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Previous genomic studies in humans indicate that SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, is involved in anxiety and depression, but the mechanisms are unclear. We previously showed that SIRT1 is highly activated in the nuclear fraction of the dentate gyrus of the chronically stressed animals and inhibits memory formation and increases anhedonic behavior during chronic stress, but specific functional targets of cytoplasmic SIRT1 are unknown. Here, we demonstrate that SIRT1 activity rapidly modulates intrinsic and synaptic properties of the dentate gyrus granule cells and anxiety behaviors through deacetylation of BK channel α subunits in control animals. Chronic stress decreases BKα channel membrane expression, and SIRT1 activity has no rapid effects on synaptic transmission or intrinsic properties in the chronically stressed animal. These results suggest SIRT1 activity rapidly modulates the physiological function of the dentate gyrus, and this modulation participates in the maladaptive stress response. Diankun Yu et al. show that deacetylase SIRT1 rapidly modulates synaptic properties of the dentate gyrus granule cells and anxiety behaviors through deacetylation of BK channel α subunits. This study provides mechanistic insight into how SIRT1 regulates fight-or-flight stress response.

Psychedelics are a broad class of drugs defined by their ability to induce an altered state of consciousness 1 , 2 . These drugs have been used for millennia in both spiritual and medicinal contexts, and a number of recent clinical successes have spurred a renewed interest in developing psychedelic therapies 3 – 9 . Nevertheless, a unifying mechanism that can account for these shared phenomenological and therapeutic properties remains unknown. Here we demonstrate in mice that the ability to reopen the social reward learning critical period is a shared property across psychedelic drugs. Notably, the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans. Furthermore, the ability to reinstate social reward learning in adulthood is paralleled by metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Finally, identification of differentially expressed genes in the ‘open state’ versus the ‘closed state’ provides evidence that reorganization of the extracellular matrix is a common downstream mechanism underlying psychedelic drug-mediated critical period reopening. Together these results have important implications for the implementation of psychedelics in clinical practice, as well as the design of novel compounds for the treatment of neuropsychiatric disease. Behavioural electrophysiological and transcriptomic studies in mice show that psychedelic drugs reopen the social reward learning critical period and suggest that this involves reorganization of the extracellular matrix.

Abstract Trust litigation often involves highly confidential information, and it is common for all concerned to want any proceedings kept as confidential as possible. In this article, we explore four different ways in which such information might nonetheless be sought by, or become available to, a wider audience, namely through: (i) the publication of trusts judgments pursuant to the principle of open justice, (ii) applications to lift the confidentiality attaching to documents disclosed in Beddoe proceedings, (iii) the cross-examination of the trust’s own lawyers on a witness summons and (iv) the deployment of letters of request (formerly “rogatory”) against an overseas trustee.

Recent analyses of Sierra Leone's eleven-year civil war have argued that the conflict was fuelled by a crisis within chiefdom authority, with emphasis on increasing tensions between rural youth and their elders. However, a counter-argument has also emerged, emphasising that customary authority is still highly regarded in post-conflict Sierra Leone and that chiefs act as an influential barrier against bureaucratic abuses of power. This article draws on fieldwork from three districts in Sierra Leone to argue that chiefdom authority indeed continues to have considerable support. In particular, section chiefs and headmen are seen as being particularly important for settling small disputes, especially in the rural areas where contact between villagers and chiefs is most apparent.

