Mapping the specific pathways to early-onset mental health disorders : the "Watch Me Grow for REAL" study protocol

Background: From birth, the human propensity to selectively attend and respond to critical super-stimuli forms the basis of future socio-emotional development and health. In particular, the first super-stimuli to preferentially engage and elicit responses in the healthy newborn are the physical touch, voice and face/eyes of caregivers. From this grows selective attention and responsiveness to emotional expression, scaffolding the development of empathy, social cognition, and other higher human capacities. In this paper, the protocol for a longitudinal, prospective birth-cohort study is presented. The major aim of this study is to map the emergence of individual differences and disturbances in the system of social-Responsiveness, Emotional Attention, and Learning (REAL) through the first 3 years of life to predict the specific emergence of the major childhood mental health problems, as well as social adjustment and impairment more generally. A further aim of this study is to examine how the REAL variables interact with the quality of environment/caregiver interactions. Methods/Design: A prospective, longitudinal birth-cohort study will be conducted. Data will be collected from four assessments and mothers' electronic medical records. Discussion: This study will be the first to test a clear developmental map of both the unique and specific causes of childhood psychopathology and will identify more precise early intervention targets for children with complex comorbid conditions

Extracellular nucleotides inhibit growth of human oesophageal cancer cells via P2Y2-receptors

Extracellular ATP is known to inhibit growth of various tumours by activating specific purinergic receptors (P2-receptors). Since the therapy of advanced oesophageal cancer is unsatisfying, new therapeutic approaches are mandatory. Here, we investigated the functional expression and potential antiproliferative effects of P2-purinergic receptors in human oesophageal cancer cells. Prolonged incubation of primary cell cultures of human oesophageal cancers as well as of the squamous oesophageal cancer cell line Kyse-140 with ATP or its stable analogue ATPγS dose-dependently inhibited cell proliferation. This was due to both an induction of apoptosis and cell cycle arrest. The expression of P2-receptors was examined by RT-PCR, immunocytochemistry, and [Ca2+]i-imaging. Application of various extracellular nucleotides dose-dependently increased [Ca2+]i. The rank order of potency was ATP=UTP>ATPγS>ADP=UDP. 2-methylthio-ATP and α,β-methylene-ATP had no effects on [Ca2+]i. Complete cross-desensitization between ATP and UTP was observed. Moreover, the phospholipase C inhibitor U73122 dose-dependently reduced the ATP triggered [Ca2+]i signal. The pharmacological features strongly suggest the functional expression of G-protein coupled P2Y2-receptors in oesophageal squamous cancer cells. P2Y2-receptors are involved in the antiproliferative actions of extracellular nucleotides. Thus, P2Y2-receptors are promising target proteins for innovative approaches in oesophageal cancer therapy

Global Carbon Budget 2023

Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere in a changing climate is critical to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe and synthesize data sets and methodology to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO2 emissions (EFOS) are based on energy statistics and cement production data, while emissions from land-use change (ELUC), mainly deforestation, are based on land-use and land-use change data and bookkeeping models. Atmospheric CO2 concentration is measured directly, and its growth rate (GATM) is computed from the annual changes in concentration. The ocean CO2 sink (SOCEAN) is estimated with global ocean biogeochemistry models and observation-based f CO2 products. The terrestrial CO2 sink (SLAND) is estimated with dynamic global vegetation models. Additional lines of evidence on land and ocean sinks are provided by atmospheric inversions, atmospheric oxygen measurements, and Earth system models. The resulting carbon budget imbalance (BIM), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and incomplete understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ. For the year 2022, EFOS increased by 0.9 % relative to 2021, with fossil emissions at 9.9 ± 0.5 Gt C yr−1 (10.2 ± 0.5 Gt C yr−1 when the cement carbonation sink is not included), and ELUC was 1.2 ± 0.7 Gt C yr−1, for a total anthropogenic CO2 emission (including the cement carbonation sink) of 11.1 ± 0.8 Gt C yr−1 (40.7±3.2 Gt CO2 yr−1). Also, for 2022, GATM was 4.6±0.2 Gt C yr−1 (2.18±0.1 ppm yr−1; ppm denotes parts per million), SOCEAN was 2.8 ± 0.4 Gt C yr−1, and SLAND was 3.8 ± 0.8 Gt C yr−1, with a BIM of −0.1 Gt C yr−1 (i.e. total estimated sources marginally too low or sinks marginally too high). The global atmospheric CO2 concentration averaged over 2022 reached 417.1 ± 0.1 ppm. Preliminary data for 2023 suggest an increase in EFOS relative to 2022 of +1.1 % (0.0 % to 2.1 %) globally and atmospheric CO2 concentration reaching 419.3 ppm, 51 % above the pre-industrial level (around 278 ppm in 1750). Overall, the mean of and trend in the components of the global carbon budget are consistently estimated over the period 1959–2022, with a near-zero overall budget imbalance, although discrepancies of up to around 1 Gt C yr−1 persist for the representation of annual to semi-decadal variability in CO2 fluxes. Comparison of estimates from multiple approaches and observations shows the following: (1) a persistent large uncertainty in the estimate of land-use changes emissions, (2) a low agreement between the different methods on the magnitude of the land CO2 flux in the northern extra-tropics, and (3) a discrepancy between the different methods on the strength of the ocean sink over the last decade. This living-data update documents changes in methods and data sets applied to this most recent global carbon budget as well as evolving community understanding of the global carbon cycle. The data presented in this work are available at https://doi.org/10.18160/GCP-2023 (Friedlingstein et al., 2023)

