The evolution and comparative neurobiology of endocannabinoid signalling

CB(1)- and CB(2)-type cannabinoid receptors mediate effects of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide in mammals. In canonical endocannabinoid-mediated synaptic plasticity, 2-AG is generated postsynaptically by diacylglycerol lipase alpha and acts via presynaptic CB(1)-type cannabinoid receptors to inhibit neurotransmitter release. Electrophysiological studies on lampreys indicate that this retrograde signalling mechanism occurs throughout the vertebrates, whereas system-level studies point to conserved roles for endocannabinoid signalling in neural mechanisms of learning and control of locomotor activity and feeding. CB(1)/CB(2)-type receptors originated in a common ancestor of extant chordates, and in the sea squirt Ciona intestinalis a CB(1)/CB(2)-type receptor is targeted to axons, indicative of an ancient role for cannabinoid receptors as axonal regulators of neuronal signalling. Although CB(1)/CB(2)-type receptors are unique to chordates, enzymes involved in biosynthesis/inactivation of endocannabinoids occur throughout the animal kingdom. Accordingly, non-CB(1)/CB(2)-mediated mechanisms of endocannabinoid signalling have been postulated. For example, there is evidence that 2-AG mediates retrograde signalling at synapses in the nervous system of the leech Hirudo medicinalis by activating presynaptic transient receptor potential vanilloid-type ion channels. Thus, postsynaptic synthesis of 2-AG or anandamide may be a phylogenetically widespread phenomenon, and a variety of proteins may have evolved as presynaptic (or postsynaptic) receptors for endocannabinoids

Human umbilical cord blood-borne fibroblasts contain marrow niche precursors that form a bone/marrow organoid in vivo

Human umbilical cord blood (CB) has attracted much attention as a reservoir for functional hematopoietic stem and progenitor cells, and, recently, as a source of blood-borne fibroblasts (CB-BFs). Previously, we demonstrated that bone marrow stromal cell (BMSC) and CB-BF pellet cultures make cartilage in vitro. Furthermore, upon in vivo transplantation, BMSC pellets remodelled into miniature bone/marrow organoids. Using this in vivo model, we asked whether CB-BF populations that express characteristics of the hematopoietic stem cell (HSC) niche contain precursors that reform the niche. CB ossicles were regularly observed upon transplantation. Compared with BM ossicles, CB ossicles showed a predominance of red marrow over yellow marrow, as demonstrated by histomorphological analyses and the number of hematopoietic cells isolated within ossicles. Marrow cavities from CB and BM ossicles included donor-derived CD146-expressing osteoprogenitors and host-derived mature hematopoietic cells, clonogenic lineage-committed progenitors and HSCs. Furthermore, human CD34+ cells transplanted into ossicle-bearing mice engrafted and maintained human HSCs in the niche. Our data indicate that CB- BFs are able to recapitulate the conditions by which the bone marrow microenvironment is formed and establish complete HSC niches, which are functionally supportive of hematopoietic tissue

Identifying Transiting Circumbinary Planets

Transiting planets manifest themselves by a periodic dimming of their host star by a fixed amount. On the other hand, light curves of transiting circumbinary (CB) planets are expected to be neither periodic nor to have a single depth while in transit, making BLS [Kovacs et al. 2002] almost ineffective. Therefore, a modified version for the identification of CB planets was developed - CB-BLS. We show that using CB-BLS it is possible to find CB planets in the residuals of light curves of eclipsing binaries (EBs) that have noise levels of 1% or more. Using CB-BLS will allow to easily harness the massive ground- and space- based photometric surveys to look for these objects. Detecting transiting CB planets is expected to have a wide range of implications, for e.g.: The frequency of CB planets depend on the planetary formation mechanism - and planets in close pairs of stars provides a most restrictive constraint on planet formation models. Furthermore, understanding very high precision light curves is limited by stellar parameters - and since for EBs the stellar parameters are much better determined, the resultant planetary structure models will have significantly smaller error bars, maybe even small enough to challenge theory.Comment: To appear on the IAU Symposium 253 proceedings. 4 pages, 4 figure

Cerebellum to motor cortex paired associative stimulation induces bidirectional STDP-like plasticity in human motor cortex

