Amyloid β-peptide directly induces spontaneous calcium transients, delayed intercellular calcium waves and gliosis in rat cortical astrocytes

The contribution of astrocytes to the pathophysiology of AD (Alzheimer's disease) and the molecular and signalling mechanisms that potentially underlie them are still very poorly understood. However, there is mounting evidence that calcium dysregulation in astrocytes may be playing a key role. Intercellular calcium waves in astrocyte networks in vitro can be mechanically induced after Aβ (amyloid β-peptide) treatment, and spontaneously forming intercellular calcium waves have recently been shown in vivo in an APP (amyloid precursor protein)/PS1 (presenilin 1) Alzheimer's transgenic mouse model. However, spontaneous intercellular calcium transients and waves have not been observed in vitro in isolated astrocyte cultures in response to direct Aβ stimulation in the absence of potentially confounding signalling from other cell types. Here, we show that Aβ alone at relatively low concentrations is directly able to induce intracellular calcium transients and spontaneous intercellular calcium waves in isolated astrocytes in purified cultures, raising the possibility of a potential direct effect of Aβ exposure on astrocytes in vivo in the Alzheimer's brain. Waves did not occur immediately after Aβ treatment, but were delayed by many minutes before spontaneously forming, suggesting that intracellular signalling mechanisms required sufficient time to activate before intercellular effects at the network level become evident. Furthermore, the dynamics of intercellular calcium waves were heterogeneous, with distinct radial or longitudinal propagation orientations. Lastly, we also show that changes in the expression levels of the intermediate filament proteins GFAP (glial fibrillary acidic protein) and S100B are affected by Aβ-induced calcium changes differently, with GFAP being more dependent on calcium levels than S100B

The momentum analyticity of two-point correlators from perturbation theory and AdS/CFT

The momentum plane analyticity of two point function of a relativistic thermal field theory at zero chemical potential is explored. A general principle regarding the location of the singularities is extracted. In the case of the N=4 supersymmetric Yang-Mills theory at large $N_c$, a qualitative change in the nature of the singularity (branch points versus simple poles) from the weak coupling regime to the strong coupling regime is observed with the aid of the AdS/CFT correspondence.Comment: 18 pages, 3 figures, typos fixed, 1 figure update

The Spin of Holographic Electrons at Nonzero Density and Temperature

We study the Green's function of a gauge invariant fermionic operator in a strongly coupled field theory at nonzero temperature and density using a dual gravity description. The gravity model contains a charged black hole in four dimensional anti-de Sitter space and probe charged fermions. In particular, we consider the effects of the spin of these probe fermions on the properties of the Green's function. There exists a spin-orbit coupling between the spin of an electron and the electric field of a Reissner-Nordstrom black hole. On the field theory side, this coupling leads to a Rashba like dispersion relation. We also study the effects of spin on the damping term in the dispersion relation by considering how the spin affects the placement of the fermionic quasinormal modes in the complex frequency plane in a WKB limit. An appendix contains some exact solutions of the Dirac equation in terms of Heun polynomials.Comment: 27 pages, 11 figures; v2: minor changes, published versio

Olfactory and solitary chemosensory cells: two different chemosensory systems in the nasal cavity of the American alligator, Alligator mississippiensis

<p>Abstract</p> <p>Background</p> <p>The nasal cavity of all vertebrates houses multiple chemosensors, either innervated by the Ist (olfactory) or the Vth (trigeminal) cranial nerve. Various types of receptor cells are present, either segregated in different compartments (e.g. in rodents) or mingled in one epithelium (e.g. fish). In addition, solitary chemosensory cells have been reported for several species. Alligators which seek their prey both above and under water have only one nasal compartment. Information about their olfactory epithelium is limited. Since alligators seem to detect both volatile and water-soluble odour cues, I tested whether different sensory cell types are present in the olfactory epithelium.</p> <p>Results</p> <p>Electron microscopy and immunocytochemistry were used to examine the sensory epithelium of the nasal cavity of the American alligator. Almost the entire nasal cavity is lined with olfactory (sensory) epithelium. Two types of olfactory sensory neurons are present. Both types bear cilia as well as microvilli at their apical endings and express the typical markers for olfactory neurons. The density of these olfactory neurons varies along the nasal cavity. In addition, solitary chemosensory cells innervated by trigeminal nerve fibres, are intermingled with olfactory sensory neurons. Solitary chemosensory cells express components of the PLC-transduction cascade found in solitary chemosensory cells in rodents.</p> <p>Conclusion</p> <p>The nasal cavity of the American alligator contains two different chemosensory systems incorporated in the same sensory epithelium: the olfactory system proper and solitary chemosensory cells. The olfactory system contains two morphological distinct types of ciliated olfactory receptor neurons.</p

VIP Enhances Phagocytosis of Fibrillar Beta-Amyloid by Microglia and Attenuates Amyloid Deposition in the Brain of APP/PS1 Mice

Vasoactive intestinal peptide (VIP) is a multifunctional neuropeptide with demonstrated immunosuppressive and neuroprotective activities. It has been shown to inhibit Amyloid beta (Aβ)-induced neurodegeneration by indirectly suppressing the production and release of a variety of inflammatory and neurotoxic factors by activated microglia. We demonstrated that VIP markedly increased microglial phagocytosis of fibrillar Aβ42 and that this enhanced phagocytotic activity depended on activation of the Protein kinase C (PKC) signaling pathway. In addition, VIP suppressed the release of tumor necrosis factor alpha (TNF-α) and nitric oxide(NO) from microglia activated by combined treatment with fibrillar Aβ42 and low dose interferon-γ (IFN-γ). We utilized an adenovirus-mediated gene delivery method to overexpress VIP constitutively in the hippocampus of APPswPS1 transgenic mice. The Aβ load was significantly reduced in the hippocampus of this animal model of Alzheimer's disease, possibly due to the accumulation and activation of cd11b-immunoactive microglial cells. The modulation of microglial activation, phagocytosis, and secretion by VIP is a promising therapeutic option for the treatment of Alzheimer's disease(AD)

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

\ua9 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations