Excitement about inhibitory presynaptic terminals

Based on extrapolation from excitatory synapses, it is often assumed that depletion of the releasable pool of synaptic vesicles is the main factor underlying depression at inhibitory synapses. In this issue of Neuron, using subcellular patch-clamp recording from inhibitory presynaptic terminals, Kawaguchi and Sakaba (2015) show that at Purkinje cell-deep cerebellar nuclei neuron synapses, changes in presynaptic action potential waveform substantially contribute to synaptic depression. Based on extrapolation from excitatory synapses, it is often assumed that depletion of the releasable pool of synaptic vesicles is the main factor underlying depression at inhibitory synapses. In this issue of Neuron, using subcellular patch-clamp recording from inhibitory presynaptic terminals, Kawaguchi and Sakaba (2015) show that at Purkinje cell-deep cerebellar nuclei neuron synapses, changes in presynaptic action potential waveform substantially contribute to synaptic depression

Parvalbumin+ interneurons obey unique connectivity rules and establish a powerful lateral-inhibition microcircuit in dentate gyrus

Parvalbumin-positive (PV+) GABAergic interneurons in hippocampal microcircuits are thought to play a key role in several higher network functions, such as feedforward and feedback inhibition, network oscillations, and pattern separation. Fast lateral inhibition mediated by GABAergic interneurons may implement a winner-takes-all mechanism in the hippocampal input layer. However, it is not clear whether the functional connectivity rules of granule cells (GCs) and interneurons in the dentate gyrus are consistent with such a mechanism. Using simultaneous patch-clamp recordings from up to seven GCs and up to four PV+ interneurons in the dentate gyrus, we find that connectivity is structured in space, synapse-specific, and enriched in specific disynaptic motifs. In contrast to the neocortex, lateral inhibition in the dentate gyrus (in which a GC inhibits neighboring GCs via a PV+ interneuron) is ~ 10-times more abundant than recurrent inhibition (in which a GC inhibits itself). Thus, unique connectivity rules may enable the dentate gyrus to perform specific higher-order computation

How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network

Pattern separation is a fundamental brain computation that converts small differences in input patterns into large differences in output patterns. Several synaptic mechanisms of pattern separation have been proposed, including code expansion, inhibition and plasticity; however, which of these mechanisms play a role in the entorhinal cortex (EC)–dentate gyrus (DG)–CA3 circuit, a classical pattern separation circuit, remains unclear. Here we show that a biologically realistic, full-scale EC–DG–CA3 circuit model, including granule cells (GCs) and parvalbumin-positive inhibitory interneurons (PV+-INs) in the DG, is an efficient pattern separator. Both external gamma-modulated inhibition and internal lateral inhibition mediated by PV+-INs substantially contributed to pattern separation. Both local connectivity and fast signaling at GC–PV+-IN synapses were important for maximum effectiveness. Similarly, mossy fiber synapses with conditional detonator properties contributed to pattern separation. By contrast, perforant path synapses with Hebbian synaptic plasticity and direct EC–CA3 connection shifted the network towards pattern completion. Our results demonstrate that the specific properties of cells and synapses optimize higher-order computations in biological networks and might be useful to improve the deep learning capabilities of technical networks

Matching Dendrochronological Dates with the Southern Hemisphere ¹⁴C Bomb Curve to Confirm Annual Tree Rings in Pseudolmedia rigida from Bolivia

This study used high-precision radiocarbon bomb-pulse dating of selected wood rings to provide an independent validation of the tree growth periodicity of Pseudolmedia rigida (Klotzsch & H. Karst.) Cuatrec. from the Moraceae family, collected in the Madidi National Park in Bolivia. ¹⁴C content was measured by accelerator mass spectrometry (AMS) in 10 samples from a single tree covering over 70 yr from 1939 to 2011. These preliminary calendar dates were determined by dendrochronological techniques and were also used to select the samples for ¹⁴C AMS. In order to validate these preliminary dates using the established Southern Hemisphere (SH) ¹⁴C atmospheric concentration data set, the targeted rings were selected to be formed during periods before and after the ¹⁴C bomb spike nuclear tests (i.e. 1950s–1960s). The excellent agreement of the dendrochronological dates and the ¹⁴C signatures in tree rings associated with the same dates provided by the bombpulse ¹⁴C atmospheric values for the SH (SHCal zone 1–2) confirms the annual periodicity of the observed growth layers, and thus the high potential of this species for tree-ring analysis. The lack of discrepancies between both data sets also suggests that there are no significant latitudinal differences between the ¹⁴C SHCal zone 1–2 curve and the ¹⁴C values obtained from the selected tree rings at this geographic location (14°33′S, 68°49′W) in South America. The annual resolution of P. rigida tree rings opens the possibility of broader applications of dendrochronological analysis for ecological and paleoclimatic studies in the Bolivian tropics, as well as the possibility of using wood samples from some tree species from this region to improve the quality of the bomb-pulse ¹⁴C SHCal curve at this latitude