The cerebellum is crucially important for motor control and adaptation. Recent non-invasive brain stimulation studies have indicated the possibility to alter the excitability of the cerebellum and its projections to the contralateral motor cortex, with behavioral consequences on motor control and adaptation. Here we sought to induce bidirectional spike-timing dependent plasticity (STDP)-like modifications of motor cortex (M1) excitability by application of paired associative stimulation (PAS) in healthy subjects. Conditioning stimulation over the right lateral cerebellum (CB) preceded focal transcranial magnetic stimulation (TMS) of the left M1 hand area at an interstimulus interval of 2 ms (CB→M1 PAS(2 ms)), 6 ms (CB→M1 PAS(6 ms)) or 10 ms (CB→M1 PAS(10 ms)) or randomly alternating intervals of 2 and 10 ms (CB→M1 PAS(Control)). Effects of PAS on M1 excitability were assessed by the motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cerebellar-motor cortex inhibition (CBI) in the first dorsal interosseous muscle of the right hand. CB→M1 PAS(2 ms) resulted in MEP potentiation, CB→M1 PAS(6 ms) and CB→M1 PAS(10 ms) in MEP depression, and CB→M1 PAS(Control) in no change. The MEP changes lasted for 30-60 min after PAS. SICI and CBI decreased non-specifically after all PAS protocols, while ICF remained unaltered. The physiological mechanisms underlying these MEP changes are carefully discussed. Findings support the notion of bidirectional STDP-like plasticity in M1 mediated by associative stimulation of the cerebello-dentato-thalamo-cortical pathway and M1. Future studies may investigate the behavioral significance of this plasticity

Mesoscopic Coulomb Blockade in One-channel Quantum Dots

Signatures of "mesoscopic Coulomb blockade" are reported for quantum dots with one fully transmitting point-contact lead, T1 = 1, T2 << 1. Unlike Coulomb blockade (CB) in weak-tunneling devices (T1, T2 << 1), one-channel CB is a mesoscopic effect requiring quantum coherence. Several distinctive features of mesoscopic CB are observed, including a reduction in CB upon breaking time-reversal symmetry with a magnetic field, relatively large fluctuations of peak position as a function of magnetic field, and strong temperature dependence on the scale of the quantum level spacing.Comment: 12 pages, including 4 figure

Allosteric p97 inhibitors can overcome resistance to ATP-competitive p97 inhibitors for potential anti-cancer therapy

A major challenge of targeted cancer therapy is the selection for drug‐resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is a central regulator of protein homeostasis and a promising anti‐cancer target because of its vital role in cell growth and survival. One ATP‐competitive p97 inhibitor, CB‐5083, has entered clinical trials. Selective pressure on HCT116 cells treated with CB‐5083 identified 5 different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB‐5083 resistant p97 mutants, N660K and T688A, were also resistant to several other ATP‐competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS‐873 and UPCDC‐30245 were unaffected by these mutations. We also established a CB‐5083 resistant cell line that harbors a new p97 double mutation (D649A/T688A). While CB‐5083, NMS‐873, and UPCDC‐30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS‐873 and UPCDC‐30245 were 30‐fold more potent than CB‐5083 in inhibiting the CB‐5083 resistant D649A/T688A double mutant. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP‐competitive p97 inhibitors arises during anti‐cancer treatment

A More Precise Extraction of |V_{cb}| in HQEFT of QCD

The more precise extraction for the CKM matrix element |V_{cb}| in the heavy quark effective field theory (HQEFT) of QCD is studied from both exclusive and inclusive semileptonic B decays. The values of relevant nonperturbative parameters up to order 1/m^2_Q are estimated consistently in HQEFT of QCD. Using the most recent experimental data for B decay rates, |V_{cb}| is updated to be |V_{cb}| = 0.0395 \pm 0.0011_{exp} \pm 0.0019_{th} from B\to D^{\ast} l \nu decay and |V_{cb}| = 0.0434 \pm 0.0041_{exp} \pm 0.0020_{th} from B\to D l \nu decay as well as |V_{cb}| = 0.0394 \pm 0.0010_{exp} \pm 0.0014_{th} from inclusive B\to X_c l \nu decay.Comment: 7 pages, revtex, 4 figure