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Background Mental disorders are the leading cause of disability for youth worldwide. However, there is a dearth of validated, brief instruments to assess mental health in low- and middle-income countries (LMIC). We aimed to facilitate identification of mental disorders in LMIC contexts by adapting and validating measures of internalizing and externalizing disorders for adolescents in Mozambique, an LMIC in southeastern Africa. Methods We selected instruments with good support for validity in high-income and other LMIC settings: the Patient Health Questionnaire Adolescent (PHQ-A), Generalized Anxiety Disorders 7 (GAD-7), and Strengths and Difficulties Questionnaire (SDQ). Instruments were adapted by local and international mental health specialists followed by cognitive interviews ( n  = 48) with Mozambican adolescents. We administered the instruments along with the Miniature International Neuropsychiatric Interview for Children and Adolescents (MINI-KID)to 485 adolescents aged 12–19 years attending two secondary schools in Maputo City, Mozambique. One week later, we re-administered instruments to a randomly selected sample of 49 adolescents. Results Participants were 66.2% ( n  = 321) female and the average age was 15.9 (S.D = 1.7).Internal consistency (alpha = 0.80, PHQ-A; 0.84, GAD-7; 0.80, SDQ) and test–retest reliabilty (ICC = 0.74, PHQ-A; 0.70, GAD-7; 0.77, SDQ) were acceptabe for the PHQ-A, GAD-7, and the full SDQ. The SDQ internalizing subscale showed poor test–retest reliability (ICC = 0.63) and the SDQ externalizing subscale showed poor internal consistency (alpha = 0.65). All instruments demonstrated good sensitivity and specificity (> 0.70). Youden’s index identified optimal cutoff scores of 8 for the PHQ-A, 5 for the GAD-7, 10 for the SDQ internalizing and 9 for the SDQ externalizing subscales, though a range of scores provided acceptable sensitivity and specificity. Conclusions Our data supports reliability and validity of the PHQ-A, GAD-7, and SDQ instruments for rapidly assessing mental health problems in Mozambican adolescents. Use of these tools in other contexts with limited specialists may asist with expanding mental health assessment. Specific instrument and cutoff selection should be based on screening goals, treatment resources, and program objectives.

Urban health inequities often reflect and follow the geographic patterns of inequality in the social, economic and environmental conditions within a city—the so-called determinants of health. Evidence of patterns within these conditions can support decision-making by identifying where action is urgent and which policies and interventions are needed to mitigate negative impacts and enhance positive impacts. Within the scope of the EU-funded project EURO-HEALTHY (Shaping EUROpean policies to promote HEALTH equitY), the City of Lisbon was selected as a case study to apply a multidimensional and participatory assessment approach of urban health whose purpose was to inform the evaluation of policies and interventions with potential to address local health gaps. In this paper, we present the set of indicators identified as drivers of urban health inequities within the City of Lisbon, exploring the added value of using a spatial indicator framework together with a participation process to orient a place-based assessment and to inform policies aimed at reducing health inequities. Two workshops with a panel of local stakeholders from health and social care services, municipal departments (e.g. urban planning, environment, social rights and education) and non-governmental and community-based organizations were organized. The aim was to engage local stakeholders to identify locally critical situations and select indicators of health determinants from a spatial equity perspective. To support the analysis, a matrix of 46 indicators of health determinants, with data disaggregated at the city neighbourhood scale, was constructed and was complemented with maps. The panel identified critical situations for urban health equity in 28 indicators across eight intervention axes: economic conditions, social protection and security; education; demographic change; lifestyles and behaviours; physical environment; built environment; road safety and healthcare resources and performance. The geographical distribution of identified critical situations showed that all 24 city neighbourhoods presented one or more problems. A group of neighbourhoods systematically perform worse in most indicators from different intervention axes, requiring not only priority action but mainly a multi- and intersectoral policy response. The indicator matrices and maps have provided a snapshot of urban inequities across different intervention axes, making a compelling argument for boosting intersectoral work across municipal departments and local stakeholders in the City of Lisbon. This study, by integrating local evidence in combination with social elements, pinpoints the importance of a place-based approach for assessing urban health equity.

Sprouting angiogenesis, where new blood vessels grow from pre-existing ones, is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and movement. Therefore, a mathematical description of sprouting angiogenesis has to take into consideration biological signals as well as relevant physical processes, in particular the mechanical interplay between adjacent endothelial cells and the extracellular microenvironment. In this work, we introduce the first phase-field continuous model of sprouting angiogenesis capable of predicting sprout morphology as a function of the elastic properties of the tissues and the traction forces exerted by the cells. The model is very compact, only consisting of three coupled partial differential equations, and has the clear advantage of a reduced number of parameters. This model allows us to describe sprout growth as a function of the cell-cell adhesion forces and the traction force exerted by the sprout tip cell. In the absence of proliferation, we observe that the sprout either achieves a maximum length or, when the traction and adhesion are very large, it breaks. Endothelial cell proliferation alters significantly sprout morphology, and we explore how different types of endothelial cell proliferation regulation are able to determine the shape of the growing sprout. The largest region in parameter space with well formed long and straight sprouts is obtained always when the proliferation is triggered by endothelial cell strain and its rate grows with angiogenic factor concentration. We conclude that in this scenario the tip cell has the role of creating a tension in the cells that follow its lead. On those first stalk cells, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of forces in sprouting, hence underlining the necessary collaboration between modelling and molecular biology techniques to improve the current state-of-the-art.

