This essay grows out of the author’s ongoing research examining issues of affect and agency as these relate to archives and recordkeeping during the post-conflict recovery and political and economic transitions occurring in countries that emerged since 1991 out of the former Socialist Federal Republic of Yugoslavia (SFRY). Specifically, since archivists in the countries play a key role in securing and providing access to records that are essential to individual, community and national recovery and transition, it contemplates possible relationships between affect and individual agency relevant to understanding their personal and professional situations. The essay also provides a synopsis of selective disciplinary literature addressing aspects of affect associated with individual experiences, memory and actions in war and post-conflict contexts. In so doing, it identifies several potentially relevant strands for further qualitative investigation of affect and its relationship to agency in the context of the individual archivist: the role of narrative, the need to integrate the social and the cultural, listening for meaningful silences, the importance of social support, the affect of place, coping mechanisms, and disenchantment with the state. The essay concludes with a brief commentary on how identifying the dimensions of affect and its relationship to agency through research such as this is an important component of understanding what professional actions, ethics and practices might be most appropriate and effective in post-conflict recovery and reconciliation, not only in these countries but also in other regions that have experienced similar extensive or recurring conflicts, especially when coupled with major political and economic transitions.

In this paper we reflect on our engagement in research in Australia and the states emerging out of the former Yugoslavia relating to the role of recordkeeping and archiving in human rights and social justice contexts, and in post-conflict societies. This research has engendered a rethinking of participatory archiving as it relates to official as well as other types of records, an expanded conceptualisation of archival activism and a new concept of archival autonomy, recently defined by Evans et al. It also provides insights into the vital transformative roles that these factors individually and collectively might play in such situations. Based on our research findings, a review of relevant critical literature in archival studies, and our own immersive experiences over many years as archival and recordkeeping researchers, and as educators and practitioners, we present an integrated set of rights in records that acknowledge and respect the interests of the different agents who are involved or implicated in records and recordkeeping processes. The guiding principles for the development of the set of rights originate in deep reflection on what constitutes ethical and pluralized recordkeeping and archiving. While we may advocate for and invoke codified rights in support of transformative practice, the driving impulse to animate and prioritize 21st century recordkeeping and archival practice in human rights, social justice and post-conflict contexts has emanated from, and, we would argue, should ideally always emanate from personal, professional, institutional and national recognition of and response to ethical exigencies rather than as a result of externally-imposed rights-based directives.

Schizophrenia remains a sizable socio-economic burden that continues to be treated with therapeutics based on 70-year old science. All currently approved therapeutics primarily target the dopamine D₂ receptor to achieve their efficacy. Whilst dopaminergic dysregulation is a key feature in this disorder, the targeting of dopaminergic machinery has yielded limited efficacy and an appreciable side effect burden. Over the recent decades, numerous drugs that engage non-dopaminergic G protein-coupled receptors (GPCRs) have yielded a promise of efficacy without the deleterious side effect profile, yet none have successfully completed clinical studies and progressed to the market. More recently, there has been increased attention around non-dopaminergic GPCR-targeting drugs, which demonstrated efficacy in some schizophrenia symptom domains. This provides renewed hope that effective schizophrenia treatment may lie outside of the dopaminergic space. Despite the potential for muscarinic receptor- (and other well-characterised GPCR families) targeting drugs to treat schizophrenia, they are often plagued with complications such as lack of receptor subtype selectivity and peripheral on-target side effects. Orphan GPCR studies have opened a new avenue of exploration with many demonstrating schizophrenia-relevant mechanisms and a favourable expression profile, thus offering potential for novel drug development. This review discusses centrally expressed orphan GPCRs: GPR3, GPR6, GPR12, GPR52, GPR85, GPR88 and GPR139 and their relationship to schizophrenia. We review their expression, signalling mechanisms and cellular function, in conjunction with small molecule development and structural insights. We seek to provide a snapshot of the growing evidence and development potential of new classes of schizophrenia therapeutics.

Background and purpose

Negative allosteric modulators (NAMs) that target the calcium-sensing receptor (CaS receptor) were originally developed for the treatment of osteoporosis by stimulating the release of endogenous parathyroid hormone, but failed in human clinical trials. Several chemically and structurally distinct NAM scaffolds have been described, but it is not known how these different scaffolds interact with the CaS receptor to inhibit receptor signalling in response to agonists.

Experimental approach

In the present study, we used a mutagenesis approach combined with analytical pharmacology and computational modelling to probe the binding sites of four distinct NAM scaffolds.

Key results

Although all four scaffolds bind to the 7-transmembrane and/or extracellular or intracellular loops, they occupy distinct regions, as previously shown for positive allosteric modulators of the CaS receptor. Furthermore, different NAM scaffolds mediate negative allosteric modulation via distinct amino acid networks.

Conclusion and implications

These findings aid our understanding of how different NAMs bind to and inhibit the CaS receptor. Elucidation of allosteric binding sites in the CaS receptor has implications for the discovery of novel allosteric modulators.

Allosteric interactions play vital roles in metabolic processes and signal transduction and, more recently, have become the focus of numerous pharmacological studies because of the potential for discovering more target-selective chemical probes and therapeutic agents. In addition to classic early studies on enzymes, there are now examples of small molecule allosteric modulators for all superfamilies of receptors encoded by the genome, including ligand- and voltage-gated ion channels, G protein-coupled receptors, nuclear hormone receptors, and receptor tyrosine kinases. As a consequence, a vast array of pharmacologic behaviors has been ascribed to allosteric ligands that can vary in a target-, ligand-, and cell-/tissue-dependent manner. The current article presents an overview of allostery as applied to receptor families and approaches for detecting and validating allosteric interactions and gives recommendations for the nomenclature of allosteric ligands and their properties.

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.