Linking maternal disrupted interaction and infant limbic volumes: The role of infant cortisol output.

Despite a large animal literature documenting the role of low maternal nurturance and elevated glucocorticoid production on offspring limbic development, these pathways have not yet been assessed during human infancy. Informed by animal models, the present study examined whether 1) maternal disrupted interaction is related to infant cortisol levels, 2) infant cortisol levels are associated with infant limbic volumes, and 3) infant cortisol levels mediate associations between maternal disrupted interaction and infant limbic volumes. Participants included 57 mother-infant dyads. Infant saliva was measured at one time point before and two time points after the Still-Face Paradigm (SFP) at age 4 months. Five aspects of maternal disrupted interaction were coded during the SFP reunion episode. Between 4 and 25 months (M age = 11.74 months, SD = 6.12), under natural sleep, infants completed an MRI. Amygdala and hippocampal volumes were calculated via automated segmentation. Results indicated that 1) maternal disrupted interaction, and specifically disoriented interaction, with the infant was associated with higher infant salivary cortisol (AUCg) levels during the SFP, 2) higher infant AUCg was related to enlarged bilateral amygdala and hippocampal volumes, and 3) infant AUCg mediated the relation between maternal disrupted interaction and infant amygdala and hippocampal volumes. Findings are consistent with controlled animal studies and provide evidence of a link between increased cortisol levels and enlarged limbic volumes in human infants. Results further suggest that established interventions to decrease maternal disrupted interaction could impact both infant cortisol levels and infant limbic volumes.

Latent profiles of maternal disrupted communication: Relations to affect and behaviour in early infancy.

Few studies have examined how mothering is organized in the first months of infancy, especially regarding risk-related interactions. Person-centred approaches, including latent profile analysis (LPA), add valuable insights about early parenting by identifying distinct profiles of interaction. First, this study aimed to identify profiles of disrupted maternal interaction during the Still-Face Paradigm among 181 mothers and their 3- to 8-month-old infants. Second, the study assessed how each maternal profile was related to infant affect and interactive behaviour. The LPA identified four profiles of maternal interaction: optimal, negative/intrusive, withdrawing and pervasively disrupted. The pervasively disrupted profile, in particular, has not been identified in past research. Each profile was associated with specific aspects of infant affect and behaviour. Recognition of disrupted behavioural profiles among at-risk mothers and infants in the early months could facilitate more precise tailoring of early interventions to the needs of mothers and infants with differing profiles of interactive risk.

A model based on Bayesian confirmation and machine learning algorithms to aid archaeological interpretation by integrating incompatible data.

The interpretation of archaeological features often requires a combined methodological approach in order to make the most of the material record, particularly from sites where this may be limited. In practice, this requires the consultation of different sources of information in order to cross validate findings and combat issues of ambiguity and equifinality. However, the application of a multiproxy approach often generates incompatible data, and might therefore still provide ambiguous results. This paper explores the potential of a simple digital framework to increase the explanatory power of multiproxy data by enabling the incorporation of incompatible, ambiguous datasets in a single model. In order to achieve this, Bayesian confirmation was used in combination with decision trees. The results of phytolith and geochemical analyses carried out on soil samples from ephemeral sites in Jordan are used here as a case study. The combination of the two datasets as part of a single model enabled us to refine the initial interpretation of the use of space at the archaeological sites by providing an alternative identification for certain activity areas. The potential applications of this model are much broader, as it can also help researchers in other domains reach an integrated interpretation of analysis results by combining different datasets.

The Zagros Epipalaeolithic revisited: New excavations and 14C dates from Palegawra cave in Iraqi Kurdistan.

Palegawra cave, alongside its neighbouring Zarzi, has been an emblematic site of the Epipalaeolithic (Zarzian) cultural horizon in the NW Zagros of Southwest Asia ever since its first exploration in 1951 by Bruce Howe and Robert Braidwood in the context of the Iraq-Jarmo project. At the time scientific excavation, sampling and analysis methods were either under-developed or did not exist. In this paper we present the first results of new excavations at Palegawra conducted in 2016-2017 by the Eastern Fertile Crescent (EFEC) project, a research collaboration of the University of Liverpool and the Sulaymaniyah Directorate of Antiquities and Heritage. Our research has produced the first radiometric evidence pushing back the chronology of the NW Zagros Epipalaeolithic to the Last Glacial Maximum, thus fully aligning it with Epipalaeolithic facies until now known only from the Levant and the south Anatolian coast. We have also unearthed, for the first time in the Palaeolithic of the Zagros, direct archaeobotanical evidence for hitherto elusive Zarzian plant exploitation and the vegetation of the NW Zagros piedmont zone from the LGM to the end of the Lateglacial (~19,600-13,000 cal BP). The new Palegawra chronology alongside our detailed studies of its material culture and faunal and botanical assemblages suggest that the prevailing Epipalaeolithic habitation pattern in the NW Zagros (centred on generalised persistent occupations of small caves and rock-shelters alongside task-oriented ephemeral open-air campsites) remained an enduring characteristic of the Zarzian horizon throughout this period. The Palegawra data clearly show that neither resource levels and climate conditions nor geographic and/or cultural isolation provide adequate explanations for the stability and longevity of Zarzian lifeways during this long timespan. More fieldwork is required, including the discovery, excavation and intensive sampling of other Zarzian sites, for reaching a data-informed understanding of the nature and evolution of the NW Zagros Epipalaeolithic.

Tracking the Near Eastern origins and European dispersal of the western house mouse.

The house mouse (Mus musculus) represents the extreme of globalization of invasive mammals. However, the timing and basis of its origin and early phases of dispersal remain poorly documented. To track its synanthropisation and subsequent invasive spread during the develoment of complex human societies, we analyzed 829 Mus specimens from 43 archaeological contexts in Southwestern Asia and Southeastern Europe, between 40,000 and 3,000 cal. BP, combining geometric morphometrics numerical taxonomy, ancient mitochondrial DNA and direct radiocarbon dating. We found that large late hunter-gatherer sedentary settlements in the Levant, c. 14,500 cal. BP, promoted the commensal behaviour of the house mouse, which probably led the commensal pathway to cat domestication. House mouse invasive spread was then fostered through the emergence of agriculture throughout the Near East 12,000 years ago. Stowaway transport of house mice to Cyprus can be inferred as early as 10,800 years ago. However, the house mouse invasion of Europe did not happen until the development of proto urbanism and exchange networks - 6,500 years ago in Eastern Europe and 4000 years ago in Southern Europe - which in turn may have driven the first human mediated dispersal of cats in Europe.

Intensive structured education for type 1 diabetes management using BERTIE: Long-term follow-up to assess impact on glycaemic control and quality of life indices.

AIMS: Bournemouth Type 1 Intensive Education (BERTIE) is a structured education course delivered 1 day a week for 4 weeks for self-management of type 1 diabetes. BERTIE outcomes were analysed to assess long-term effectiveness: primary outcome assessed impact of BERTIE on glycaemic control, secondary outcomes assessed impact on Problem Area in Diabetes (PAID) scale, severe hypoglycaemia and diabetic ketoacidosis incidence (DKA). METHODS: Prospectively collected outcome data from attendees included glycated haemoglobin (HbA1c), PAID, severe hypoglycaemia and DKA incidence recorded pre-course, 6 months and 1 year post-attendance, with HbA1c assessed annually at subsequent clinic visits. RESULTS: Between 1999 and 2015, 524 people attended BERTIE with 5 year follow-up in 316 (60.3%) attendees. HbA1c was reduced from 74 ±â€¯17 mmol/mol (8.9 ±â€¯1.6%) at baseline to 71 ±â€¯15 mmol/mol (8.6 ±â€¯1.4%) at 1 year and 70 ±â€¯15 mmol/mol (8.6 ±â€¯1.3%) at 5 years (p < 0.0001); severe hypoglycaemia incidence reduced from 0.8 ±â€¯2.1 to 0.4 ±â€¯2.2 episodes/person/year at 1 year (p < 0.0001); PAID scale reduced from 23 ±â€¯16 to 15 ±â€¯12 (p < 0.0001) at 1 year; DKA incidence was 0.06 ±â€¯0.34 episodes/person/year pre-course and 0.03 ±â€¯0.21 at 1 year (p = 0.5271). CONCLUSIONS: BERTIE outcome data demonstrate favorable biochemical and psychological outcomes supporting recommendations that structured education be provided to adults with type 1 diabetes.

Agricultural origins on the Anatolian plateau.

