Bats, although mammals, are not phylogenetically very close to humans, so we would not expect them to harbor many harmful viruses to our species.

Source: Вых Пыхманн via Wikipedia

The order of bats contains more than 1,200 species. Because of this genetic diversity, information about one species may not apply to other species. In recent years, however, it has emerged that viruses have spread from bats to other mammals. For example, serological evidence and detection of viruses linked to ebolaviruses in bats suggest that bats are indeed one of the reservoirs of the virus.

However, although bats harbor many different viruses, their spread to other animals is extremely rare. One reason is that for such an event to occur, several factors should be conducive to transmission.

The ability of bats to host many viruses without showing pathology suggests that bats have developed immune mechanisms different from those of other mammals. This tolerance to viruses goes hand in hand with reduced inflammation.To explain this singular characteristic, it is necessary to compare it with another singular characteristic of bats: It is a mammal with the capacity to fly.

The metabolic rate of bats in flight is double that of running rodents of similar size. The increased metabolic rate that accompanies the flight would result in higher levels of oxygen-free radicals. To mount an immune response to the damage caused by this high metabolism, would be energetically expensive.

Bats have therefore developed mechanisms leading to reduced inflammation. It would also explain why bats of some species live longer than expected given their high metabolism and small size. Some bats can live up to 40 years, while a rodent of the same size can live only two years.

Small animals with a fast heart rate and metabolism generally have a shorter lifespan than larger animals with a slower heartbeat and a slower metabolism. But bats are unique because they have a much longer lifespan than other mammals of the same size.

But a reduced inflammatory response enables rapid replication of viruses, especially in stressful conditions that affect the immune system.

• The awakening of hibernation is a stressful event for bats. Many large brown bats are latently infected and Gerowet and his colleagues have shown that the virus reactivates when it comes out of hibernation. This reactivation is also associated with a low level of antibodies to the virus. After hibernation, antibody levels rise, which puts the virus back to latency.

• The virus also reactivates when bats are infected with a bacterial or fungal infection. Small brown bats are particularly susceptible to an often fatal fungal infection known as white nose syndrome. A study examining the effects of stress induced by this infection showed that bats infected with fungi had 60 times more coronavirus in their intestines than uninfected bats. The specific protection mechanisms of these bats results in a rapid response that blocks the virus outside the cells. Indeed, paradoxically a host that tolerates well the presence of viruses, because it controls inflammation, allows viruses to increase their rate of replication, by genetic selection, without damaging their host.

• Disturbances in bat habitat also seem to stress these animals and cause them to spread even more viruses in their saliva, urine and feces which can infect other animals. "Increased environmental threats to bats can add to the threat of zoonosis," said Brook, who is also working with a Madagascar-based field project that explores the link between loss of bat habitat and spread of bat viruses to other animals and humans.

Such rapidly reproducing viruses generate extreme virulence when overflowing to hosts that do not have the same immune capabilities as bats.

When these virulent viruses travel from bats to animals without a rapid response immune system, they quickly overwhelm their new hosts.

Brook and Boots are developing a more formal model of disease progression in bats to better understand the spread of the virus to other animals and humans.

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A scientist from the Universitätsklinikum Erlangen, Heiko Bruns, pursues an innovative hypothesis on cancer metastases. He wrote his doctoral thesis on tuberculosis bacteria hidding in macrophages, and his postdoctoral thesis focused on the importance of macrophages in the context of cancer metastasis.

Macrophages are a type of white blood cell, which gobbles up and digests cell debris, foreign substances, microbes and cancer cells. Macrophages enter damaged tissues by the endothelium of blood vessels, a process known as extravasation. This process is very similar to what is currently thought to be the metastasis process.

Classical conception of the metastasis process Source: doi: 10.1038 / nri3789

It is well known that macrophages can contribute to the growth and progression of cancers. Macrophages can also positively and negatively influence the results of anti-cancer treatments. Unfortunately some pathogens managed to lives inside those powerful macrophages. This allows them to escape from the immune system. This is the case with Mycobacterium tuberculosis or HIV.