Myocardial ischaemia is associated with an exacerbated inflammatory response, as well as with a deregulation of intercellular communication systems. Macrophages have been implicated in the maintenance of heart homeostasis and in the progression and resolution of the ischaemic injury. Nevertheless, the mechanisms underlying the crosstalk between cardiomyocytes and macrophages remain largely underexplored. Extracellular vesicles (EVs) have emerged as key players of cell‐cell communication in cardiac health and disease. Hence, the main objective of this study was to characterize the impact of cardiomyocyte‐derived EVs upon macrophage activation. Results obtained demonstrate that EVs released by H9c2 cells induced a pro‐inflammatory profile in macrophages, via p38MAPK activation and increased expression of iNOS, IL‐1β and IL‐6, being these effects less pronounced with ischaemic EVs. EVs derived from neonatal cardiomyocytes, maintained either in control or ischaemia, induced a similar pattern of p38MAPK activation, expression of iNOS, IL‐1β, IL‐6, IL‐10 and TNFα. Importantly, adhesion of macrophages to fibronectin was enhanced by EVs released by cardiomyocytes under ischaemia, whereas phagocytic capacity and adhesion to cardiomyocytes were higher in macrophages incubated with control EVs. Additionally, serum‐circulating EVs isolated from human controls or acute myocardial infarction patients induce macrophage activation. According to our model, in basal conditions, cardiomyocyte‐derived EVs maintain a macrophage profile that ensure heart homeostasis, whereas during ischaemia, this crosstalk is affected, likely impacting healing and post‐infarction remodelling.

The end of the Middle Pleistocene Transition (MPT, ~ 800-670 thousand years before present, ka) was characterised by the emergence of large glacial ice-sheets associated with anomalously warm North Atlantic sea surface temperatures enhancing moisture production. Still, the direction and intensity of moisture transport across Eurasia towards potential ice-sheets is poorly constrained. To reconstruct late MPT moisture production and dispersal, we combine records of upper ocean temperature and pollen-based Mediterranean forest cover, a tracer of westerlies and precipitation, from a subtropical drill-core collected off South-West Iberia, with records of East Asia summer monsoon (EASM) strength and West Pacific surface temperatures, and model simulations. Here we show that south-western European winter precipitation and EASM strength reached high levels during the Marine Isotope Stage 18 glacial. This anomalous situation was caused by nearly-continuous moisture supply from both oceans and its transport to higher latitudes through the westerlies, likely fuelling the accelerated expansion of northern hemisphere ice-sheets during the late MPT. Iberian margin and Chinese Plateau climatic records combined with climate modeling reveal a warm ice age centered at ~730,000 years ago, which would have contributed to the accumulation of ice triggering the transition from the 40,000-year to the current 100,000-year climate cycles.

In this study, we aimed to characterize the clinical phenotype of a SHANK1-related disorder and define the functional consequences of SHANK1 truncating variants. Exome sequencing (ES) was performed for six individuals who presented with neurodevelopmental disorders. Individuals were ascertained with the use of GeneMatcher and Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER). We evaluated potential nonsense-mediated decay (NMD) of two variants by making knock-in cell lines of endogenous truncated SHANK1, and expressed the truncated SHANK1 complementary DNA (cDNA) in HEK293 cells and cultured hippocampal neurons to examine the proteins. ES detected de novo truncating variants in SHANK1 in six individuals. Evaluation of NMD resulted in stable transcripts, and the truncated SHANK1 completely lost binding with Homer1, a linker protein that binds to the C-terminus of SHANK1. These variants may disrupt protein–protein networks in dendritic spines. Dispersed localization of the truncated SHANK1 variants within the spine and dendritic shaft was also observed when expressed in neurons, indicating impaired synaptic localization of truncated SHANK1. This report expands the clinical spectrum of individuals with truncating SHANK1 variants and describes the impact these variants may have on the pathophysiology of neurodevelopmental disorders.

