Intraparenchymal Striatal Transplants Required for Maintenance of Behavioral Recovery in an Animal Model of Huntington's Disease

Rats which receive injections of kainic acid (KA) into the striatum show many of the anatomical, biochemical and behavioral abnormalities seen in patients with Huntington's disease. Recently, it has been reported that fetal striatal transplants into the lesioned striatum could normalize the neurological and behavioral abnormalities produced by the KA lesion. The present study examined the issue of transplant integration in producing behavioral recovery. In one experiment, lesioned animals with transplants located within the lateral ventricle were compared against parenchymally transplanted rats. It was found that unless the ventricular transplant grew into the lesioned striatum there was no recovery. The second experiment demonstrated that electrolytic destruction of a successful fetal striatal transplant could reverse the transplant-induced behavioral recovery. These results suggest that the integrity of the transplant is important in maintaining behavioral recovery. A continuing functional interaction between the host brain and transplanted tissue may be a vital element in the success of the fetal striatal transplant

Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response

IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development

Radial anisotropy in ω Cen limiting the room for an intermediate-mass black hole

Finding an intermediate-mass black hole (IMBH) in a globular cluster (or proving its absence) would provide valuable insights into our understanding of galaxy formation and evolution. However, it is challenging to identify a unique signature of an IMBH that cannot be accounted for by other processes. Observational claims of IMBH detection are indeed often based on analyses of the kinematics of stars in the cluster core, the most common signature being a rise in the velocity dispersion profile towards the centre of the system. Unfortunately, this IMBH signal is degenerate with the presence of radially-biased pressure anisotropy in the globular cluster. To explore the role of anisotropy in shaping the observational kinematics of clusters, we analyse the case of ω Cen by comparing the observed profiles to those calculated from the family of LIMEPY models, that account for the presence of anisotropy in the system in a physicallymotivated way. The best-fit radially anisotropicmodels reproduce the observational profiles well, and describe the central kinematics as derived from Hubble Space Telescope proper motions without the need for an IMBH

A stellar-mass black hole population in the globular cluster NGC 6101?

Dalessandro et al. observed a similar distribution for blue straggler stars and main-sequence turn-off stars in the Galactic globular cluster NGC 6101, and interpreted this feature as an indication that this cluster is not mass-segregated. Using direct N-body simulations, we find that a significant amount of mass segregation is expected for a cluster with the mass, radius and age of NGC 6101. Therefore, the absence of mass segregation cannot be explained by the argument that the cluster is not yet dynamically evolved. By varying the retention fraction of stellar-mass black holes, we show that segregation is not observable in clusters with a high black hole retention fraction (>50 per cent after supernova kicks and >50 per cent after dynamical evolution). Yet all model clusters have the same amount of mass segregation in terms of the decline of the mean mass of stars and remnants with distance to the centre. We also discuss how kinematics can be used to further constrain the presence of a stellar-mass black hole population and distinguish it from the effect of an intermediate-mass black hole. Our results imply that the kick velocities of black holes are lower than those of neutron stars. The large retention fraction during its dynamical evolution can be explained if NGC 6101 formed with a large initial radius in a Milky Way satellite

Mass modelling globular clusters in the Gaia era: a method comparison using mock data from an N-body simulation of M 4

As we enter a golden age for studies of internal kinematics and dynamics of Galactic globular clusters (GCs), it is timely to assess the performance of modelling techniques in recovering the mass, mass profile, and other dynamical properties of GCs. Here, we compare different mass-modelling techniques (distribution-function (DF)-based models, Jeans models, and a grid of N-body models) by applying them to mock observations from a star-by-star N-body simulation of the GCM4 by Heggie. The mocks mimic existing and anticipated data for GCs: surface brightness or number density profiles, local stellar mass functions, line-of-sight velocities, and Hubble Space Telescope- and Gaia-like proper motions. We discuss the successes and limitations of the methods. We find that multimass DF-based models, Jeans, and N-body models provide more accurate mass profiles compared to single-mass DF-based models. We highlight complications in fitting the kinematics in the outskirts due to energetically unbound stars associated with the cluster (“potential escapers”, not captured by truncated DF models nor by N-body models of clusters in isolation), which can be avoided with DF-based models including potential escapers, or with Jeans models. We discuss ways to account for mass segregation. For example, three-component DF-based models with freedom in their mass function are a simple alternative to avoid the biases of single-mass models (which systematically underestimate the total mass, half-mass radius, and central density), while more realistic multimass DF-based models with freedom in the remnant content represent a promising avenue to infer the total mass and the mass function of remnants

New insights from old data - Hunting for compounds with novel mechanisms using cellular high-throughput screening profiles with Grey Chemical Matter

Identifying high quality chemical starting points is a critical and challenging step in drug discovery, which typically involves screening large compound libraries or repurposing of compounds with known mechanisms of actions (MoAs). Here we introduce a novel cheminformatics approach that mines existing large-scale, phenotypic high throughput screening (HTS) data. Our method aims to identify bioactive compounds with distinct and specific MoAs, serving as a valuable complement to existing focused library collections. This approach identifies chemotypes with selectivity across multiple cell-based assays and characterized by persistent and broad structure activity relationships (SAR). We prospectively demonstrate the validity of the approach in broad cellular profiling assays (cell painting, DRUG-seq, Promotor Signature Profiling) and chemical proteomics experiments where the compounds behave similarly to known chemogenetic libraries, but with a bias towards novel protein targets and required no synthetic effort to improve compound properties. A public set of such compounds is provided based on the PubChem BioAssay dataset for use by the scientific community