Revisiting Metchnikoff: Age-related alterations in microbiota-gut-brain axis in the mouse

Over the last decade, there has been increased interest in the role of the gut microbiome in health including brain health. This is by no means a new theory; Elie Metchnikoff proposed over a century ago that targeting the gut by consuming lactic acid bacteria such as those in yogurt, could improve or delay the onset of cognitive decline associated with ageing. However, there is limited information characterising the relationship between the behavioural and physiological sequelae of ageing and alterations in the gut microbiome. To this end, we assessed the behavioural, physiological and caecal microbiota profile of aged male mice. Older mice (20–21 months old) exhibited deficits in spatial memory and increases in anxiety-like behaviours compared to younger mice (2–3 months old). They also exhibited increased gut permeability, which was directly correlated with elevations in peripheral pro-inflammatory cytokines. Furthermore, stress exacerbated the gut permeability of aged mice. Examination of the caecal microbiota revealed significant increases in phylum TM7, family Porphyromonadaceae and genus Odoribacter of aged mice. This represents a shift of aged microbiota towards a profile previously associated with inflammatory disease, particularly gastrointestinal and liver disorders. Furthermore, Porphyromonadaceae, which has also been associated with cognitive decline and affective disorders, was directly correlated with anxiety-like behaviour in aged mice. These changes suggest that changes in the gut microbiota and associated increases in gut permeability and peripheral inflammation may be important mediators of the impairments in behavioural, affective and cognitive functions seen in ageing

Multimodality imaging in takotsubo syndrome : a joint consensus document of the European Association of Cardiovascular Imaging (EACVI) and the Japanese Society of Echocardiography (JSE)

This article is co-published in the journals the European Heart Journal—Cardiovascular Imaging https://doi.org/10.1093/ehjci/jeaa149 and Journal of Echocardiography https://doi.org/10.1007/s12574-020-00480-y.Peer reviewedPublisher PD

Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD

Cirene : air-sea iInteractions in the Seychelles-Chagos thermocline ridge region

Author Posting. © American Meteorological Society, 2009. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 90 (2009): 1337-1350, doi:10.1175/2008BAMS2499.1.The Vasco—Cirene program ex-plores how strong air—sea inter-actions promoted by the shallow thermocline and high sea surface temperature in the Seychelles—Chagos thermocline ridge results in marked variability at synoptic, intraseasonal, and interannual time scales. The Cirene oceano-graphic cruise collected oceanic, atmospheric, and air—sea flux observations in this region in Jan-uary—February 2007. The contem-poraneous Vasco field experiment complemented these measure-ments with balloon deployments from the Seychelles. Cirene also contributed to the development of the Indian Ocean observing system via deployment of a moor-ing and 12 Argo profilers. Unusual conditions prevailed in the Indian Ocean during Janu-ary and February 2007, following the Indian Ocean dipole climate anomaly of late 2006. Cirene measurements show that the Seychelles—Chagos thermocline ridge had higher-than-usual heat content with subsurface anomalies up to 7°C. The ocean surface was warmer and fresher than average, and unusual eastward currents prevailed down to 800 m. These anomalous conditions had a major impact on tuna fishing in early 2007. Our dataset also sampled the genesis and maturation of Tropical Cyclone Dora, including high surface temperatures and a strong diurnal cycle before the cyclone, followed by a 1.5°C cool-ing over 10 days. Balloonborne instruments sampled the surface and boundary layer dynamics of Dora. We observed small-scale structures like dry-air layers in the atmosphere and diurnal warm layers in the near-surface ocean. The Cirene data will quantify the impact of these finescale features on the upper-ocean heat budget and atmospheric deep convection.CNES funded the Vasco part of the experiment; INSU funded the Cirene part. R/V Suroît is an Ifremer ship. The contributions from ODU, WHOI, and FOI (Sweden) are supported by the National Science Foundation under Grant Number 0525657. The participation of the University of Miami group was funded though NASA (NNG04HZ33C). PMEL participation was supported through NOAA’s Office of Climate Observation

PI3K(p110 alpha) Protects Against Myocardial Infarction-Induced Heart Failure Identification of PI3K-Regulated miRNA and mRNA

Objective: Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110α)] is considered a new strategy for the treatment o

Force-length recording of eye muscles during local-anesthesia surgery in 32 strabismus patients

Abstract. Force-length recordings were made from isolated human eye muscles during strabismus surgery in local, eye-drop anesthesia in 32 adult patients. From each muscle three recordings were made: (1) while the patient looked with the other eye into the field of action of the recorded muscle, (2) looked ahead, and (3) looked out of the field of action of the recorded muscle. Non-innervated eye muscles (state 3) had an approximately exponential relation between force and length. During contraction evoked by letting the patient look ahead or into the field of action of the muscle (states I or 2), the relation between force and length was grossly linear. The approximate spring constants of horizontal rectus muscles that had not been operated on before ranged from 2 to 4 g/mm. In palsies, the degree of muscle paresis could be quantified accurately using this method and, accordingly, cases of true superior oblique palsy could be well differentiated from strabismus sursoadductorius (= upshoot in adduction) that may mimic a superior oblique palsy. In seven patients with Graves' disease of recent onset, affected muscles were found to be very stiff when the other eye looked ahead. It was expected that these stiff muscles would be able to shorten to some extent but would not be able to lengthen, due to fibrosis of the muscle. We found, however, that the affected muscles lengthened considerably when the other eye looked out of the field of action of the muscle. This implies that, in these cases of Graves' disease of recent onset, the raised muscle tension and reduced elasticity of the affected muscles and, hence, the strabismus were primarily caused by active muscle contraction, not by fibrosis

