When one childhood meets another : maternal child maltreatment and offspring child psychopathology

Studies have shown that a mother’s history of child maltreatment is associated with her child’s experience of internalising and externalising difficulties. This study aimed to characterise the mediating pathways that may underpin this association. Data on a mother’s history of child maltreatment, depression during pregnancy, depression after birth, maladaptive parenting practices and her child’s experience of maltreatment and preadolescent internalising and externalising difficulties were analysed in a sample of 9,397 mother-child dyads followed prospectively from pregnancy to child age 13. The results showed that maternal history of child maltreatment was significantly associated with child internalising and externalising difficulties in preadolescence. Maternal antenatal depression, post-birth depression, maladaptive parenting and child maltreatment were observed to significantly mediate this association. The study concluded that psychological and psychosocial interventions focused around treating maternal depression, particularly during pregnancy, and improving parenting skills, could be offered to mothers with traumatic childhood experiences to help protect against psychopathology in the next generatio

SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons.

The mechanism for the earliest response of central neurons to hypoxia-an increase in voltage-gated sodium current (INa)-has been unknown. Here, we show that hypoxia activates the Small Ubiquitin-like Modifier (SUMO) pathway in rat cerebellar granule neurons (CGN) and that SUMOylation of NaV1.2 channels increases INa. The time-course for SUMOylation of single NaV1.2 channels at the cell surface and changes in INa coincide, and both are prevented by mutation of NaV1.2-Lys38 or application of a deSUMOylating enzyme. Within 40 s, hypoxia-induced linkage of SUMO1 to the channels is complete, shifting the voltage-dependence of channel activation so that depolarizing steps evoke larger sodium currents. Given the recognized role of INa in hypoxic brain damage, the SUMO pathway and NaV1.2 are identified as potential targets for neuroprotective interventions

K2P channels and their protein partners.

A decade since their discovery, the K2P channels are recognized as pathways dedicated to regulated background leakage of potassium ions that serve to control neuronal excitability. The recent identification of protein partners that directly interact with K2P channels (SUMO, 14-3-3 and Vpu1) has exposed new regulatory pathways. Reversible linkage to SUMO silences K2P1 plasma membrane channels; phosphorylation of K2P3 enables 14-3-3 binding to affect forward trafficking, whereas it decreases open probability of K2P2; and, Vpu1, an HIV encoded partner, mediates assembly-dependent degradation of K2P3. An operational strategy has emerged: tonic inhibition of K2P channels allows baseline neuronal activity until enhanced potassium leak is required to suppress excitability

Individual IKs channels at the surface of mammalian cells contain two KCNE1 accessory subunits.

KCNE1 (E1) β-subunits assemble with KCNQ1 (Q1) voltage-gated K(+) channel α-subunits to form IKslow (IKs) channels in the heart and ear. The number of E1 subunits in IKs channels has been an issue of ongoing debate. Here, we use single-molecule spectroscopy to demonstrate that surface IKs channels with human subunits contain two E1 and four Q1 subunits. This stoichiometry does not vary. Thus, IKs channels in cells with elevated levels of E1 carry no more than two E1 subunits. Cells with low levels of E1 produce IKs channels with two E1 subunits and Q1 channels with no E1 subunits--channels with one E1 do not appear to form or are restricted from surface expression. The plethora of models of cardiac function, transgenic animals, and drug screens based on variable E1 stoichiometry do not reflect physiology

A Role for K2P Channels in the Operation of Somatosensory Nociceptors

The ability to sense mechanical, thermal, and chemical stimuli is critical to normal physiology and the perception of pain. Contact with noxious stimuli triggers a complex series of events that initiate innate protective mechanisms designed to minimize or avoid injury. Extreme temperatures, mechanical stress, and chemical irritants are detected by specific ion channels and receptors clustered on the terminals of nociceptive sensory nerve fibers and transduced into electrical information. Propagation of these signals, from distant sites in the body to the spinal cord and the higher processing centers of the brain, is also orchestrated by distinct groups of ion channels. Since their identification in 1995, evidence has emerged to support roles for K2P channels at each step along this pathway, as receptors for physiological and noxious stimuli, and as determinants of nociceptor excitability and conductivity. In addition, the many subtypes of K2P channels expressed in somatosensory neurons are also implicated in mediating the effects of volatile, general anesthetics on the central and peripheral nervous systems. Here, I offer a critical review of the existing data supporting these attributes of K2P channel function and discuss how diverse regulatory mechanisms that control the activity of K2P channels act to govern the operation of nociceptors

Hypoxia Produces Pro-arrhythmic Late Sodium Current in Cardiac Myocytes by SUMOylation of NaV1.5 Channels.

Acute cardiac hypoxia produces life-threatening elevations in late sodium current (ILATE) in the human heart. Here, we show the underlying mechanism: hypoxia induces rapid SUMOylation of NaV1.5 channels so they reopen when normally inactive, late in the action potential. NaV1.5 is SUMOylated only on lysine 442, and the mutation of that residue, or application of a deSUMOylating enzyme, prevents hypoxic reopenings. The time course of SUMOylation of single channels in response to hypoxia coincides with the increase in ILATE, a reaction that is complete in under 100 s. In human cardiac myocytes derived from pluripotent stem cells, hypoxia-induced ILATE is confirmed to be SUMO-dependent and to produce action potential prolongation, the pro-arrhythmic change observed in patients

The truncated and evolving inner accretion disc of the black hole GX 339-4

The nature of accretion onto stellar mass black holes in the low/hard state remains unresolved, with some evidence suggesting that the inner accretion disc is truncated and replaced by a hot flow. However, the detection of relativistic broadened Fe emission lines, even at relatively low luminosities, seems to require an accretion disc extending fully to its innermost stable circular orbit. Modelling such features is however highly susceptible to degeneracies, which could easily bias any interpretation. We present the first systematic study of the Fe line region to track how the inner accretion disc evolves in the low/hard state of the black hole GX 339$-$4. Our four observations display increased broadening of the Fe line over two magnitudes in luminosity, which we use to track any variation of the disc inner radius. We find that the disc extends closer to the black hole at higher luminosities, but is consistent with being truncated throughout the entire low/hard state, a result which renders black hole spin estimates inaccurate at these stages of the outburst. Furthermore, we show that the evolution of our spectral inner disc radius estimates corresponds very closely to the trend of the break frequency in Fourier power spectra, supporting the interpretation of a truncated and evolving disc in the hard state.Comment: Accepted for publication in A&A. Some typos corrected from version

Revealing accretion onto black holes: X-ray reflection throughout three outbursts of GX 339-4

Understanding the dynamics behind black hole state transitions and the changes they reflect in outbursts has become long-standing problem. The X-ray reflection spectrum describes the interaction between the hard X-ray source (the power-law continuum) and the cool accretion disc it illuminates, and thus permits an indirect view of how the two evolve. We present a systematic analysis of the reflection spectrum throughout three outbursts (500+ observations) of the black hole binary GX 339-4, representing the largest study applying a self-consistent treatment of reflection to date. Particular attention is payed to the coincident evolution of the power-law and reflection, which can be used to determine the accretion geometry. The hard state is found to be distinctly reflection weak, however the ratio of reflection to power-law gradually increases as the source luminosity rises. In contrast the reflection is found dominate the power-law throughout most of the soft state, with increasing supremacy as the source decays. We discuss potential dynamics driving this, favouring inner disc truncation and decreasing coronal height for the hard and soft states respectively. Evolution of the ionisation parameter, power-law slope and high-energy cut-off also agree with this interpretation.Comment: Accepted for publication in MNRA