NAAA-regulated lipid signaling governs the transition from acute to chronic pain

Chronic pain affects 1.5 billion people worldwide but remains woefully undertreated. Understanding the molecular events leading to its emergence is necessary to discover disease-modifying therapies. Here we show that N-acylethanolamine acid amidase (NAAA) is a critical control point in the progression to pain chronicity, which can be effectively targeted by small-molecule therapeutics that inhibit this enzyme. NAAA catalyzes the deactivating hydrolysis of palmitoylethanolamide, a lipid-derived agonist of the transcriptional regulator of cellular metabolism, peroxisome proliferator-activated receptor-α (PPAR-α). Our results show that disabling NAAA in spinal cord during a 72-h time window following peripheral tissue injury halts chronic pain development in male and female mice by triggering a PPAR-α-dependent reprogramming of local core metabolism from aerobic glycolysis, which is transiently enhanced after end-organ damage, to mitochondrial respiration. The results identify NAAA as a crucial control node in the transition to chronic pain and a molecular target for disease-modifying medicines

Recommendations and guidelines from the ISMRM Diffusion Study Group for preclinical diffusion MRI: Part 1 -- In vivo small-animal imaging

The value of in vivo preclinical diffusion MRI (dMRI) is substantial. Small-animal dMRI has been used for methodological development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. Many of the influential works in this field were first performed in small animals or ex vivo samples. The steps from animal setup and monitoring, to acquisition, analysis, and interpretation are complex, with many decisions that may ultimately affect what questions can be answered using the data. This work aims to serve as a reference, presenting selected recommendations and guidelines from the diffusion community, on best practices for preclinical dMRI of in vivo animals. In each section, we also highlight areas for which no guidelines exist (and why), and where future work should focus. We first describe the value that small animal imaging adds to the field of dMRI, followed by general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in animal species and disease models and discuss how they are appropriate for different studies. We then give guidelines for in vivo acquisition protocols, including decisions on hardware, animal preparation, imaging sequences and data processing, including pre-processing, model-fitting, and tractography. Finally, we provide an online resource which lists publicly available preclinical dMRI datasets and software packages, to promote responsible and reproducible research. An overarching goal herein is to enhance the rigor and reproducibility of small animal dMRI acquisitions and analyses, and thereby advance biomedical knowledge.Comment: 69 pages, 6 figures, 1 tabl

Advances in MRI-Based Detection of Cerebrovascular Changes after Experimental Traumatic Brain Injury

Traumatic brain injury is a heterogeneous and multifaceted neurological disorder that involves diverse pathophysiological pathways and mechanisms. Thorough characterization and monitoring of the brain’s status after neurotrauma is therefore highly complicated. Magnetic resonance imaging (MRI) provides a versatile tool for in vivo spatiotemporal assessment of various aspects of central nervous system injury, such as edema formation, perfusion disturbances and structural tissue damage. Moreover, recent advances in MRI methods that make use of contrast agents have opened up additional opportunities for measurement of events at the level of the cerebrovasculature, such as blood–brain barrier permeability, leukocyte infiltration, cell adhesion molecule upregulation and vascular remodeling. It is becoming increasingly clear that these cerebrovascular alterations play a significant role in the progression of post-traumatic brain injury as well as in the process of post-traumatic brain repair. Application of advanced multiparametric MRI strategies in experimental, preclinical studies may significantly aid in the elucidation of pathomechanisms, monitoring of treatment effects, and identification of predictive markers after traumatic brain injury

Rac1 and Rac3 GTPases Regulate the Development of Hilar Mossy Cells by Affecting the Migration of Their Precursors to the Hilus

We have previously shown that double deletion of the genes for Rac1 and Rac3 GTPases during neuronal development affects late developmental events that perturb the circuitry of the hippocampus, with ensuing epileptic phenotype. These effects include a defect in mossy cells, the major class of excitatory neurons of the hilus. Here, we have addressed the mechanisms that affect the loss of hilar mossy cells in the dorsal hippocampus of mice depleted of the two Rac GTPases. Quantification showed that the loss of mossy cells was evident already at postnatal day 8, soon after these cells become identifiable by a specific marker in the dorsal hilus. Comparative analysis of the hilar region from control and double mutant mice revealed that synaptogenesis was affected in the double mutants, with strongly reduced presynaptic input from dentate granule cells. We found that apoptosis was equally low in the hippocampus of both control and double knockout mice. Labelling with bromodeoxyuridine at embryonic day 12.5 showed no evident difference in the proliferation of neuronal precursors in the hippocampal primordium, while differences in the number of bromodeoxyuridine-labelled cells in the developing hilus revealed a defect in the migration of immature, developing mossy cells in the brain of double knockout mice. Overall, our data show that Rac1 and Rac3 GTPases participate in the normal development of hilar mossy cells, and indicate that they are involved in the regulation of the migration of the mossy cell precursor by preventing their arrival to the dorsal hilus