Metastases are responsible for most of the deaths caused by cancer. Dr. Bruns believes that it is currently unclear how metastases form. So far, it has been assumed that they spread throughout the body via the lymphatic vessels and the bloodstream. But this mechanistic hypothesis cannot explain why some organs are preferably targeted in metastasis while other are relatively preserved. This was first discussed as the "seed and soil" theory by Stephen Paget in 1889. Source Mikael Häggström via Wikipedia

Paradoxically, cancer patients with a high number of macrophages have a reduced life expectancy. In a mouse model, tumor growth almost stops when the macrophages where removed.

Heiko Bruns assumes that individual tumor cells are consumed by phagocytes, but are not necessarily eliminated by them. Instead, he suspects that tumor cells are using macrophages as "Trojans horses". They could thus escape detection and travel through the body to colonize other organs.

Dr. Heiko Bruns' idea was accepted into the 'Experiment! In search of bold research ideas' based on this unusual question. This idea received funding of 120,000 euros from the Volkswagen Foundation until the end of 2021.

Un scientifique de l'Universitätsklinikum Erlangen, Heiko Bruns, poursuit une hypothèse innovante sur les métastases cancéreuses. Il a rédigé sa thèse de doctorat sur la survie des bactéries de la tuberculose dans les macrophages, et sa thèse postdoctorale porte sur l'importance des macrophages dans le contexte de la métastase cancéreuse.

Les macrophages sont un type de globules blancs du système immunitaire, qui engloutit et digère les débris cellulaires, les substances étrangères, les microbes, les cellules cancéreuses. Les macrophages pénètrent dans les tissus endommagés par l'endothélium d'un vaisseau sanguin, un processus connu sous le nom d'extravasation de leucocytes. Ce processus ressemble beaucoup à celui qu’on pense être celui de la métastase.

Classical conception of the metastasis process Source: doi: 10.1038 / nri3789

Il est bien connu que les macrophages peuvent contribuer à la croissance et à la progression des cancers. Les macrophages peuvent également influencer positivement et négativement les résultats des traitements anti-cancéreux. Cependant certains agents pathogènes réussissent à vivre même à l'intérieur des macrophages. Cela permet alors à l'agent pathogène d’échapper au système immunitaire. C'est le cas de Mycobacterium tuberculosis ou du VIH.

Les métastases sont responsables de la plupart des décès causés par le cancer. Le Dr Bruns pense qu'à l'heure actuelle, on ne sait pas vraiment comment les métastases se forment. Jusqu'à présent, on a supposé qu'elles se propageaient dans tout le corps via les vaisseaux lymphatiques et la circulation sanguine.

Paradoxalement, les patients cancéreux avec un nombre élevé de macrophages ont une espérance de vie diminuée. Un modèle de souris a démontré que la croissance tumorale s'arrête pratiquement lorsque les macrophages ont été retirés.

Heiko Bruns suppose que les cellules tumorales individuelles sont consommées par les phagocytes, mais ne sont pas nécessairement éliminées par ceux-ci. Au lieu de cela, il soupçonne que les cellules tumorales utilisent les macrophages comme «chevaux de Troie». Elles pourraient ainsi échapper à la détection et voyager à travers le corps pour coloniser d'autres organes.

L’idée du docteur Heiko Bruns a été acceptée au programme de financement «Expérience! A la recherche d'idées de recherche audacieuses 'sur la base de cette question inhabituelle. Il a reçu un financement de 120 000 euros de la Fondation Volkswagen jusqu'à fin 2021. Le projet devrait démarrer au printemps.

It has long been assumed that lifespan and health are strongly correlated, but although there has been an overall increase in human life expectancy in recent decades, it is too often accompanied by deterioration of health.

