Small obstacle in a large polar flock

We show that arbitrarily large polar flocks are susceptible to the presence of a single small obstacle. In a wide region of parameter space, the obstacle triggers counterpropagating dense bands leading to reversals of the flow. In very large systems, these bands interact, yielding a never-ending chaotic dynamics that constitutes a new disordered phase of the system. While most of these results were obtained using simulations of aligning self-propelled particles, we find similar phenomena at the continuous level, not when considering the basic Toner-Tu hydrodynamic theory, but in simulations of truncations of the relevant Boltzmann equation

Prevalence of Fabry Disease in Young Patients with Stroke in Argentina

Background Fabry disease (FD) is an underdiagnosed cause of stroke in young adults, but the frequency of this association is largely unknown. We estimated the prevalence of FD in a nationwide cohort of young adults who had stroke and transient ischemic attack (TIA) in Argentina. Methods This was a prospective, multicenter study of stroke and FD in young adults (18-55 years) conducted in Argentina between 2011 and 2015. Patients were enrolled if they had had a TIA or an ischemic or hemorrhagic stroke within the previous 180 days. FD was diagnosed by measuring α-galactosidase A activity (males) and through genetic studies (females). Results We enrolled 311 patients (54% men, mean age: 41 years). Ischemic events occurred in 89% of patients (80% infarcts, 9% TIA) and hemorrhagic strokes in 11%. One female (.3% of the total group, 1% of the cryptogenic ischemic strokes) had the pathogenic mutation c.888G>A/p.Met296Ile /Exon 6 on the GAL gene. Her only other manifestation of FD was angiokeratoma. Eighteen females had nonpathogenic intronic variations: c.-10C>T, c.-12G>A, or both. Two patients had the nonpathogenic mutation D313Y, while a third had the likely benign mutation S126G. Conclusions FD was identified in 1 patient (.3%) in this first Latin American study. The patient presented with a late-onset oligo-symptomatic form of the disease. A large number of nonpathogenic mutations were present in our cohort, and it is essential that they not be mistaken for pathogenic mutations to avoid unnecessary enzyme replacement treatment.Instituto de Estudios Inmunológicos y Fisiopatológico

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Hippocampal alterations after spinal cord injury