Extracellular vesicles (EVs) have been associated with the transport of molecules related to the pathological processes in neurodegenerative diseases. Machado-Joseph disease (MJD) is a neurodegenerative disorder triggered by mutant ataxin-3 protein that causes protein misfolding and aggregation resulting in neuronal death. To evaluate EVs’ role in the potential spread of disease-associated factors in MJD, in this study, EVs were isolated from human Control (CNT) and MJD induced-pluripotent stem cell-derived neuroepithelial stem cells (iPSC-derived NESC) and their differentiated neural cultures (cell cultures composed of neurons and glia). EVs were characterized and investigated for their ability to interfere with cell mechanisms known to be impaired in MJD. The presence of mRNA and proteins related to autophagy, cell survival, and oxidative stress pathways, and the mutant ataxin-3, was evaluated in the EVs. SOD1, p62, and Beclin-1 were found present both in CNT and MJD EVs. Lower levels of the p62 autophagy-related protein and higher levels of the oxidative stress-related SOD1 protein were found in MJD EVs. The oxidative stress-related CYCS mRNA and autophagy-related SQSTM1 , BECN1 , UBC , ATG12 , and LC3B mRNAs were detected in EVs and no significant differences in their levels were observed between CNT and MJD EVs. The internalization of EVs by human CNT neurons was demonstrated, and no effect of the EVs administration was observed on cell viability. Moreover, the incubation of MJD EVs (isolated from NESC or differentiated neural cultures) with human CNT differentiated neural cells resulted in the reduction of SOD1 and autophagy-related proteins ATG3, ATG7, Beclin-1, LC3B, and p62 levels. Finally, a tendency for accumulation of ataxin-3-positive aggregates in CNT differentiated neural cells co-cultured with MJD differentiated neural cells was observed. Overall, our data indicate that EVs carry autophagy- and oxidative stress-related proteins and mRNAs and provide evidence of MJD EVs-mediated interference with autophagy and oxidative stress pathways.

A high-resolution record of central Mediterranean Sea Surface Temperatures (SSTs) based on the alkenone U-37(K') index and planktic delta O-18 values for the surface-dweller G. ruber has been reconstructed across the Pliocene/Pleistocene transition at Monte San Nicola (Sicily), reference area for the GSSP (Global Boundary Stratotype Section and Point) of the Gelasian Stage. Spectral analyses indicate that the SST record is predominantly paced by a cyclicity in the similar to 47 kyr time domain, consistent with the obliquity driven glacial-interglacial variability that is expected to dominate in the interval of relevance. In addition, two suborbital periodicities in the similar to 5 kyr and similar to 8 kyr time domains provide a pervasive spectral signal that proves to be especially strong during the MIS (Marine Isotope Stage) 100 glacial, at the inception of the Northern Hemisphere Glaciation. This high frequency climatic instability, a prominent feature of the early Gelasian, might reflect episodic events of massive disruption of the Atlantic Meridional Overturning Circulation with increased production of cold, low-salinity water masses in the North Atlantic. Alternatively, it may be interpreted as the resonance (i.e., harmonics) of the low-latitude precessional forcing in mid-latitude regions. Although the driving mechanisms of these processes remain largely unconstrained, our study emphasizes the role of the central Mediterranean as the main reference for high-resolution paleoclimatic studies in the Neogene and the Quaternary.

Across the last deglaciation, the atmospheric CO2 concentration (CO2) increased substantially from ∼ 180 to ∼ 280 ppm, yet its impact on vegetation dynamics across this major climatic transition remains insufficiently understood. In particular, Iberian pollen records reveal an intriguing feature that can be related to an often overlooked role of CO2 in shaping vegetation responses during the last deglaciation. These records reveal the near disappearance of forests during the cold Last Glacial Maximum (LGM) and Heinrich Stadial 1 (HS1) phases and an unexpected recovery during the Younger Dryas (YD) cold phase when CO2 increased. Here, we present high-resolution tracers of terrestrial (pollen, C29 : C31 organic biomarker) and marine (alkenone-derived Sea Surface Temperature, C37 : 4 %, and long-chain n-alkanes ratios) conditions from the southwestern (SW) Iberian margin Integrated Ocean Drilling Program Site U1385 (“Shackleton site”) for the last 22 cal kyr BP. This direct land-sea comparison approach allows us to investigate how the Iberian Peninsula vegetation responded to major global CO2 changes during the last deglaciation. Our results show that cool and moderately humid conditions of the LGM supported a grassland-heathland mosaic ecosystem, but low CO2 likely caused physiological drought and suppressed forest development. HS1, the coldest and most arid period, combined with sustained low CO2 values, almost suppressed forest growth in favour of Mediterranean steppe. In contrast, the warmer Bølling-Allerød, characterised by a temperature optimum and variable but generally wetter conditions, along with the rise of CO2 above 225 ppm at ∼ 15 cal kyr BP, contributed to substantial forest development. During the YD, sufficient moisture combined with increasing CO2 enabled the persistence of a mixed grassland-forest mosaic despite cooler temperatures. Our study suggests that during cool and humid periods (LGM and YD) different pCO2 values led to contrasting SW Iberian vegetation responses. In contrast, during periods of relatively high CO2, temperature and precipitation played the main role in shaping the distribution and composition of the vegetation.