A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia

Loss‐of‐function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC‐derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC‐microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β‐Amyloid phagocytosis. These findings have ramifications for microglial focussed‐treatments in AD

Strangeness in the nucleon and the ratio of proton-to-neutron neutrino-induced quasi-elastic yield

The electroweak form factors of the nucleon as obtained within a three flavor pseudoscalar vector meson soliton model are employed to predict the ratio of the proton and neutron yields from $^{12}C$, which are induced by quasi-elastic neutrino reactions. These predictions are found to vary only moderately in the parameter space allowed by the model. The antineutrino flux of the up-coming experiment determining this ratio was previously overestimated. The corresponding correction is shown to have only a small effect on the predicted ratio. However, it is found that the experimental result for the ratio crucially depends on an accurate measurement of the energy of the knocked out nucleon.Comment: 17 pages, LaTeX, 2 tables, 4 figures, Discussion on shape of strange form factors added, Z. Phys. A, to be publishe

Populating the swampland: the case of U(1)^496 and E_8 x U(1)^248

For d=10 N=1 SUGRA coupled to d=10 N=1 SYM, anomaly cancellation places severe constraints on the allowed gauge groups. Besides the ones known to appear in string theory, only U(1)^496 and E_8 x U(1)^248 are allowed. There are no known theories of quantum gravity that reduce in some limit to these two last supergravity theories, and in this note I present some evidence that those quantum theories might not exist. The first observation is that, upon compactification, requring that the quantum theory possesses a moduli space with finite volume typically implies the existence of singularities where the 4d gauge group is enhanced, but for these two theories that gauge enhancement is problematic from the 10d point of view. I also point out that while these four supergravity theories present repulson-type singularities, the known mechanism that repairs those singularities for the first two - the non-Abelian enhancon - is not available for the last two theories. In short, these two supergravity theories might be too Abelian for their own good.Comment: 12 page

The entropy of black holes: a primer

After recalling the definition of black holes, and reviewing their energetics and their classical thermodynamics, one expounds the conjecture of Bekenstein, attributing an entropy to black holes, and the calculation by Hawking of the semi-classical radiation spectrum of a black hole, involving a thermal (Planckian) factor. One then discusses the attempts to interpret the black-hole entropy as the logarithm of the number of quantum micro-states of a macroscopic black hole, with particular emphasis on results obtained within string theory. After mentioning the (technically cleaner, but conceptually more intricate) case of supersymmetric (BPS) black holes and the corresponding counting of the degeneracy of Dirichlet-brane systems, one discusses in some detail the ``correspondence'' between massive string states and non-supersymmetric Schwarzschild black holes.Comment: 51 pages, 4 figures, talk given at the "Poincare seminar" (Paris, 6 December 2003), to appear in Poincare Seminar 2003 (Birkhauser

Complement-Mediated Virus Infectivity Neutralisation by HLA Antibodies Is Associated with Sterilising Immunity to SIV Challenge in the Macaque Model for HIV/AIDS.

Sterilising immunity is a desired outcome for vaccination against human immunodeficiency virus (HIV) and has been observed in the macaque model using inactivated simian immunodeficiency virus (SIV). This protection was attributed to antibodies specific for cell proteins including human leucocyte antigens (HLA) class I and II incorporated into virions during vaccine and challenge virus preparation. We show here, using HLA bead arrays, that vaccinated macaques protected from virus challenge had higher serum antibody reactivity compared with non-protected animals. Moreover, reactivity was shown to be directed against HLA framework determinants. Previous studies failed to correlate serum antibody mediated virus neutralisation with protection and were confounded by cytotoxic effects. Using a virus entry assay based on TZM-bl cells we now report that, in the presence of complement, serum antibody titres that neutralise virus infectivity were higher in protected animals. We propose that complement-augmented virus neutralisation is a key factor in inducing sterilising immunity and may be difficult to achieve with HIV/SIV Env-based vaccines. Understanding how to overcome the apparent block of inactivated SIV vaccines to elicit anti-envelope protein antibodies that effectively engage the complement system could enable novel anti-HIV antibody vaccines that induce potent, virolytic serological response to be developed

Joint PDF modelling of turbulent flow and dispersion in an urban street canyon

The joint probability density function (PDF) of turbulent velocity and concentration of a passive scalar in an urban street canyon is computed using a newly developed particle-in-cell Monte Carlo method. Compared to moment closures, the PDF methodology provides the full one-point one-time PDF of the underlying fields containing all higher moments and correlations. The small-scale mixing of the scalar released from a concentrated source at the street level is modelled by the interaction by exchange with the conditional mean (IECM) model, with a micro-mixing time scale designed for geometrically complex settings. The boundary layer along no-slip walls (building sides and tops) is fully resolved using an elliptic relaxation technique, which captures the high anisotropy and inhomogeneity of the Reynolds stress tensor in these regions. A less computationally intensive technique based on wall functions to represent boundary layers and its effect on the solution are also explored. The calculated statistics are compared to experimental data and large-eddy simulation. The present work can be considered as the first example of computation of the full joint PDF of velocity and a transported passive scalar in an urban setting. The methodology proves successful in providing high level statistical information on the turbulence and pollutant concentration fields in complex urban scenarios.Comment: Accepted in Boundary-Layer Meteorology, Feb. 19, 200

Measurement of the antineutrino neutral-current elastic differential cross section

arXiv:1309.7257v1 [hep-ex

Amyloid in the islets of Langerhans: Thoughts and some historical aspects

Deposition of amyloid, derived from the polypeptide hormone islet amyloid polypeptide (IAPP; ‘amylin’) is the single most typical islet alteration in type 2 diabetes. Islet amyloid was described as hyalinization already in 1901, but not until 1986 was it understood that it is a polymerization product of a novel β-cell regulatory product. The subject of this focused review deals with the pathogenesis and importance of the islet amyloid itself, not with the biological effect of the polypeptide. Similar to the situation in Alzheimer's disease, it has been argued that the amyloid may not be of importance since there is no strict correlation between the degree of islet amyloid infiltration and the disease. However, it is hardly discussable that the amyloid is important in subjects where islets have been destroyed by pronounced islet amyloid deposits. Even when there is less islet amyloid the deposits are widely spread, and β-cells show ultrastructural signs of cell membrane destruction. It is suggested that type 2 diabetes is heterogeneous and that in one major subtype aggregation of IAPP into amyloid fibrils is determining the progressive loss of β-cells. Interestingly, development of islet amyloid may be an important event in the loss of β-cell function after islet transplantation into type 1 diabetic subjects