A new study published on February 26 in Nature shows the influence of two epigenetic regulators on aging. Scientists led by Jie Yuan from the Chinese Academy of Sciences in Shanghai have studied the BAZ-2 and SET-6 proteins in Caenorhabditis elegans worms, which are orthologs of the human proteins BAZ2B and EHMT1.

Through genome-wide RNA-interference-based screening of genes that regulate behavioral deterioration in aging C. elegans, the researchers identified 59 genes as potential health modulators during aging. Essentially the proteins expressed by these genes, read and write epigenetic signals.

Among these modulators, they found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone SET-6, accelerate the deterioration of the behavior of C. elegans by reducing the mitochondrial function, and repressing the expression of the encoded mitochondrial proteins. in the cell nucleus.

The researchers found that the levels of the two proteins increase with age in C. elegans and mice, which in turn attenuates the expression of genes involved in mitochondrial function.

BAZ-2 and SET-6 are complementary epigenetic mechanisms. SET-6 is an "epigenetic writer" and BAZ-2 is an "epigenetic reader" which recognizes modified histones and recruits transcriptional regulators.

Histones are proteins located in the nucleus of eukaryotic cells. They are the main protein components of chromosomes. They are closely associated with DNA and allow their compaction, but they also modify the expression of proteins by various epigenetic mechanisms known as the "histone code".

Source Wikipedia.

How do BAZ-2 and SET-6 accelerate aging? The researchers found that the two proteins bind together to the promoter regions of more than 2,000 genes, and decrease their expression via methylation of histones. Among these target genes are many mitochondrial genes encoded nuclear. By suppressing the expression of these genes, BAZ-2 and SET-6 reduce oxygen consumption and ATP production, and decrease the critical stress responses that maintain mitochondrial proteostasis. The resulting metabolic slowdown discourages the worms from assimilating their food and they mate less.

This mechanism is conserved in the neurons of cultured mice and human cells. What about the orthologs of these epigenetic proteins in humans? A review of the databases shows that expression by human orthologs of the two proteins mentioned above, BAZ2B and EHMT1, increases with age and is positively correlated with the progression of Alzheimer's disease. Researchers have verified that ablation of BAZ-2 mouse ortholog Baz2b attenuates age-dependent body weight gain and prevents cognitive decline in aging mice.

While wild-type mice grew fat with age, animals lacking both copies of the epigenetic reader Baz2b stayed trim, indicating improved mitochondrial function. [Yuan et al., Nature, 2020.]

However, it must be asked whether BAZ-2 and SET-6 would rather mediate age-related physiological adaptation, rather than the agents of aging itself. Indeed their action could reflect a mechanism of adaptation to a progressively more hostile biological environment.

Le syndrome de soins post-intensifs (PICS) décrit un ensemble de troubles qui sont courants chez les patients ayant subis une maladie grave et/ou des soins intensifs. Étant donné que la majorité de la littérature en médecine des soins intensifs se concentre sur les résultats à court terme (par exemple, la survie), la compréhension de l’évolution du malade sur le long terme, est relativement limitée, puisque celui-ci est alors considéré comme étant guéri.

Les troubles cognitifs comprennent des déficits de mémoire, d'attention, de vitesse de traitement mental et de résolution de problèmes. Ces déficiences touchent jusqu'à 80% des personnes ayant éprouvé une maladie grave. Les symptômes de la plupart des patients s'améliorent voire disparaissent complètement au cours de la première année qui suit le traitement en unité de soins intensifs.

La physiopathologie sous-jacente de la déficience cognitive chez les survivants des soins intensifs n'est pas bien comprise, mais une inflammation prolongée peut jouer un rôle important

Il a été montré sur des animaux de laboratoire, que High Mobility Group Box 1 (HMGB1), une protéine libérée dans les lésions tissulaires et au cours d'une inflammation sévère, subsiste à une concentration élevée longtemps après le traumatisme et peut provoquer une inflammation hippocampique et des troubles cognitifs. Source: Life Science Databases(LSDB) via Wikipedia.

Les humains et les autres mammifères ont deux hippocampes, un de chaque côté du cerveau. L'hippocampe fait partie du système limbique. Dans la maladie d'Alzheimer, l'hippocampe est l'une des premières régions du cerveau à subir des dommages; la perte de mémoire à court terme et la désorientation font partie des premiers symptômes. Les personnes atteintes de lésions hippocampiques bilatérales étendues peuvent souffrir d'amnésie antérograde: c'est à dire l'incapacité de former et de conserver de nouveaux souvenirs.

La forme de plasticité neurale connue sous le nom de potentialisation à long terme (LTP) a été initialement découverte dans l'hippocampe et a souvent été étudiée dans cette structure. La LTP est considérée comme l'un des principaux mécanismes neuronaux par lesquels les souvenirs sont stockés dans le cerveau.

Un traitement anti-HMGB1 administré plusieurs jours après une maladie grave peut atténuer le déclin cognitif chez la souris

Des chercheurs du Karolinska Institutet en Suède ont mené une étude de suivi prospective sur 6 mois des taux plasmatiques de HMGB1 et de la fonction cognitive chez les survivants des soins intensifs (essai clinique NCT02914756). 917 patients admis aux soins intensifs ont été dépistés, parmi ceux-ci 100 patients ont été inclus dans l’essai clinique, et ils ont été soumis à des tests de la fonction cognitive et à la mesure des taux plasmatiques de HMGB1 à 3 et 6 mois après la sortie

Les observations ont été effectuées chez ces patients montrent une élévation significative du plasma HMGB1 à 3 et 6 mois après la sortie, et est associée à un dysfonctionnement cognitif.

La source cellulaire de ce HMGB1 systémique est inconnue, mais il est à noter que le HMGB1 est habituellement sécrété par les cellules immunitaires (comme les macrophages, les monocytes et les cellules dendritiques) en tant que médiateur des cytokines de l'inflammation.

Compte tenu de ces propriétés pro-inflammatoires bien établies du HMGB1 extracellulaire, cela suggère une inflammation continue sans résolution de l’inflammation. À la lumière des résultats expérimentaux sur l'atténuation du dysfonctionnement cognitif chez des animaux de laboratoire par la thérapie anti-HMGB1, il est tentant de se demander si le blocage de l'activité pro-inflammatoire du HMGB1 chez les survivants en USI pourrait améliorer les résultats cognitifs.

Post Intensive Care Syndrome (PICS) describes a set of disorders that are common in patients with severe illness and / or intensive care. Since the majority of the literature in intensive care medicine focuses on short-term outcomes (for example, survival), understanding of the patient's long-term development is relatively limited, since the latter is then considered to be healed.

Cognitive impairment includes deficits in memory, attention, speed of mental processing and problem solving. These impairments affect up to 80% of people who have experienced a serious illness. Most patients' symptoms improve or even disappear completely within the first year after treatment in the intensive care unit.

The underlying pathophysiology of cognitive impairment in critical care survivors is not well understood, but prolonged inflammation can play an important role

High Mobility Group Box 1 (HMGB1), a protein released in tissue damage and during severe inflammation, has been shown in laboratory animals to remain in high concentration long after the trauma and can cause inflammation hippocampal and cognitive impairment. Source: Life Science Databases(LSDB) via Wikipedia.

Humans and other mammals have two seahorses, one on each side of the brain. The hippocampus is part of the limbic system. In Alzheimer's disease, the hippocampus is one of the first areas of the brain to be damaged; short-term memory loss and disorientation are among the first symptoms. People with extensive bilateral hippocampal lesions may suffer from anterograde amnesia: the inability to form and retain new memories.

The form of neural plasticity known as long-term potentiation (LTP) was originally discovered in the hippocampus and has often been studied in this structure. LTP is considered to be one of the main neural mechanisms by which memories are stored in the brain.