This paper explores the explanations for, and consequences of, the early appearance of food production outside the Fertile Crescent of Southwest Asia, where it originated in the 10th/9th millennia cal BC. We present evidence that cultivation appeared in Central Anatolia through adoption by indigenous foragers in the mid ninth millennium cal BC, but also demonstrate that uptake was not uniform, and that some communities chose to actively disregard cultivation. Adoption of cultivation was accompanied by experimentation with sheep/goat herding in a system of low-level food production that was integrated into foraging practices rather than used to replace them. Furthermore, rather than being a short-lived transitional state, low-level food production formed part of a subsistence strategy that lasted for several centuries, although its adoption had significant long-term social consequences for the adopting community at Boncuklu. Material continuities suggest that Boncuklu's community was ancestral to that seen at the much larger settlement of Çatalhöyük East from 7100 cal BC, by which time a modest involvement with food production had been transformed into a major commitment to mixed farming, allowing the sustenance of a very large sedentary community. This evidence from Central Anatolia illustrates that polarized positions explaining the early spread of farming, opposing indigenous adoption to farmer colonization, are unsuited to understanding local sequences of subsistence and related social change. We go beyond identifying the mechanisms for the spread of farming by investigating the shorter- and longer-term implications of rejecting or adopting farming practices.

An assessment of African lion Panthera leo sociality via social network analysis: prerelease monitoring for an ex situ reintroduction program.

The wild population of the African lion Panthera leo continues to decline, requiring alternate conservation programs to be considered. One such program is ex situ reintroduction. Prior to release, long-term monitoring and assessment of behavior is required to determine whether prides and coalitions behave naturally and are sufficiently adapted to a wild environment. Social network analysis (SNA) can be used to provide insight into how the pride as a whole and individuals within it, function. Our study was conducted upon 2 captive-origin prides who are part of an ex situ reintroduction program, and 1 wild pride of African lion. Social interactions were collected at all occurrence for each pride and categorized into greet, social grooming, play, and aggression. Betweenness centrality showed that offspring in each pride were central to the play network, whereas degree indicated that adults received (indegree) the greatest number of overall social interactions, and the adult males of each pride were least likely to initiate (outdegree) any interactions. Through the assessment of individual centrality and degree values, a social keystone adult female was identified for each pride. Social network results indicated that the 2 captive-origin prides had formed cohesive social units and possessed relationships and behaviors comparable with the wild pride for the studied behaviors. This study provided the first SNA comparison between captive-bred origin and a wild pride of lions, providing valuable information on individual and pride sociality, critical for determining the success of prides within an ex situ reintroduction program.

Chronic hypoxia down-regulates tight junction protein ZO-2 expression in children with cyanotic congenital heart defect.

AIMS: Tight junction protein zonula occludens protein 2 (ZO-2) is a member of the membrane-associated guanylate kinases protein family known to be expressed at tight junctions of epithelial and endothelial cells and at adherens junctions (AJs) in cardiomyocytes. Little is known about ZO-2 expression and function in the human heart. Here, we examined the hypothesis that chronic hypoxia down-regulates ZO-2 expression in human myocardium and cultured rat cardiomyocytes. METHODS AND RESULTS: Patients with a diagnosis of cyanotic (n = 10) or acyanotic (n = 10) Tetralogy of Fallot undergoing surgical repair were used to examine ZO-2 messenger RNA and protein expression by real time-PCR, immunohistochemistry, and western blotting. A model of cultured rat cardiomyocytes was used to measure ZO-2 and AJ proteins levels in response to hypoxia and to investigate ZO-2 cellular localization. We showed that ZO-2 is expressed in myocardial tissue in acyanotic and cyanotic children with congenital heart defects. ZO-2 was specifically down-regulated in cyanotic myocardium at both the messenger RNA and protein levels when compared with acyanotic patients. This specific down-regulation can be mimicked in cultured rat cardiomyocytes by treating them with hypoxic conditions confirming that ZO-2 gene down-regulation is specifically due to cyanosis. Furthermore, in addition to its cytoplasmic expression, ZO-2 showed nuclear expression in cultured rat cardiomyocytes suggesting potential role in transcription regulation. CONCLUSIONS: Hypoxia down-regulates ZO-2 expression in both cyanotic patient's myocardium and cultured rat cardiomyocytes. This down-regulation suggest an involvement of ZO-2 in cardiac remodelling of AJs in cyanotic children and may explain the greater susceptibility of cyanotic patients to corrective heart surgery.

Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo.