Still connecting the dots: An investigation into infants\u27 attentional bias to threat using an eye-tracking task

An attentional bias toward threat has been theorized to be a normative aspect of infants\u27 threat and safety learning, and an indicator of risk for internalizing psychopathology in older populations. To date, only four studies have examined this bias using the dot-probe task in infancy and the findings are mixed. We extended the literature by examining patterns of attention to threat in a culturally and linguistically diverse sample of infants aged 5-11 months old (N = 151) using all measures previously employed in the infant dot-probe literature. Given that an attentional bias toward threat is associated with higher risk of developing anxiety disorders later in life, we also examined how negative affect-an early correlate of later anxiety disorders-is related to attentional bias toward threat in infancy. This study was the first to use a consistent measure of negative affect across the whole sample. An eye-tracking dot-probe task was used to examine attentional bias toward threat (i.e., angry faces) relative to positive (i.e., happy faces) stimuli. Results showed that an attention bias to threat was not characteristic of infants at this age, and negative affect did not moderate the putative relationship between attention and emotional faces (angry, happy). These findings therefore suggest that attention biases to socio-emotional threat may not have emerged by 11 months old

Still connecting the dots: An investigation into infants' attentional bias to threat using an eye-tracking task

An attentional bias toward threat has been theorized to be a normative aspect of infants' threat and safety learning, and an indicator of risk for internalizing psychopathology in older populations. To date, only four studies have examined this bias using the dot-probe task in infancy and the findings are mixed. We extended the literature by examining patterns of attention to threat in a culturally and linguistically diverse sample of infants aged 5–11 months old (N = 151) using all measures previously employed in the infant dot-probe literature. Given that an attentional bias toward threat is associated with higher risk of developing anxiety disorders later in life, we also examined how negative affect—an early correlate of later anxiety disorders—is related to attentional bias toward threat in infancy. This study was the first to use a consistent measure of negative affect across the whole sample. An eye-tracking dot-probe task was used to examine attentional bias toward threat (i.e., angry faces) relative to positive (i.e., happy faces) stimuli. Results showed that an attention bias to threat was not characteristic of infants at this age, and negative affect did not moderate the putative relationship between attention and emotional faces (angry, happy). These findings therefore suggest that attention biases to socio-emotional threat may not have emerged by 11 months old.</p

Prospects for immunotherapy of malignant disease

The majority of T cell-recognized tumour antigens in humans are encoded by genes that are also present in normal tissues. Low levels of gene expression in normal cells can lead to the inactivation of high-avidity T cells by immunological tolerance mechanisms. As a consequence, low-avidity T cell responses in patients are often inadequate in providing tumour protection. Recently, several technologies have been developed to overcome tolerance, allowing the isolation of high-affinity, HLA-restricted receptors specific for tumour-associated peptide epitopes. Furthermore, transfer of HLA-restricted antigen receptors provides an opportunity to empower patient T cells with new tumour-reactive specificities that cannot be retrieved from the autologous T cell repertoire