Anti-HMGB1 treatment given several days after a serious illness can reduce cognitive decline in mice

Researchers at the Karolinska Institutet in Sweden conducted a 6-month prospective follow-up study of HMGB1 plasma levels and cognitive function in survivors of intensive care (clinical trial NCT02914756). 917 patients admitted to intensive care were screened, of which 100 patients were included in the clinical trial, and they were subjected to cognitive function tests and to the measurement of plasma levels of HMGB1 at 3 and 6 months after discharge

The observations were made in these patients show a significant elevation of HMGB1 plasma at 3 and 6 months after discharge, and is associated with cognitive dysfunction.

The cellular source of this systemic HMGB1 is unknown, but it should be noted that HMGB1 is usually secreted by immune cells (such as macrophages, monocytes and dendritic cells) as a mediator of the cytokines of inflammation.

Given these well-established pro-inflammatory properties of extracellular HMGB1, this suggests continued inflammation without resolution of the inflammation. In light of the experimental results on the attenuation of cognitive dysfunction in laboratory animals by anti-HMGB1 therapy, it is tempting to ask whether blocking the pro-inflammatory activity of HMGB1 in ICU survivors could improve cognitive outcomes.

Un approvisionnement adéquat en sang est essentiel au fonctionnement normal du cerveau. D'un autre côté, les déficits du flux sanguin cérébral et le dysfonctionnement de la barrière hémato-encéphalique sont des signes précoces de troubles neurodégénératifs chez l'homme et les modèles animaux.

Un approvisionnement suffisant en sang des 86 milliards de neurones du cerveau humain, est obtenu grâce à un vaste réseau vasculaire bien régulé d'artères, d'artérioles, de capillaires, de veinules et de veines atteignant environ 600 km de longueur. L'activité neuronale déclenche une augmentation de l'approvisionnement régional en sang oxygéné en quelques millisecondes. C'est ce que l'on appelle la réponse hémodynamique ou le couplage reurovasculaire.

Deux nouvelles études décrivent les éléments de la physiologie neurovasculaire qui rendent cet exploit possible. L'un, publié dans Nature le 19 février 2020 et dirigé par Chenghua Gu à la Harvard Medical School, rapporte que les cellules endothéliales qui tapissent les artérioles arborent une myriade d'entrées, appelées cavéoles, qui contrôlent en quelque sorte la dilatation rapide des artérioles en réponse à la stimulation neuronale. L'autre, publié le 20 janvier dans Nature Communications et dirigé par Martin Lauritzen de l'Université de Copenhague, décrit des sphincters spécialisés qui contrôlent le flux sanguin des artérioles du cerveau vers ses vastes lits capillaires.

En plus de la maladie d'Alzheimer, le système vasculaire cérébral a été impliqué dans la pathogenèse de la démence frontotemporale, la maladie de Parkinson, la maladie de Huntington, la sclérose latérale amyotrophique (SLA), la sclérose en plaques et d'autres conditions neurodégénératives telles que le trouble neurocognitif induit par le VIH.

Les patients SLA développent également des déficits de perfusion dans le cortex fronto-pariétal.

Le modèle conventionnel postule que la réponse hémodynamique est médié par des facteurs vasodilatateurs dérivés des neurones qui détendent directement les cellules musculaires lisses artérielles. Pourtant, d'après des travaux récents, il semble que les cellules endothéliales cérébrales puissent également détecter l'activité neuronale. Peut-être alors que les signaux vasodilatateurs agissent d'abord sur les cellules endothéliales cérébrales avant d'être relayés aux cellules musculaires lisses artérielles.

Chow et al. explorent ce potentiel couplage neurovasculaire médiée par les cellules endothéliales cérébrales en adoptant une approche très élégante. Ils se sont concentré sur le cortex somatosensible de souris de laboratoire, où la stimulation des moustaches déclenche de manière fiable l'activité neurale, la dilatation des vaisseaux et le flux sanguin. Ils montrent que la détection classique d’oxyde nitrique dans les cellules musculaires lisses est insuffisante pour un couplage neurovasculaire complet.