Autism spectrum disorders (ASD) are commonly characterized by abnormal social behaviors. Fragile X syndrome (FXS) is the most common inherited intellectual disability in humans and the most common single-gene cause of ASD symptoms. FXS is caused by the loss or malfunction of the fragile X mental retardation protein (FMRP), an mRNA-binding protein that regulates numerous synaptic proteins, both translationally and through direct protein-protein interactions. One direct-binding target is the large-conductance potassium (BK) channel. BK channels have been shown to be hypoactive in FXS, and represent possible targets for treatment in both general ASD and in FXS specifically. Also, two members of the KCNQ class of voltage-activated potassium channels, KV7.2 and KV7.3, have been identified as FMRP translation targets. Finally, a commonly observed abnormality in the ASD brain is an imbalance in the ratio of excitatory to inhibitory signaling (E/I balance) causing general hyperexcitability in numerous brain areas. One area in which altered E/I balance is often observed is the medial prefrontal cortex (mPFC), which is involved with the processing of social information. Therefore, the goal of this dissertation was to determine if stimulating potassium channel function in the mPFC of Fmr1 KO mice would correct abnormal social behavior. In addition, the possible mechanistic determinants and effects on E/I balance were investigated in WT and Fmr1 KO mice.Infusion of the potassium channel activator, BMS-204352, into the mPFC of KO mice had no effect on social approach behavior, but corrected social novelty impairments as measured by a 3-Chamber Test. Whole-cell patch clamp recordings of pyramidal neurons in layer V of the mPFC revealed no differences in mEPSCs between KO and WT mice, but did reveal higher frequency of mIPSCs in KO mice. Treatment with BMS-204352 resulted in a decrease in mEPSC amplitude in both genotypes, which was blocked by the BK channel antagonist, paxilline. Effects of BMS-204352 treatment on mIPSCs revealed two possible populations of cell types. One population of exhibited a decrease in frequency of mIPSCs, an effect seen in both genotypes. The other population exhibited a slight increase in frequency of mIPSCs, but this was seen only in KO cells. Treatment with paxilline caused a decrease in mIPSC frequency in both genotypes, which was not altered with subsequent BMS-204352 treatment. Pretreatment with the KV7 channel antagonist XE 991 prevented BMS-204352-induced cross-genotype decrease in mIPSC frequency, but did not prevent BMS-204352-induced frequency increase in KO cells. Western blot analyses revealed no changes between genotypes in BK channel expression, but a trend to increased KV7.3 expression in the PFC of KOs compared to WTs. With these data, it was concluded that aberrant activity of potassium channels in the mPFC of KOs mediates some of the social abnormalities observed in the phenotype, that KOs may exhibit increased KV7.3 expression as a potential compensatory mechanism for BK channel dysfunction, and that potassium channels are a promising potential target for future treatment of ASD symptoms

This article is based upon a talk given at the Wilberforce Chambers Trust Litigation Day on 22nd January 2018 by Jonathan Hilliard QC and Edward Sawyer.

In 1976, the generation-skipping transfer tax (GST tax) was enacted to address perceived transfer tax avoidance in certain wealth transfers. One type of transfer subject to GST tax under the TRA 86 provisions, but not the original legislation, was a direct skip transfer of property by a grandparent to a trust for the benefit of a grandchild. To avoid the immediate imposition of a second transfer tax in these circumstances, estate planners began to draft trust instruments to provide the intervening generation with an interest in the trust that prevented that generation from being skipped for GST tax purposes. This article discusses the nature of the interest the intervening generation must have to avoid the immediate imposition of the second transfer tax on transfers to trusts with multi-generational beneficiaries, with particular emphasis on the treatment of general powers of appointment in favor of the intervening generation. A general power of appointment gives the holder a present right to receive the trust principal for GST tax purposes irrespective of whether the power is current or testamentary.

In 1976, the generation-skipping transfer tax (GST tax) was enacted to address perceived transfer tax avoidance in certain wealth transfers. Because of controversy surrounding the GST tax, the effective date was extended multiple times. Ultimately, in 1986, the original legislation was repealed retroactively to the date of its enactment and replaced with the GST tax provisions in the Tax Reform Act of 1986. The original GST tax was intended to tax only transfers to a trust with beneficiaries in more than one generation below that of the donor (e.g., where both a child and grandchild of the transferor were beneficiaries). The IRS's failure to conduct an in-depth analysis of the relevant authorities discussed led to the incorrect conclusion set forth in PLR 200814016. The imposition of three transfer taxes on two generations of taxpayers clearly contradicts the legislative intent of the GST tax that one, and only one, transfer tax be imposed at the level of each generation.

The nation's social agenda for improving education and training has converged with national economic forces. The emphasis on educating, training and developing the workforce, growing demands for ever-improving productivity and significant technological advancements have resulted in new tools to deliver education and training at a distance when and where it is required. The emergence of online learning has provided new opportunities for managers to reap the rewards of a well-educated and trained workforce. The primary methodology that was applied in this exploratory study was the emergent, inductive approach of content analysis through a cross case analysis of 607 research reports published over a two year period to establish the existence and frequency of the dependent variables goals, benefits and problems. This analysis resulted in the identification of 61 goals that have been set for online learning programs, 131 benefits that have been documented, and 371 problems that have been encountered. The resulting frequency distribution tables were both quantitatively and qualitatively analyzed. Quantitative analysis showed correlations and patterns of interest in the dependent variables by the academic, dissertation, government and NGO research sponsors. Conceptual and relational analysis were concurrently applied to identify key concepts and their semantic relationships which resulted in the development of a concept map that, when combined with the content analysis, led to the identification of seven recommended online learning Communities of Practice. The findings and implications include a presentation of the Communities of Practice and a decision-aid/analysis tool for online learning managers, developers, deliverers, supporters, suppliers, researchers and learners related to the goals, benefits and problems that they encounter.

Under the title \"The Flow Through Submerged Outlets,\" there appeared in the June number of this Magazine, a translation of an article by M. Alfred Salles, published in the \"Memoires of the Bureau des Ponts et Chausees\" for 1884,--which will grievously mislead those who take it as embodying the present...