Analysis of Adhesion Molecules and Basement Membrane Contributions to Synaptic Adhesion at the Drosophila Embryonic NMJ

Synapse formation and maintenance crucially underlie brain function in health and disease. Both processes are believed to depend on cell adhesion molecules (CAMs). Many different classes of CAMs localise to synapses, including cadherins, protocadherins, neuroligins, neurexins, integrins, and immunoglobulin adhesion proteins, and further contributions come from the extracellular matrix and its receptors. Most of these factors have been scrutinised by loss-of-function analyses in animal models. However, which adhesion factors establish the essential physical links across synaptic clefts and allow the assembly of synaptic machineries at the contact site in vivo is still unclear. To investigate these key questions, we have used the neuromuscular junction (NMJ) of Drosophila embryos as a genetically amenable model synapse. Our ultrastructural analyses of NMJs lacking different classes of CAMs revealed that loss of all neurexins, all classical cadherins or all glutamate receptors, as well as combinations between these or with a Laminin deficiency, failed to reveal structural phenotypes. These results are compatible with a view that these CAMs might have no structural role at this model synapse. However, we consider it far more likely that they operate in a redundant or well buffered context. We propose a model based on a multi-adaptor principle to explain this phenomenon. Furthermore, we report a new CAM-independent adhesion mechanism that involves the basement membranes (BM) covering neuromuscular terminals. Thus, motorneuronal terminals show strong partial detachment of the junction when BM-to-cell surface attachment is impaired by removing Laminin A, or when BMs lose their structural integrity upon loss of type IV collagens. We conclude that BMs are essential to tie embryonic motorneuronal terminals to the muscle surface, lending CAM-independent structural support to their adhesion. Therefore, future developmental studies of these synaptic junctions in Drosophila need to consider the important contribution made by BM-dependent mechanisms, in addition to CAM-dependent adhesion

Intrafollicular growth differentiation factor 9: Bone morphogenetic 15 ratio determines litter size in mammals

We previously showed that rat, pig, sheep, and red deer oocytes express species-specific ratios of GDF9: BMP15 mRNA (3.7, 0.5, 1.26, and 0.1, respectively), and with the exception of the pig, they are directly correlated to litter size. The purpose of this study was to determine the alternative mechanism that enables pig oocytes to secrete low ratios whilst maintaining a large litter size. Herein, we performed same-and cross-species coincubations of oocytes with granulosa cells (GCs) of rat, pig, sheep, and red deer to compare the proliferation rate, mRNA expression levels of growth factor receptors, and downstream signalling pathways in GCs. A decreased proliferation rate, lower Bmpr1b and Bmpr2 mRNA expression levels, and higher SMAD1/5/8 protein levels were exhibited in rat GCs cocultured with red deer oocytes, compared to all other species. Pig GCs unequivocally expressed GDF9 mRNA, suggesting that, similar to rat GCs, the proliferation of pig GCs is regulated mainly by GDF9, despite lower intraoocyte expression of GDF9 mRNA. In support, a higher basal proliferation, and their ability to proliferate readily when coincubated with red deer oocytes, was observed in pig GCs. In contrast, red deer GC proliferation is likely to be mainly regulated by BMP15 in vivo with only red deer oocytes capable of altering SMAD1/5/8 and pSMAD2/3 levels, while both GDF9 and BMP15 appear important for sheep GC proliferation. In summary, this study strengthens our hypothesis that the ratio of GDF9: BMP15 in the intrafollicular milieu is directly correlated with litter size, and that the GCs of each species have evolved to respond to these unique ratios

Extracting the speed of sound in the strongly interacting matter created in ultrarelativistic lead-lead collisions at the LHC

International audienceUltrarelativistic nuclear collisions create a strongly interacting state of hot and dense quark-gluon matter that exhibits a remarkable collective flow behavior with minimal viscous dissipation. To gain deeper insights into its intrinsic nature and fundamental degrees of freedom, we extracted the speed of sound in this medium created using lead-lead (PbPb) collisions at a center-of-mass energy per nucleon pair of 5.02 TeV. The data were recorded by the CMS experiment at the CERN LHC and correspond to an integrated luminosity of 0.607 nb$^{-1}$. The measurement is performed by studying the multiplicity dependence of the average transverse momentum of charged particles emitted in head-on PbPb collisions. Our findings reveal that the speed of sound in this matter is nearly half the speed of light, with a squared value of 0.241 $\pm$ 0.002 (stat) $\pm$ 0.016 (syst) in natural units. The effective medium temperature, estimated using the mean transverse momentum, is 219 $\pm$ 8 (syst) MeV. The measured squared speed of sound at this temperature aligns precisely with predictions from lattice quantum chromodynamic (QCD) calculations. This result provides a stringent constraint on the equation of state of the created medium and direct evidence for a deconfined QCD phase being attained in relativistic nuclear collisions

Identification of common variants associated with human hippocampal and intracranial volumes

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease1, 2 and is reduced in schizophrenia3, major depression4 and mesial temporal lobe epilepsy5. Whereas many brain imaging phenotypes are highly heritable6, 7, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7)