Au lieu de cela, les cavéoles enrichies en cellules endothéliales cérébrales artériolaires sont également nécessaires pour un couplage efficace. À l'aide de divers modèles de souris spécifiques au type cellulaire et de gène global de knockout et de surexpression, ils confirment que les cavéoles dans les cellules endothéliales cérébrales – et non les cellules musculaires lisses artérielles - sont nécessaires pour le couplage neurovasculaire.

Ces découvertes inspirent des questions passionnantes pour comprendre la biologie du système vasculaire cérébral en matière de santé, de vieillissement et de maladie.

Quel est le mécanisme par lequel les cavéoles médient le couplage neurovasculaire? Quelles sont les molécules vasodilatatrices spécifiques? Existe-t-il des mécanismes pour engager préférentiellement les cavéoles cellules endothéliales cérébrales par rapport à la voie oxyde nitrique? Comment les changements documentés de l'expression des gènes cellules endothéliales cérébrales avec le vieillissement sont-ils liés au couplage neurovasculaire? Enfin, comment ce modèle évolue-t-il avec la maladie? Par exemple, l'accumulation vasculaire de β-amyloïde dans l'angiopathie amyloïde cérébrale a été corrélée à une perte de cellules musculaires lisses artérielles.

En bref, la présente étude donne un nouvel élan à l'étude de la complexité fascinante du système vasculaire cérébral et, espérons-le, ouvrira la voie à une meilleure compréhension de la façon dont cette structure dégénère avec l'âge et la maladie.

An adequate blood supply is essential for normal brain function. On the other hand, deficits in cerebral blood flow and dysfunction of the blood-brain barrier are early signs of neurodegenerative disorders in humans and animal models.

A sufficient supply of blood from the 86 billion neurons in the human brain is obtained through a large, well-regulated vascular network of arteries, arterioles, capillaries, venules and veins up to approximately 600 km (400 miles) in length. Neural activity triggers an increase in the regional supply of oxygenated blood within milliseconds. This is called either haemodynamic response or reurovascular coupling.

Two new studies describe the elements of neurovascular physiology that make this feat possible. One, published in Nature on February 19, 2020 and edited by Chenghua Gu at Harvard Medical School, reports that the endothelial cells lining the arterioles have a myriad of entries, called caveolae, which somehow control the rapid dilatation of the arterioles in response to neural stimulation. The other, published on January 20 in Nature Communications and directed by Martin Lauritzen of the University of Copenhagen, describes specialized sphincters that control blood flow from arterioles from the brain into its large capillary beds.

In addition to Alzheimer's disease, the cerebrovascular system has been implicated in the pathogenesis of frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis and others neurodegenerative conditions such as HIV-induced neurocognitive disorder.

ALS patients also develop perfusion deficits in the fronto-parietal cortex.

The conventional model postulates that neurovascular coupling is mediated by vasodilator factors derived from neurons that directly relax the arterial smooth muscle cells. However, according to recent work, it seems that brain endothelial cells can also detect neuronal activity. Perhaps then the vasodilator signals first act on the brain endothelial cells before being relayed to the arterial smooth muscle cells.

Chow et al. explore this potential neurovascular coupling mediated by brain endothelial cells by adopting a very elegant approach. They focused on the somatosensory cortex of laboratory mice, where stimulation of the whiskers reliably triggers neural activity, dilated vessels and blood flow. They show that conventional detection of nitric oxide in smooth muscle cells is insufficient for complete neurovascular coupling.

Instead, the caveolae enriched with arteriolar cerebral endothelial cells are also necessary for efficient coupling. Using various cell-type specific mouse models and the overall knockout and overexpression gene, they confirm that the celloles in cerebral endothelial cells - not arterial smooth muscle cells - are necessary for neurovascular coupling.

These discoveries inspire fascinating questions to understand the biology of the cerebrovascular system in terms of health, aging and disease.

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