Luego de las lesiones de la médula espinal los pacientes experimentan déficits cognitivos relacionados con funciones hipocampales. En este sentido, el objetivo general de esta Tesis es estudiar las bases neurobiológicas responsables de dichos déficits. Para cumplirlo desarrollamos un modelo de lesión espinal parcial por compresión en ratas y ratones que permite evaluar el estado cognitivo de los animales lesionados, ya que estos tienen la misma actividad locomotora que los animales Sham pero severos problemas en la coordinación de sus pasos.Los resultados demostraron que luego de 60 días de la injuria espinal los animales presentaron déficits en la memoria de reconocimiento y en la memoria de trabajo espacial. Estos déficits coinciden con una disminución del número de neuronas del hileo, de CA1 y de la capa granular. También se observó una disminución de la neurogénesis tanto en la etapa aguda como en la crónica. En la fase aguda encontramos una disminución del número de progenitoras neurales amplificadas (ANP) mientras que en la etapa crónica se observó una disminución de la taza de proliferación de las células madres neurales (RGL) y de los ANP. Las alteraciones neuronales observadas en la etapa crónica coincidieron con alteraciones en la respuesta de las poblaciones de células gliales. De hecho en la etapa crónica, aumentó el número de astrocitos reactivos en ratas y ratones.Además, se produjo en ratas un incremento de las células microgliales activas, aumentando la expresión del ARNm de TNFα e IL-1β y disminuyendo el porcentaje de células microgliales del fenotipo M2 (anti-inflamatorio). En la etapa aguda, si bien el número de astrocitos reactivos y células de la microglía aumentaron, no se incrementaron los niveles del ARNm para TNFα e IL-1β.Con respecto a los mecanismos por los cuales la lesión espinal genera estas alteraciones hipocampales exploramos el rol de los glucocorticoides (GC) y de la degeneración9transneuronal de los axones seccionados. En cuanto a los GC describimos que los animales sólo tuvieron altos niveles plasmáticos en la etapa aguda alcanzando valores similares a animales intactos en la etapa crónica. Mediante dos abordajes experimentales diferentes se bloqueó la acción de los GC en la etapa aguda y se estudió en la etapa crónica el proceso de neurogénesis y el desempeño cognitivo. Los resultados mostraron que la neurogénesis fue parcialmente restaurada, sin embargo los déficits cognitivos persistieron. Por otro lado, realizamos una hemisección de la médula espinal mediante la cual sólo los haces del funículo ventrolateral, que en su mayoría decusan, fueron dañados y medimos la neurogénesis 60 días después en el hipocampo ipsilateral y contralateral a la lesión. Observamos que la neurogénesis del lado contralateral a la lesión disminuyó con respecto al lado ipsilateral, involucrando a la degeneración transneuronal en esta disminución. El desarrollo de este trabajo sugiere que las alteraciones hipocampales descriptas en las neuronas maduras, en la neurogénesis y en el ambiente glial podrían explicar los déficits cognitivos observados en los roedores y en los pacientes. Los resultados sugieren que la lesión espinal podría generar un ambiente inflamatorio en la etapa crónica que conduzca eventualmente a la neurodegeneración hipocampal. Con respecto a los mecanismos subyacentes comenzamos estudiando la disminución de la neurogénesis y demostramos que los GC generados en la etapa aguda en parte fueron responsables de la disminución del proceso en la etapa crónica. También observamos que otro factor involucrado en la disminución de la neurogénesis en la etapa crónica fue la degeneración transneuronal. Este trabajo es pionero en el estudio de la encefalopatía luego de la lesión espinal y abre nuevas perspectivas que permiten la comprensión integral de la fisiopatología del paciente con lesión medular.Patients experience cognitive deficits related to hippocampal functions after spinal cord injury. In this regard, the general objective of this Thesis is to study the neurobiological bases responsible for these deficits. To achieve this goal a model of spinal cord compression injury was developed, which allows assessing the cognitive status of injured rodents, since they have the same locomotor activity as Sham animals but severe coordination problems. The results showed that after 60 days of spinal cord injury the animals showed deficits in recognition memory and spatial working memory. These deficits coincide with a decrease in the number of neurons in the hilus, CA1 and the granular cell layer. Neurogenesis decrease was also observed in both the acute and chronic phases. However, the number of amplified neural progenitors (ANP) decreased in the acute phase while a down regulation in the activation of both the neural stem cells (RGL) and the ANP was observed in the chronic phase. These neuronal alterations coincided with alterations in glial cell population. Regarding astrocytes, there was an increase in the number of reactive astrocytes in both rats and mice. Regarding microglial cells, their number was upregulated in rats during the chronic phase, increasing the expression of TNFα and IL-1β mRNAs and decreasing the percentage of M2 microglial cells (anti-inflammatory phenotype). During the acute phase, despite that the number of reactive astrocytes and microglial cells increased, mRNA levels for TNFα and IL-1β did not increase. Concerning the mechanisms by which spinal injury generated these hippocampal alterations, the role of GC and transneuronal degeneration of severed axons was explored. With regard to GC, plasma levels were high in the acute phase reaching Sham values in the chronic phase. Using two different experimental approaches, GC action was blocked in the acute phase and neurogenesis and cognitive performance was studied in the chronic phase. The results showed that neurogenesis was partially restored, yet cognitive deficits persisted. On the other hand, a spinal cord hemisection was performed in order to lacerate axons of only one side and neurogenesis 60 days after injury was measured in the ipsilateral and contralateral hippocampus. Neurogenesis only in the contralateral side decreased with respect to the ipsilateral side, involving transneuronal degeneration in this downregulation. The development of this work suggests that the hippocampal alterations described in mature neurons, neurogenesis and glial cells could explain the cognitive deficits observed in rodents and patients. The results suggest that spinal cord injury could generate an inflammatory environment that eventually leads to hippocampal neurodegeneration. Regarding the underlying mechanisms, our results demonstrated that GC generated in the acute phase were partly responsible for neurogenesis reduction in the chronic phase. Transneuronal degeneration turned out to be another factor that downregulated neurogenesis after chronic spinal cord injury. This work has pioneered the study of spinal cord injury encephalopathy and opens new perspectives to comprehensively understand the pathophysiology of spinal cord injured patients.Fil: Jure, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Spinal cord injury drives chronic brain changes

Only a few studies have considered changes in brain structures other than sensory and motor cortex after spinal cord injury, although cognitive impairments have been reported in these patients. Spinal cord injury results in chronic brain neuroinflammation with consequent neurodegeneration and cognitive decline in rodents. Regarding the hippocampus, neurogenesis is reduced and reactive gliosis increased. These long-term abnormalities could explain behavioral impairments exhibited in humans patients suffering from spinal cord trauma

Progesterone effects on oligodendrocyte differentiation in injured spinal cord

Spinal cord lesions result in chronic demyelination as a consequence of secondary injury. Although oligodendrocyte precursor cells proliferate the differentiation program fails. Successful differentiation implies progressive decrease of transcriptional inhibitors followed by upregulation of activators. Progesterone emerges as an anti-inflammatory and pro-myelinating agent which improves locomotor outcome after spinal cord injury. In this study, we have demonstrated that spinal cord injury enhanced oligodendrocyte precursor cell number and decreased mRNA expression of transcriptional inhibitors (Id2, Id4, hes5). However, mRNA expression of transcriptional activators (Olig2, Nkx2.2, Sox10 and Mash1) was down-regulated 3 days post injury. Interestingly, a differentiation factor such as progesterone increased transcriptional activator mRNA levels and the density of Olig2- expressing oligodendrocyte precursor cells. The differentiation program is regulated by extracellular signals which modify transcriptional factors and epigenetic players. As TGFβ1 is a known oligodendrocyte differentiation factor which is regulated by progesterone in reproductive tissues, we assessed whether TGFβ1 could mediate progesterone remyelinating actions after the lesion. Notwithstanding that astrocyte, oligodendrocyte precursor and microglial cell density increased after spinal cord injury, the number of these cells which expressed TGFβ1 remained unchanged regarding sham operated rats. However, progesterone treatment increased TGFβ1 mRNA expression and the number of astrocytes and microglial TGFβ1 expressing cells which would indirectly enhance oligodendrocyte differentiation. Therefore, TGFβ1 arises as a potential mediator of progesterone differentiating effects on oligodendrocyte linage.Fil: Jure, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Labombarda, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentin

Spinal Cord Injury Leads to Hippocampal Glial Alterations and Neural Stem Cell Inactivation

The hippocampus encodes spatial and contextual information involved in memory and learning. The incorporation of new neurons into hippocampal networks increases neuroplasticity and enhances hippocampal-dependent learning performances. Only few studies have described hippocampal abnormalities after spinal cord injury (SCI) although cognitive defcits related to hippocampal function have been reported in rodents and even humans. The aim of this study was to characterize in further detail hippocampal changes in the acute and chronic SCI. Our data suggested that neurogenesis reduction in the acute phase after SCI could be due to enhanced death of amplifying neural progenitors (ANPs). In addition, astrocytes became reactive and microglial cells increased their number in almost all hippocampal regions studied. Glial changes resulted in a non-infammatory response as the mRNAs of the major pro-infammatory cytokines (IL-1β, TNFα, IL-18) remained unaltered, but CD200R mRNA levels were downregulated. Long-term after SCI, astrocytes remained reactive but on the other hand, microglial cell density decreased. Also, glial cells induced a neuroinfammatory environment with the upregulation of IL-1β, TNFα and IL-18 mRNA expression and the decrease of CD200R mRNA. Neurogenesis reduction may be ascribed at later time points to inactivation of neural stem cells (NSCs) and inhibition of ANP proliferation. The number of granular cells and CA1 pyramidal neurons decreased only in the chronic phase. The release of pro-infammatory cytokines at the chronic phase might involve neurogenesis reduction and neurodegeneration of hippocampal neurons. Therefore, SCI led to hippocampal changes that could be implicated in cognitive defcits observed in rodents and humans.Fil: Jure, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Encinas, Juan Manuel. Centro Vasco Achucarro de Neurociencias. Laboratorio de Células Madre Neuronales y Neurogénesis; EspañaFil: Labombarda, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentin

IGF1 gene therapy reversed cognitive deficits and restored hippocampal alterations after chronic spinal cord injury

The hippocampus is implicated in the generation of memory and learning, processes which involve extensive neuroplasticity. The generation of hippocampal adult-born neurons is particularly regulated by glial cells of the neurogenic niche and the surrounding microenvironment. Interestingly, recent evidence has shown that spinal cord injury (SCI) in rodents leads to hippocampal neuroinflammation, neurogenesis reduction, and cognitive impairments. In this scenario, the aim of this work was to evaluate whether an adenoviral vector expressing IGF1 could reverse hippocampal alterations and cognitive deficits after chronic SCI. SCI caused neurogenesis reduction and impairments of both recognition and working memories. We also found that SCI increased the number of hypertrophic arginase-1 negative microglia concomitant with the decrease of the number of ramified surveillance microglia in the hilus, molecular layer, and subgranular zone of the dentate gyrus. RAd-IGF1 treatment restored neurogenesis and improved recognition and working memory impairments. In addition, RAd-IGF1 gene therapy modulated differentially hippocampal regions. In the hilus and molecular layer, IGF1 gene therapy recovered the number of surveillance microglia coincident with a reduction of hypertrophic microglia cell number. However, in the neurogenic niche, IGF1 reduced the number of ramified microglia and increased the number of hypertrophic microglia, which as a whole expressed arginase-1. In summary, RAd-IGF1 gene therapy might surge as a new therapeutic strategy for patients with hippocampal microglial alterations and cognitive deficits such as those with spinal cord injury and other neurodegenerative diseases.Fil: Jure, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Falomir Lockhart, Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Bellini, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Labombarda, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentin

Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells

UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas, whereas this function was lost in Batf3(-/-) mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects. SIGNIFICANCE: Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory mAbs.Work at the I. Melero lab is funded by MICINN (SAF200803294 and SAF2011-22831), Departamento de salud del Gobierno de Navarra, Redes temáticas de investigación cooperativa RETIC (RD06/0020/0065), and the European commission 7th framework program (ENCITE and IACT). Work in the D. Sancho laboratory is funded by the CNIC and grants from the Spanish Ministry of Economy and Competitiveness (SAF-2013-42920R) and the European Research Council (ERC Starting Independent Researcher Grant 2010, ERC-2010-StG 260414). The CNIC is supported by the Spanish Ministry of Economy and Competitiveness and the Pro-CNIC Foundation. I. Melero and D. Sancho are funded by the European Commission (635122-PROCROP H2020).S