The fast declining Type Ia supernova 2003gs, and evidence for a significant dispersion in near-infrared absolute magnitudes of fast decliners at maximum light

We obtained optical photometry of SN 2003gs on 49 nights, from 2 to 494 days after T(B_max). We also obtained near-IR photometry on 21 nights. SN 2003gs was the first fast declining Type Ia SN that has been well observed since SN 1999by. While it was subluminous in optical bands compared to more slowly declining Type Ia SNe, it was not subluminous at maximum light in the near-IR bands. There appears to be a bimodal distribution in the near-IR absolute magnitudes of Type Ia SNe at maximum light. Those that peak in the near-IR after T(B_max) are subluminous in the all bands. Those that peak in the near-IR prior to T(B_max), such as SN 2003gs, have effectively the same near-IR absolute magnitudes at maximum light regardless of the decline rate Delta m_15(B). Near-IR spectral evidence suggests that opacities in the outer layers of SN 2003gs are reduced much earlier than for normal Type Ia SNe. That may allow gamma rays that power the luminosity to escape more rapidly and accelerate the decline rate. This conclusion is consistent with the photometric behavior of SN 2003gs in the IR, which indicates a faster than normal decline from approximately normal peak brightness.Comment: 41 pages, 13 figures, to be published in the December, 2009, issue of the Astronomical Journa

Global meteorological influences on the record UK rainfall of winter 2013-14

The UK experienced record average rainfall in winter 2013–14, leading to widespread and prolonged flooding. The immediate cause of this exceptional rainfall was a very strong and persistent cyclonic atmospheric circulation over the North East Atlantic Ocean. This was related to a very strong North Atlantic jet stream which resulted in numerous damaging wind storms. These exceptional meteorological conditions have led to renewed questions about whether anthropogenic climate change is noticeably influencing extreme weather. The regional weather pattern responsible for the extreme UK winter coincided with highly anomalous conditions across the globe. We assess the contributions from various possible remote forcing regions using sets of ocean–atmosphere model relaxation experiments, where winds and temperatures are constrained to be similar to those observed in winter 2013–14 within specified atmospheric domains. We find that influences from the tropics were likely to have played a significant role in the development of the unusual extra-tropical circulation, including a role for the tropical Atlantic sector. Additionally, a stronger and more stable stratospheric polar vortex, likely associated with a strong westerly phase of the stratospheric Quasi-Biennial Oscillation (QBO), appears to have contributed to the extreme conditions. While intrinsic climatic variability clearly has the largest effect on the generation of extremes, results from an analysis which segregates circulation-related and residual rainfall variability suggest that emerging climate change signals made a secondary contribution to extreme rainfall in winter 2013–14

Can patient-led surveillance detect subsequent new primary or recurrent melanomas and reduce the need for routinely scheduled follow-up? A protocol for the MEL-SELF randomised controlled trial

This research project is funded by a National Health and Medical Research Council (NHMRC) Project grant (#1163054). The funder had no role in the design of the study and will have no role in the collection, analysis, and interpretation of the data; the writing of the report; or the decision to submit the report for publication. Funding Information: AEC is funded by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; 1147843). JFT is a recipient of an NHMRC Program Grant (1093017). RPMS is supported by Melanoma Institute Australia. RAS is supported by a NHMRC Program Grant and Practitioner Fellowship. For RAS, support from the from colleagues at Melanoma Institute Australia, Royal Prince Alfred Hospital and NSW Health Pathology is also gratefully acknowledged. RLM is supported with an NHMRC Investigator grant (1194703) and a University of Sydney Robinson Fellowship. HPS holds an NHMRC MRFF Next Generation Clinical Researchers Program Practitioner Fellowship (APP1137127). JH is supported by an NHMRC Early Career Fellowship (1112509). KB is supported by an NHMRC Investigator Grant (1174523) and a University of Sydney Research Accelerator (SOAR) Prize.Peer reviewedPublisher PD

Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs

Quantum state preparation and macroscopic entanglement in gravitational-wave detectors

Long-baseline laser-interferometer gravitational-wave detectors are operating at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within a broad frequency band. Such a low classical noise budget has already allowed the creation of a controlled 2.7 kg macroscopic oscillator with an effective eigenfrequency of 150 Hz and an occupation number of 200. This result, along with the prospect for further improvements, heralds the new possibility of experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical behavior of objects in the realm of everyday experience - using gravitational-wave detectors. In this paper, we provide the mathematical foundation for the first step of a MQM experiment: the preparation of a macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum state, which is possible if the interferometer's classical noise beats the SQL in a broad frequency band. Our formalism, based on Wiener filtering, allows a straightforward conversion from the classical noise budget of a laser interferometer, in terms of noise spectra, into the strategy for quantum state preparation, and the quality of the prepared state. Using this formalism, we consider how Gaussian entanglement can be built among two macroscopic test masses, and the performance of the planned Advanced LIGO interferometers in quantum-state preparation

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure