptors and regulatory proteins also led to new therapeutic approaches for pain management. Following some successful examples, already in the clinics or under clinical trials, the improved understanding of pain mechanisms, and the advances in peptide permeation and/or delivery, could afford new analgesic peptides in the near future.
Intrinsically Disordered Proteins (IDPs) lack a tertiary structure. Amyloidogenic IDPs (aIDPs) in particular have attracted great interest due to their implication in several devastating diseases as well as in critical functions. However, the conformational changes that trigger amyloid formation in aIDPs are largely unknown. aIDPs’ conformational polymorphism at the monomer level encumbers their study using bulk techniques. Single-molecule techniques like Atomic Force Microscopy-based Single-Molecule Force Spectroscopy are a promising approach and a “carrier-guest” strategy, in which the protein of interest is mechanically protected, was developed to overcome the spurious signals from the noisy proximal region. However, since carrier and single-molecule markers have similar mechanostabilities, their signals can intermingle in the force-extension recordings, making peak selection and analysis very laborious, cumbersome and prone to error. Here we have developed a new carrier, the c8C module from the CipC scaffoldin, with a higher mechanostability so that the signals from the protected protein will appear at the end of the recordings. This assures an accurate, more efficient and expert-independent analysis, simplifying both the selection and analysis of single-molecule data. Furthermore, this modular design can be integrated into any SMFS polyprotein-based vector, thus constituting a useful utensil to the growing toolbox of protein nanomechanics.
We present a range of cross section measurements for the low-energy scattering of positrons from pyridine, for incident positron energies of less than 20 eV, as well as the independent atom model with the screening corrected additivity rule including interference effects calculation, of positron scattering from pyridine, with dipole rotational excitations accounted for using the Born approximation. Comparisons are made between the experimental measurements and theoretical calculations. For the positronium formation cross section, we also compare with results from a recent empirical model. In general, quite good agreement is seen between the calculations and measurements although some discrepancies remain which may require further investigation. It is hoped that the present study will stimulate development of ab initio level theoretical methods to be applied to this important scattering system.
Ethnopharmacological relevance:
Most ethnobotanical research bases its analyses on individual taxa catalogues and their uses, rather than on mixtures. However, mixtures constitute an important chapter of our different lines of research and they represent a large volume of information. The relevance of these data in folk medicine could be explained as a response to the cure of multicausal etiology diseases or by a possible polyvalent effect of the mixture as opposed to the effect of each taxon alone.
Aims of the study:
The main goals are: i) to perform qualitative and quantitative analyses of these mixtures; ii) to carry out a comparison among the mixtures in two Catalan territories and their floristic composition; iii) to assess the worth of families association; and, iv) to evaluate whether the plants claimed to be used in mixtures have contraindications or possible negative interactions according to phytopharmaceutical literature. The ultimate goal is to test a protocol that can be implemented in similar studies.
Materials and methods:
We have used data on medicinal plant mixtures obtained from two extensive ethnobotanical field studies carried out in two Catalan districts, Alt Empordà and Ripollès. The quantitative analyses by means of descriptive statistics were carried out with Excel. New contributions like the implementation of the Shannon index to quantify the diversity of families in plant combinations, the creation of a new index to calculate the taxon importance in mixtures, or the use of a social network analysis to study the connection between botanical families have been employed in this work.
Results:
In total, a set of 484 mixtures from Alt Empordà and Ripollès (Catalonia, Iberian Peninsula) have been analysed: 462 for human use and 22 for veterinary. Thymus vulgaris and Rosmarinus officinalis are among the most commonly used species in mixtures. The aerial part of the plant is the most used, and the anticatarrhal usage is the most frequent in both territories. A wide diversity of families has been observed in mixtures and reflects a strong bond between the number of taxa and the number of families in each mixture, being almost equal to one. The Shannon diversity index applied to mixtures has the maximum value at 0.86. No exclusive plants are used in mixtures, as reflected on the index of taxon usefulness in mixtures (ITUM), proposed in the present work. The association of families is strong between Lamiaceae (12.12%) and Asteraceae with Lamiaceae (11.69%). Finally, the informant consensus factor (0.85) reflects the strong consistency of data reported by the interviewees.
Conclusions:
The present analysis has confirmed that it is possible to study the data of plants in mixtures as thoroughly as when they are considered in isolation in an ethnofloristic catalogue, and maybe this kind of ethnobotanical investigation could be a first step for future pharmacological studies that may result in a relevant complement to the current phytotherapy market.
The past 5 years have seen an unprecedented rate of discovery of genes that cause rare diseases and with it a commensurate increase in the number of diagnosable but nevertheless untreatable disorders. Here, we discuss the increasing opportunity for diagnosis and therapy of rare diseases and how to tackle the associated challenges.
The gut-brain axis communicates the brain with the gut microbiota, a bidirectional conduit that has received increasing attention in recent years thanks to its emerging role in brain development and function. Alterations in microbiota composition have been associated to neurological and psychiatric disorders, and several studies suggest that the immune system plays a fundamental role in the gut-brain interaction. Recent advances in brain imaging and in microbiome sequencing have generated a large amount of information, yet the data from both these sources needs to be combined efficiently to extract biological meaning, and any diagnostic and/or prognostic benefit from these tools. In addition, the causal nature of the gut-brain interaction remains to be fully established, and preclinical findings translated to humans. In this "Perspective" article, we discuss recent efforts to combine data on the gut microbiota with the features that can be obtained from the conversion of brain images into mineable data. The subsequent analysis of these data for diagnostic and prognostic purposes is an approach we call radiomicrobiomics and it holds tremendous potential to enhance our understanding of this fascinating connection.