Ancient Plasmodium genomes shed light on the history of human malaria

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia bce, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.This project was funded by the National Science Foundation, grants BCS-2141896 and BCS-1528698; the European Research Council (ERC) under the European Union’s Horizon 2020 programme, grants 851511-MICROSCOPE (to S. Schiffels), 771234-PALEoRIDER (to W.H.) and starting grant 805268-CoDisEASe (to K.I.B.); and the ERC starting grant Waves ERC758967 (supporting K. Nägele and S.C.). We thank the Max Planck-Harvard Research Center for the Archaeoscience of the Ancient Mediterranean for supporting M. Michel, E. Skourtanioti, A.M., R.A.B., L.C.B., G.U.N., N.S., V.V.-M., M. McCormick, P.W.S., C.W. and J.K.; the Kone Foundation for supporting E.K.G. and A.S.; and the Faculty of Medicine and the Faculty of Biological and Environmental Sciences at the University of Helsinki for grants to E.K.G. A.S. thanks the Magnus Ehrnrooth Foundation, the Sigrid Jusélius Foundation, the Finnish Cultural Foundation, the Academy of Finland, the Life and Health Medical Foundation and the Finnish Society of Sciences and Letters. M.C.B. acknowledges funding from: research project PID2020-116196GB-I00 funded by MCIN/AEI/10.13039/501100011033; the Spanish Ministry of Culture; the Chiang Ching Kuo Foundation; Fundación Palarq; the EU FP7 Marie Curie Zukunftskolleg Incoming Fellowship Programme, University of Konstanz (grant 291784); STAR2-Santander Universidades and Ministry of Education, Culture and Sports; and CEI 2015 project Cantabria Campus Internacional. M.E. received support from the Czech Academy of Sciences award Praemium Academiae and project RVO 67985912 of the Institute of Archaeology of the Czech Academy of Sciences, Prague. This work has been funded within project PID2020-115956GB-I00 ‘Origen y conformación del Bronce Valenciano’, granted by the Ministry of Science and Innovation of the Government of Spain, and grants from the Canadian Institutes for Health Research (MZI187236), Research Nova Scotia (RNS 2023-2565) and The Center for Health Research in Developing Countries. D.K. is the Canada research chair in translational vaccinology and inflammation. R.L.K. acknowledges support from a 2019 University of Otago research grant (Human health and adaptation along Silk Roads, a bioarchaeological investigation of a medieval Uzbek cemetery). P.O. thanks the Jane and Aatos Erkko Foundation, the Finnish Cultural Foundation and the Academy of Finland. S. Peltola received support from the Emil Aaltonen Foundation and the Ella and Georg Ehrnrooth Foundation. D.C.S.-G. thanks the Generalitat Valenciana (CIDEGENT/2019/061). E.W.K. acknowledges support from the DEEPDEAD project, HERA-UP, CRP (15.055) and the Horizon 2020 programme (grant 649307). M. Spyrou thanks the Elite program for postdocs of the Baden-Württemberg Stiftung. Open access funding provided by Max Planck Society

New mechanistic insights, novel treatment paradigms, and clinical progress in cerebrovascular diseases

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress

3D quantification of brain microvessels exposed to heavy particle radiation

Space radiation with high energy particles and cosmic rays presents a significant hazard to spaceflight crews. Recent reviews of the health risk to astronauts from ionizing radiation concluded to establish a level of risk which may indicate the possible performance decrements and decreased latency of late dysfunction syndromes (LDS) of the brain. A hierarchical imaging approach developed at ETH Zürich and PSI, which relies on synchrotron based X-ray Tomographic Microscopy (SRXTM), was used to visualize and analyze 3D vascular structures down to the capillary level in their precise anatomical context. Various morphological parameters, such as overall vessel volume, vessel thickness and spacing, are extracted to characterize the vascular structure within a region of interest. For a first quantification of the effect of high energy particles on the vasculature we scanned a set of 6 animals, all of same age. The animals were irradiated with 1 Gy, 2 Gy and 4 Gy of 600MeV 56Fe heavy particles simulating the space radiation environment. We found that with increasing dose the diameter of vessels and the overall vessel volume are decreased whereas the vessel spacing is increased. As these parameters reflect blood flow in three-dimensional space they can be used as indicators for the degree of vascular efficiency which can have an impact on the function and development of lung tissue or tumors