The Wnt pathway is an evolutionarily conserved and tightly regulated signaling network with important roles in embryonic development and adult tissue regeneration. Impaired Wnt pathway regulation, arising from mutations in Wnt signaling components, such as Axin, APC, and ß-catenin, results in uncontrolled cell growth and triggers oncogenesis. To explore the reported link between CK2 kinase activity and Wnt pathway signaling, we sought to identify a potent, selective inhibitor of CK2 suitable for proof of concept studies in vivo. Starting from a pyrazolo[1,5-a]pyrimidine lead (2), we identified compound 7h, a potent CK2 inhibitor with picomolar affinity that is highly selectivity against other kinase family enzymes and inhibits Wnt pathway signaling (IC50 = 50 nM) in DLD-1 cells. In addition, compound 7h has physicochemical properties that are suitable for formulation as an intravenous solution, has demonstrated good pharmacokinetics in preclinical species, and exhibits a high level of activity as a monotherapy in HCT-116 and SW-620 xenografts.

Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors.

AKT1(E17K) mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1(E17K) mutation is not known. Expression of exogenous copies of AKT1(E17K) in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. Both AKT inhibitors caused highly significant growth inhibition of breast cancer explant models with AKT1(E17K) mutation. Furthermore, in a phase I clinical study, the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with tumors containing AKT1(E17K) mutations. In MGH-U3 bladder cancer xenografts, which contain both AKT1(E17K) and FGFR3(Y373C) mutations, AZD5363 monotherapy did not significantly reduce tumor growth, but tumor regression was observed in combination with the FGFR inhibitor AZD4547. The data show that tumors with AKT1(E17K) mutations are rational therapeutic targets for AKT inhibitors, although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the same tumor.

Measuring and managing radiologist workload: application of lean and constraint theories and production planning principles to planning radiology services in a major tertiary hospital.

INTRODUCTION: We describe how techniques traditionally used in the manufacturing industry (lean management, the theory of constraints and production planning) can be applied to planning radiology services to reduce the impact of constraints such as limited radiologist hours, and to subsequently reduce delays in accessing imaging and in report turnaround. METHODS: Targets for imaging and reporting were set aligned with clinical needs. Capacity was quantified for each modality and for radiologists and recorded in activity lists. Demand was quantified and forecasting commenced based on historical referral rates. To try and mitigate the impact of radiologists as a constraint, lean management processes were applied to radiologist workflows. A production planning process was implemented. RESULTS: Outpatient waiting times to access imaging steadily decreased. Report turnaround times improved with the percentage of overnight/on-call reports completed by a 1030 target time increased from approximately 30% to 80 to 90%. The percentage of emergency and inpatient reports completed within one hour increased from approximately 15% to approximately 50% with 80 to 90% available within 4 hours. The number of unreported cases on the radiologist work-list at the end of the working day reduced. The average weekly accuracy for demand forecasts for emergency and inpatient CT, MRI and plain film imaging was 91%, 83% and 92% respectively. For outpatient CT, MRI and plain film imaging the accuracy was 60%, 55% and 77% respectively. Reliable routine weekly and medium to longer term service planning is now possible. CONCLUSIONS: Tools from industry can be successfully applied to diagnostic imaging services to improve performance. They allow an accurate understanding of the demands on a service, capacity, and can reliably predict the impact of changes in demand or capacity on service delivery.

Comparison of methods for image-based profiling of cellular morphological responses to small-molecule treatment.

Quantitative microscopy has proven a versatile and powerful phenotypic screening technique. Recently, image-based profiling has shown promise as a means for broadly characterizing molecules' effects on cells in several drug-discovery applications, including target-agnostic screening and predicting a compound's mechanism of action (MOA). Several profiling methods have been proposed, but little is known about their comparative performance, impeding the wider adoption and further development of image-based profiling. We compared these methods by applying them to a widely applicable assay of cultured cells and measuring the ability of each method to predict the MOA of a compendium of drugs. A very simple method that is based on population means performed as well as methods designed to take advantage of the measurements of individual cells. This is surprising because many treatments induced a heterogeneous phenotypic response across the cell population in each sample. Another simple method, which performs factor analysis on the cellular measurements before averaging them, provided substantial improvement and was able to predict MOA correctly for 94% of the treatments in our ground-truth set. To facilitate the ready application and future development of image-based phenotypic profiling methods, we provide our complete ground-truth and test data sets, as well as open-source implementations of the various methods in a common software framework.

Transcriptomic analysis of patients with tetralogy of Fallot reveals the effect of chronic hypoxia on myocardial gene expression.

OBJECTIVES: In cyanotic patients undergoing repair of heart defects, chronic hypoxia is thought to lead to greater susceptibility to ischemia and reoxygenation injury. We sought to find an explanation to such a hypothesis by investigating the cardiac gene expression in patients with tetralogy of Fallot undergoing cardiac surgery. METHODS: The myocardial gene profile was investigated in right ventricular biopsy specimens obtained from 20 patients with a diagnosis of cyanotic (n = 11) or acyanotic (n = 9) tetralogy of Fallot undergoing surgical repair. Oligonucleotide microarray analyses were performed on the samples, and the array results were validated with Western blotting and enzyme-linked immunosorbent assay. RESULTS: Data revealed 795 differentially expressed genes in cyanotic versus acyanotic hearts, with 198 upregulated and 597 downregulated. Growth/morphogenesis, remodeling, and apoptosis emerged as dominant functional themes for the upregulated genes and included the apoptotic gene TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), the remodeling factor OPN (osteopontin), and the mitochondrial function gene COX11 (cytochrome-c oxidase 11). In contrast, transcription, mitogen-activated protein kinase signaling, and contractile machinery were the dominant functional classes for the downregulated genes, which included the calcium-handling gene NCX1 (sodium-calcium exchanger). Protein levels of COX11, NCX1, OPN, and LYZ (lysozyme) in the myocardium followed the same pattern obtained by means of transcriptomics. The TRAIL level did not change in myocardium but increased in circulating blood of cyanotic patients, suggesting the myocardium as a possible source. Additionally, our data showed increased protein expression of apoptosis markers in cyanotic myocardium. CONCLUSIONS: Chronic hypoxia in cyanotic children with tetralogy of Fallot induced the expression of genes associated with apoptosis and remodeling and reduced the expression of genes associated with myocardium contractility and function.

Bidirectional regulation of kainate receptor surface expression in hippocampal neurons.

Kainate receptors (KARs) are crucial for the regulation of both excitatory and inhibitory neurotransmission, but little is known regarding the mechanisms controlling KAR surface expression. We used super ecliptic pHluorin (SEP)-tagged KAR subunit GluR6a to investigate real-time changes in KAR surface expression in hippocampal neurons. Sindbis virus-expressed SEP-GluR6 subunits efficiently co-assembled with native KAR subunits to form heteromeric receptors. Diffuse surface-expressed dendritic SEP-GluR6 is rapidly internalized following either N-methyl-d-aspartate or kainate application. Sustained kainate or transient N-methyl-d-aspartate application resulted in a slow decrease of base-line surface KAR levels. Surprisingly, however, following the initial loss of surface receptors, a short kainate application caused a long lasting increase in surface-expressed KARs to levels significantly greater than those prior to the agonist challenge. These data suggest that after initial endocytosis, transient agonist activation evokes increased KAR exocytosis and reveal that KAR surface expression is bidirectionally regulated. This process may provide a mechanism for hippocampal neurons to differentially adapt their physiological responses to changes in synaptic activation and extrasynaptic glutamate concentration.

Inhibition of Arp2/3-mediated actin polymerization by PICK1 regulates neuronal morphology and AMPA receptor endocytosis.

The dynamic regulation of actin polymerization plays crucial roles in cell morphology and endocytosis. The mechanistic details of these processes and the proteins involved are not fully understood, especially in neurons. PICK1 is a PDZ-BAR-domain protein involved in regulated AMPA receptor (AMPAR) endocytosis in neurons. Here, we demonstrate that PICK1 binds filamentous (F)-actin and the actin-nucleating Arp2/3 complex, and potently inhibits Arp2/3-mediated actin polymerization. RNA interference (RNAi) knockdown of PICK1 in neurons induces a reorganization of the actin cytoskeleton resulting in aberrant cell morphology. Wild-type PICK1 rescues this phenotype, but a mutant PICK1, PICK1(W413A), that does not bind or inhibit Arp2/3 has no effect. Furthermore, this mutant also blocks NMDA-induced AMPAR internalization. This study identifies PICK1 as a negative regulator of Arp2/3-mediated actin polymerization that is critical for a specific form of vesicle trafficking, and also for the development of neuronal architecture.