Bardet-Biedl Syndrome ciliopathy is linked to altered hematopoiesis and dysregulated self-tolerance

Bardet–Biedl Syndrome (BBS) is a pleiotropic genetic disease caused by the dysfunction of primary cilia. The immune system of patients with ciliopathies has not been investigated. However, there are multiple indications that the impairment of the processes typically associated with cilia may have influence on the hematopoietic compartment and immunity. In this study, we analyze clinical data of BBS patients and corresponding mouse models carrying mutations in Bbs4 or Bbs18. We find that BBS patients have a higher prevalence of certain autoimmune diseases. Both BBS patients and animal models have altered red blood cell and platelet compartments, as well as elevated white blood cell levels. Some of the hematopoietic system alterations are associated with BBS‐induced obesity. Moreover, we observe that the development and homeostasis of B cells in mice is regulated by the transport complex BBSome, whose dysfunction is a common cause of BBS. The BBSome limits canonical WNT signaling and increases CXCL12 levels in bone marrow stromal cells. Taken together, our study reveals a connection between a ciliopathy and dysregulated immune and hematopoietic systems

The event generator DECAY4 for simulation of double beta processes and decay of radioactive nuclei

The computer code DECAY4 is developed to generate initial energy, time and angular distributions of particles emitted in radioactive decays of nuclides and nuclear (atomic) deexcitations. Data for description of nuclear and atomic decay schemes are taken from the ENSDF and EADL database libraries. The examples of use of the DECAY4 code in several underground experiments are described.Comment: 8 pages, 1 fi

A unifying mathematical framework for experimental TCR-pMHC kinetic constants

Receptor binding and triggering are central in Immunology as T cells activated through their T cell receptors (TCR) by protein antigens orchestrate immune responses. In order to understand receptor-ligand interactions, many groups working with different experimental techniques and assays have generated a vast body of knowledge during the last decades. However, in recent years a type of assays, referred to as two-dimensional or membrane-to-membrane, has questioned our current understanding of the role of different kinetic constants (for instance, on- versus off-rate constants) on TCR-ligand interaction and subsequent T cell activation. Here we present a general mathematical framework that provides a unifying umbrella to relate fundamental and effective (or experimentally determined) kinetic constants, as well as describe and compare state-of-the-art experimental methods. Our framework is able to predict the correlations between functional output, such as 1/EC50, and effective kinetic constants for a range of different experimental assays (in two and three dimensions). Furthermore, our approach can be applied beyond Immunology, and serve as a “translation method” for the biochemical characterization of receptor-ligand interactions

Natural Changes in Brain Temperature Underlie Variations in Song Tempo during a Mating Behavior

The song of a male zebra finch is a stereotyped motor sequence whose tempo varies with social context – whether or not the song is directed at a female bird – as well as with the time of day. The neural mechanisms underlying these changes in tempo are unknown. Here we show that brain temperature recorded in freely behaving male finches exhibits a global increase in response to the presentation of a female bird. This increase strongly correlates with, and largely explains, the faster tempo of songs directed at a female compared to songs produced in social isolation. Furthermore, we find that the observed diurnal variations in song tempo are also explained by natural variations in brain temperature. Our findings suggest that brain temperature is an important variable that can influence the dynamics of activity in neural circuits, as well as the temporal features of behaviors that some of these circuits generate

Paternal Origins and Migratory Episodes of Domestic Sheep

Deng et al. show that domestic sheep harbor four Y chromosome lineages and early expansions of sheep were associated with the segregation of primitive and fat-tailed phenotypes as well as traits selected for different purposes

Synthesis and solution properties of a temperature-responsive PNIPAM–b-PDMS–b-PNIPAM triblock copolymer

In this paper, we report the synthesis and self-assembly of a novel thermoresponsive PNIPAM60–b-PDMS70–b-PNIPAM60 triblock copolymer in aqueous solution. The copolymer used a commercially available precursor modified with an atom transfer radical polymerization (ATRP) initiator to produce an ABA triblock copolymer via ATRP. Small-angle neutron scattering (SANS) was used to shed light on the structures of nanoparticles formed in aqueous solutions of this copolymer at two temperatures, 25 and 40 °C. The poly(dimethylsiloxane) block is very hydrophobic and poly(N-isopropylacrylamide) (PNIPAM) is thermoresponsive. SANS data at 25 °C indicates that the solutions of PNIPAM–b-PDMS–b-PNIPAM copolymers form well-defined aggregates with presumably core–shell structures below cloud point temperature. The scattering curves originating from nanoparticles formed at 40 °C in 100% D2O or 100% H2O were successfully fitted with the Beaucage model describing aggregates with hierarchical structure

Minimalism in Radiation Synthesis of Biomedical Functional Nanogels

A scalable, single-step, synthetic approach for the manufacture of biocompatible, functionalized micro- and nanogels is presented. In particular, poly(N-vinyl pyrrolidone)-grafted-(aminopropyl)methacrylamide microgels and nanogels were generated through e-beam irradiation of PVP aqueous solutions in the presence of a primary amino-group-carrying monomer. Particles with different hydrodynamic diameters and surface charge densities were obtained at the variance of the irradiation conditions. Chemical structure was investigated by different spectroscopic techniques. Fluorescent variants were generated through fluorescein isothiocyanate attachment to the primary amino groups grafted to PVP, to both quantify the available functional groups for bioconjugation and follow nanogels localization in cell cultures. Finally, a model protein, bovine serum albumin, was conjugated to the nanogels to demonstrate the attachment of biologically relevant molecules for targeting purposes in drug delivery. The described approach provides a novel strategy to fabricate biohybrid nanogels with a very promising potential in nanomedicine

Encoding optical control in LCK kinase to quantitatively investigate its activity in live cells.

LCK is a tyrosine kinase that is essential for initiating T-cell antigen receptor (TCR) signaling. A complete understanding of LCK function is constrained by a paucity of methods to quantitatively study its function within live cells. To address this limitation, we generated LCK*, in which a key active-site lysine is replaced by a photocaged equivalent, using genetic code expansion. This strategy enabled fine temporal and spatial control over kinase activity, thus allowing us to quantify phosphorylation kinetics in situ using biochemical and imaging approaches. We find that autophosphorylation of the LCK active-site loop is indispensable for its catalytic activity and that LCK can stimulate its own activation by adopting a more open conformation, which can be modulated by point mutations. We then show that CD4 and CD8, T-cell coreceptors, can enhance LCK activity, thereby helping to explain their effect in physiological TCR signaling. Our approach also provides general insights into SRC-family kinase dynamics