Spherical Lactic Acid Bacteria Activate Plasmacytoid Dendritic Cells Immunomodulatory Function via TLR9-Dependent Crosstalk with Myeloid Dendritic Cells

Plasmacytoid dendritic cells (pDC) are a specialized sensor of viral and bacterial nucleic acids and a major producer of IFN-α that promotes host defense by priming both innate and acquired immune responses. Although synthetic Toll-like receptor (TLR) ligands, pathogenic bacteria and viruses activate pDC, there is limited investigation of non-pathogenic microbiota that are in wide industrial dietary use, such as lactic acid bacteria (LAB). In this study, we screened for LAB strains, which induce pDC activation and IFN-α production using murine bone marrow (BM)-derived Flt-3L induced dendritic cell culture. Microbial strains with such activity on pDC were absent in a diversity of bacillary strains, but were observed in certain spherical species (Lactococcus, Leuconostoc, Streptococcus and Pediococcus), which was correlated with their capacity for uptake by pDC. Detailed study of Lactococcus lactis subsp. lactis JCM5805 and JCM20101 revealed that the major type I and type III interferons were induced (IFN-α, -β, and λ). IFN-α induction was TLR9 and MyD88-dependent; a slight impairment was also observed in TLR4-/- cells. While these responses occurred with purified pDC, IFN-α production was synergistic upon co-culture with myeloid dendritic cells (mDC), an interaction that required direct mDC-pDC contact. L. lactis strains also stimulated expression of immunoregulatory receptors on pDC (ICOS-L and PD-L1), and accordingly augmented pDC induction of CD4+CD25+FoxP3+ Treg compared to the Lactobacillus strain. Oral administration of L. lactis JCM5805 induced significant activation of pDC resident in the intestinal draining mesenteric lymph nodes, but not in a remote lymphoid site (spleen). Taken together, certain non-pathogenic spherical LAB in wide dietary use has potent and diverse immunomodulatory effects on pDC potentially relevant to anti-viral immunity and chronic inflammatory disease

MAP Kinase Pathways in Brain Endothelial Cells and Crosstalk with Pericytes and Astrocytes Mediate Contrast-Induced Blood–Brain Barrier Disruption

Neurointervention with contrast media (CM) has rapidly increased, but the impact of CM extravasation and the related side effects remain controversial. This study investigated the effect of CM on blood–brain barrier (BBB) integrity. We established in vitro BBB models using primary cultures of rat BBB-related cells. To assess the effects of CM on BBB functions, we evaluated transendothelial electrical resistance, permeability, and tight junction (TJ) protein expression using immunohistochemistry (IHC) and Western blotting. To investigate the mechanism of iopamidol-induced barrier dysfunction, the role of mitogen-activated protein (MAP) kinases in brain endothelial cells was examined. We assessed the effect of conditioned medium derived from astrocytes and pericytes under iopamidol treatment. Short-term iopamidol exposure on the luminal side induced transient, while on the abluminal side caused persistent BBB dysfunction. IHC and immunoblotting revealed CM decreased the expression of TJ proteins. Iopamidol-induced barrier dysfunction was improved via the regulation of MAP kinase pathways. Conditioned medium from CM-exposed pericytes or astrocytes lacks the ability to enhance barrier function. CM may cause BBB dysfunction. MAP kinase pathways in brain endothelial cells and the interactions of astrocytes and pericytes mediate iopamidol-induced barrier dysfunction. CM extravasation may have negative effects on clinical outcomes in patients

The role of potential vorticity anomalies in the Somali Jet on Indian summer monsoon intraseasonal variability

The climate of the Indian subcontinent is dominated by rainfall arising from the Indian summer monsoon (ISM) during the summer season (June to September). Intraseasonal variability during the monsoon is characterized by periods of heavy rainfall interspersed by drier periods, known as active and break events respectively. Understanding and predicting such events is of vital importance for forecasting human impacts such as water resources. The Somali Jet is a key regional feature of this circulation. In the present study, we find that the spatial structure of Somali Jet potential vorticity (PV) anomalies varies considerably during active and break periods. Analysis of these anomalies shows a mechanism whereby sea surface temperature (SST) anomalies propagate north/northwestwards through the Arabian Sea, caused by a positive feedback loop joining anomalies in SST, convection, modification of PV by diabatic heating and mixing in the atmospheric boundary layer, wind stress curl, and upwelling processes. The feedback mechanism is consistent with observed coupled ocean-atmosphere system variability timescales of approximately 20 days. This research suggests that better understanding and prediction of monsoon subseasonal variability in the South Asian monsoon may be gained by analysis of the day-to-day dynamical evolution of PV in the Somali Jet