Based on an analysis of the discourses, the ideological appropriation and the practical influence of mental hygiene in Spanish psychiatry during the early years of the Francoist regime, this article examines its decline and subsequent replacement by the new concept of mental health promoted by the World Health Organization and other international bodies from the mid-twentieth century. The old approach, essentially focused on the prophylaxis of insanity within the framework of a set of interventionist policies of social defence, was thus transformed from the beginning of the 1960s into a much more ambitious and comprehensive project which sought to promote the psychosocial balance and performance of individuals in the context of increasingly socialized health-related discourses and networks of care.
Since the 1980s the world has witnessed the global emergence of new epidemic infections (HIV/AIDS being the most dramatic so far), and the reappearance of known infectious diseases, such as tuberculosis, malaria, and syphilis, that had seemed for some time to be under control. In the field of public health, these events have led to the designation of a new nosological category: emerging and re-emerging infectious diseases. Such diseases pose a growing threat to the hegemony of biomedicine, raising many questions about the adequacy of biomedical discourse and practices to meet the global challenge of infectious diseases. This chapter analyzes the construction of this new nosological category and examines the implications of (re)emerging diseases for public health, food security, and human development on a worldwide scale.
Adaptive optics is a relatively new field, yet it is spreading rapidly and allows new questions to be asked about how the visual system is organized. The editors of this feature issue have posed a series of question to scientists involved in using adaptive optics in vision science. The questions are focused on three main areas. In the first we investigate the use of adaptive optics for psychophysical measurements of visual system function and for improving the optics of the eye. In the second, we look at the applications and impact of adaptive optics on retinal imaging and its promise for basic and applied research. In the third, we explore how adaptive optics is being used to improve our understanding of the neurophysiology of the visual system.
Prostate cancer is the second most frequently diagnosed cancer in men worldwide. Currently prostate specific antigen (PSA) serum concentration is the most used prostate cancer marker, but it only shows limited specificity. Because PSA glycosylation is altered by prostate cancer, detecting glycosylation changes could increase PSA specificity as a prostate cancer marker. Changes in PSA glycosylation can modify its electrophoretic- behavior and techniques such as capillary zone electrophoresis (CZE) and two-dimensional electrophoresis (2-DE) could be applied to detect changes in PSA glycosylation.
With the recent emergence of reports on resistant Gram-negative ‘superbugs’, infections caused by multidrug-resistant (MDR) Gram-negative bacteria have been named as one of the most urgent global health threats due to the lack of effective and biocompatible drugs. Here, we show that a class of antimicrobial agents, termed ‘structurally nanoengineered antimicrobial peptide polymers’ (SNAPPs) exhibit sub-μM activity against all Gram-negative bacteria tested, including ESKAPE and colistin-resistant and MDR (CMDR) pathogens, while demonstrating low toxicity. SNAPPs are highly effective in combating CMDR Acinetobacter baumannii infections in vivo, the first example of a synthetic antimicrobial polymer with CMDR Gram-negative pathogen efficacy. Furthermore, we did not observe any resistance acquisition by A. baumannii (including the CMDR strain) to SNAPPs. Comprehensive analyses using a range of microscopy and (bio)assay techniques revealed that the antimicrobial activity of SNAPPs proceeds via a multimodal mechanism of bacterial cell death by outer membrane destabilization, unregulated ion movement across the cytoplasmic membrane and induction of the apoptotic-like death pathway, possibly accounting for why we did not observe resistance to SNAPPs in CMDR bacteria. Overall, SNAPPs show great promise as low-cost and effective antimicrobial agents and may represent a weapon in combating the growing threat of MDR Gram-negative bacteria.
The hope for precision medicine has long been on the drug discovery horizon, well before Human Genome Project gave it promise at the turn of the 21st century. In oncology, the concept has finally been realized and is now firmly embedded, with most recent therapies involving some level of patient/disease stratification, including some highly personalized treatments. In addition, several drugs for rare diseases have been recently approved or are in late-stage clinical development, and new delivery modalities in cell and gene therapy and oligonucleotide approaches are yielding exciting new medicines for rare diseases of unmet need. For common complex diseases, however, the GWAS-driven advances in annotation of the genetic architecture over the past decade have not led to a concomitant shift in refined treatments. Similarly, attempts to disentangle treatment responders from non-responders via genetic predictors in pharmacogenetics studies have not met their anticipated success. It is possible that common diseases are simply lagging behind due to the inherent time lag with drug discovery, but it is also possible that their inherent multifactorial nature and their etiological and clinical heterogeneity will prove more resistant to refined treatment paradigms. The emergence of population-based resources in electronic health records, coupled with the rapid expansion of mobile devices and digital health may help to refine the measurement of phenotypic outcomes to match the exquisite detail emerging at the molecular level.