The impact of out-of-home care on brain development: a brief review of the neuroscientific evidence informing our understanding of children's attachment outcomes.

Researchers interested in the effects of early experiences of caregiving adversity have employed neuroscientific methods to illuminate whether and how such environmental input impacts on brain development, and whether and how such impacts underpin poor socioemotional outcomes in this population. Evidence is compelling in documenting negative effects on the individual's neurodevelopment following exposure to adverse or disadvantaged environments such as institutionalization or maltreatment. Neuroimaging research focused specifically on attachment-relevant processing of socioemotional stimuli and attachment outcomes among children looked-after is scarcer, but largely consistent. This review begins by summarizing the key general brain structural and functional alterations associated with caregiving deprivation. Then, neuroscientific evidence that is more directly relevant for understanding these children's attachment outcomes, both by employing social stimuli and by correlating children's neural markers with their attachment profiles, is reviewed. Brief interpretations of findings are suggested, and key limitations and gaps in the literature identified.

CK1δ and CK1ε Signaling Sustains Mitochondrial Metabolism and Cell Survival in Multiple Myeloma.

Multiple myeloma remains an incurable malignancy due to acquisition of intrinsic programs that drive therapy resistance. Here we report that casein kinase-1δ (CK1δ) and CK1ε are therapeutic targets in multiple myeloma that are necessary to sustain mitochondrial metabolism. Specifically, the dual CK1δ/CK1ε inhibitor SR-3029 had potent in vivo and ex vivo anti-multiple myeloma activity, including against primary multiple myeloma patient specimens. RNA sequencing (RNA-seq) and metabolic analyses revealed inhibiting CK1δ/CK1ε disables multiple myeloma metabolism by suppressing genes involved in oxidative phosphorylation (OxPhos), reducing citric acid cycle intermediates, and suppressing complexes I and IV of the electron transport chain. Finally, sensitivity of multiple myeloma patient specimens to SR-3029 correlated with elevated expression of mitochondrial genes, and RNA-seq from 687 multiple myeloma patient samples revealed that increased CSNK1D, CSNK1E, and OxPhos genes correlate with disease progression and inferior outcomes. Thus, increases in mitochondrial metabolism are a hallmark of multiple myeloma progression that can be disabled by targeting CK1δ/CK1ε. SIGNIFICANCE: CK1δ and CK1ε are attractive therapeutic targets in multiple myeloma whose expression increases with disease progression and connote poor outcomes, and that are necessary to sustain expression of genes directing OxPhos.

Neural correlates of face familiarity in institutionalised children and links to attachment disordered behaviour.

BACKGROUND: One of the most well-documented sequelae of early maltreatment and institutionalisation is attachment problems, including behaviours under the labels of reactive attachment disorder (RAD) and disinhibited social engagement disorder (DSED). Despite growing evidence of the neurobiological effects of institutionalisation, the neural correlates of these behavioural patterns are largely unknown. METHODS: The current study examined effects of both institutionalisation in general and attachment disordered behaviour, in particular, on brain-based markers of face processing, in 100 Portuguese children (70 currently institutionalised, 30 continuously raised by their families). Children's neural processing of caregiver's and stranger's faces was assessed with Event-Related Potentials (ERPs). RESULTS: Compared to children from the community, institutionalised children showed smaller amplitudes in the N170, to both stranger and caregiver faces. Amongst the institutionalised group, living in a setting with a higher children-to-caregivers' ratio was associated with smaller P400 amplitudes. The display of DSED symptoms was associated with a smaller P1 to both faces, as well as a reduced differentiation between faces in P400 amplitudes and smaller P400 to the stranger's face. In contrast, RAD symptoms were not associated with any ERP measures. CONCLUSIONS: Results replicate previously reported hypoactivation in institutionalised children, in a less-globally deprived setting than past work, indicating that such a pattern is associated with lack of individualised care and increased symptoms of DSED.

Metabolic Changes Are Associated with Melphalan Resistance in Multiple Myeloma.

Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the United States. Treatment for eligible patients involves induction, consolidation with stem cell rescue, and maintenance. High-dose therapy with a DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem-cell transplantation; as such, melphalan resistance remains a relevant clinical challenge. Here, we describe a proteometabolomic approach to examine mechanisms of acquired melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP, data available at PRIDE: PXD019725), acute-treatment metabolomics, and western blot analyses have allowed us to further elucidate metabolic processes associated with melphalan resistance. Proteometabolomic data indicate that drug-resistant cells have higher levels of pentose phosphate pathway metabolites. Purine, pyrimidine, and glutathione metabolisms were commonly altered, and cell-line-specific changes in metabolite levels were observed, which could be linked to the differences in steady-state metabolism of naïve cells. Inhibition of selected enzymes in purine synthesis and pentose phosphate pathways was evaluated to determine their potential to improve melphalan's efficacy. The clinical relevance of these proteometabolomic leads was confirmed by comparison of tumor cell transcriptomes from newly diagnosed MM patients and patients with relapsed disease after treatment with high-dose melphalan and autologous stem-cell transplantation. The observation of common and cell-line-specific changes in metabolite levels suggests that omic approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the use of high-dose melphalan.

Proteometabolomics of Melphalan Resistance in Multiple Myeloma.

Drug resistance remains a critical problem for the treatment of multiple myeloma (MM), which can serve as a specific example for a highly prevalent unmet medical need across almost all cancer types. In MM, the therapeutic arsenal has expanded and diversified, yet we still lack in-depth molecular understanding of drug mechanisms of action and cellular pathways to therapeutic escape. For those reasons, preclinical models of drug resistance are developed and characterized using different approaches to gain insights into tumor biology and elucidate mechanisms of drug resistance. For MM, numerous drugs are used for treatment, including conventional chemotherapies (e.g., melphalan or L-phenylalanine nitrogen mustard), proteasome inhibitors (e.g., Bortezomib), and immunomodulators (e.g., Lenalidomide). These agents have diverse effects on the myeloma cells, and several mechanisms of drug resistance have been previously described. The disparity of these mechanisms and the complexity of these biological processes lead to the formation of complicated hypotheses that require omics approaches for efficient and effective analysis of model systems that can then be interpreted for patient benefit. Here, we describe the combination of metabolomics and proteomics to assess melphalan resistance in MM by examining three specific areas: drug metabolism, modulation of endogenous metabolites to assist in therapeutic escape, and changes in protein activity gauged by ATP probe uptake.

Patterns of host use by brood parasitic Maculinea butterflies across Europe.

The range of hosts exploited by a parasite is determined by several factors, including host availability, infectivity and exploitability. Each of these can be the target of natural selection on both host and parasite, which will determine the local outcome of interactions, and potentially lead to coevolution. However, geographical variation in host use and specificity has rarely been investigated. Maculinea (= Phengaris) butterflies are brood parasites of Myrmica ants that are patchily distributed across the Palæarctic and have been studied extensively in Europe. Here, we review the published records of ant host use by the European Maculinea species, as well as providing new host ant records for more than 100 sites across Europe. This comprehensive survey demonstrates that while all but one of the Myrmica species found on Maculinea sites have been recorded as hosts, the most common is often disproportionately highly exploited. Host sharing and host switching are both relatively common, but there is evidence of specialization at many sites, which varies among Maculinea species. We show that most Maculinea display the features expected for coevolution to occur in a geographic mosaic, which has probably allowed these rare butterflies to persist in Europe. This article is part of the theme issue 'The coevolutionary biology of brood parasitism: from mechanism to pattern'.

INDISCRIMINATE BEHAVIOR OBSERVED IN THE STRANGE SITUATION AMONG INSTITUTIONALIZED TODDLERS: RELATIONS TO CAREGIVER REPORT AND TO EARLY FAMILY RISK.

Socially disinhibited or indiscriminate behavior (IB) has traditionally been investigated using caregiver reports. More recently, an observational measure based on the Strange Situation Procedure (M. Ainsworth, M. Blehar, E. Waters, & S. Wall, 1978), the Rating of Infant and Stranger Engagement (RISE; C. Riley, A. Atlas-Corbett, & K. Lyons-Ruth, 2005), was validated in home-reared at-risk children. The present study aimed to validate the RISE in an institutionally reared sample using the caregiver report, to assess whether IB assessed with the RISE was elevated among the institutionalized children, and to explore potential risk factors associated with IB. The study was conducted among 74 institutionalized toddlers aged 11 to 30 months. Sociodemographic questionnaires were used to assess pre-admission experiences, and aspects of institutional placement were coded from the children's files in the institution and staff's report. Institutionalized children displayed high frequencies of IB as assessed on the RISE, and this instrument was validated against caregiver report. Pre-admission experiences of the institutionalized children in their biological families-namely, prenatal risk and maternal emotional neglect risk-predicted IB. Results suggest that the RISE is adequate to use among institutionally reared toddlers and point to aspects of the early familial environment that may be implicated in IB.