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Objective To identify cervicovaginal fluid ( CVF) biomarkers predictive of spontaneous preterm birth in women with symptoms of preterm labour. Design Retrospective cohort study. Setting Melbourne, Australia. Population Women with a singleton pregnancy admitted to the Emergency Department between 22 and 36 weeks of gestation presenting with symptoms of preterm labour. Methods Two-dimensional electrophoresis was used to analyse the CVF proteome. Validation of putative biomarkers was performed using enzyme-linked immunosorbent assay ( ELISA) in an independent cohort. Optimal concentration thresholds of putative biomarkers were determined and the predictive efficacy for preterm birth was compared with that of fetal fibronectin. Main outcome measures Prediction of spontaneous preterm labour within 7 days. Results Differentially expressed proteins were identified by proteomic analysis in women presenting with 'threatened' preterm labour without cervical change who subsequently delivered preterm ( n = 12 women). ELISA validation using an independent cohort ( n = 129 women) found albumin and vitamin D-binding protein ( VDBP) to be significantly altered between women who subsequently experienced preterm birth and those who delivered at term. Prediction of preterm delivery within 7 days using a dual biomarker model (albumin/ VDBP) provided 66.7% sensitivity, 100% specificity, 100% positive predictive value ( PPV) and 96.7% negative predictive value ( NPV), compared with fetal fibronectin yielding 66.7, 87.9, 36.4 and 96.2%, respectively ( n = 64). Using the maximum number of screened samples, the predictive utility of albumin/ VDBP yielded a sensitivity of 77.8%, specificity and PPV of 100% and NPV of 98.0% ( n = 109). Conclusions The dual biomarker model of albumin/ VDBP is more efficacious than fetal fibronectin in predicting spontaneous preterm delivery in symptomatic women within 7 days. A clinical diagnostic trial is required to test this model on a larger population to confirm these findings and to further refine the predictive values. [ABSTRACT FROM AUTHOR]

Abstract: Forkhead box O (FoxO) proteins function primarily as transcription factors in the nucleus where they bind to their cognate DNA targeting sequences. FoxO regulated genes include those involved in cellular stress responses, inflammation and apoptosis; all of which are involved in the processes of human labour and delivery. We have previously identified Forkhead box O4 (FoxO4) proteins in human gestational tissues; there is, however, no data is available on the role of FoxO4 in the processes of human labour and delivery. Thus the aim of this study was to determine the effect of (i) human labour, preterm chorioamnionitis and pro-inflammatory stimuli on the expression of FoxO4 in human placenta and fetal membranes; and (ii) FoxO4 knockdown by siRNA on the expression of pro-labour mediators. Quantitative RT-PCR (qRT-PCR), immunohistochemistry and/or Western blotting was used to analyse the expression of FoxO4 (n = 6 per group). Human labour and preterm chorioamnionitis significantly decreased cytoplasmic FoxO4 expression in placenta and/or choriodecidua. Knockdown of FoxO4 mRNA and protein in JEG-3 cells using siRNA was associated with decreased COX-2 mRNA expression concomitant with lower PGF2α secretion. However, in BeWo cells, siRNA inhibition of FoxO4 was not associated with inflammation, oxidative stress or apoptosis. In summary, human term labour and chorioamnionitis is characterised by lower FoxO4 mRNA and/or protein expression in placenta and/or choriodecidua. Although the exact role of FoxO4 in human pregnancy remains to be fully elucidated, our data demonstrate that it can regulate COX-2 expression and subsequent prostaglandin expression. [Copyright &y& Elsevier]

1. The present study examines the effects of the microtubule depolarizing agent colchicine on secretory type II phospholipase A2 (PLA2) function in Chinese hamster ovary (CHO) cells that specifically overexpress human type II PLA2 and the effect of both colchicine and tubulazole on the release of type II PLA2 and prostaglandin (PG) F2α from human placental explants. 2. Significant suppression by colchicine (0.01–10 μmol/L) of PLA2 activity (P < 0.00001), immunoreactive type II PLA2 (irPLA2; P < 0.00001) and PGF2α release (P < 0.01) was observed in medium from overexpressing CHO cells. These effects were significantly reduced (P < 0.0001) in the presence of 10 μmol/L taxol, an agent that prevents depolymerization of microtubules. The addition of 30 μmol/L arachidonic acid significantly reduced (P < 0.0001) the inhibition of PGF2α production in CHO cell lines. 3. The addition of 1 μmol/L colchicine to human placental explants for 24 h significantly reduced irPLA2 (P < 0.00001) and PGF2α production (P < 0.00001). Similarly, 1 μmol/L tubulazole significantly blocked irPLA2 (P < 0.001) and PGF2α (P < 0.0001). 4. At 10 μmol/L, taxol significantly reduced irPLA2 inhibition by colchicine (n = 8; P < 0.05) and tubulazole (n = 8; P < 0.05). Similarly, taxol significantly reduced the reduction in PGF2α production caused by colchicine (P < 0.001) and by tubulazole (P < 0.001). 5. These results suggest that integrity of the microtubule system is required for PLA2 function and the subsequent production of pro-inflammatory mediators. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to investigate the temporal changes in immunoreactive cystatin A and the enzymatic activity of cathepsins B, H, L, and S in human cervicovaginal fluid (CVF) in late pregnancy and spontaneous labor. STUDY DESIGN: CVF was collected weekly (n = 95 women) from 36 weeks gestation until spontaneous term labor. Cystatin A was quantified using enzyme-linked immunosorbent assay. The enzyme activity of cathepsins B, H, L, and S was measured with fluorometric enzyme assay kits. RESULTS: Cystatin A significantly decreased towards (P = .016, 2-way analysis of variance) and during labor (P < .001, 2-way analysis of variance). Enzymatic activity of cathepsins B, H, and S did not change with labor onset (P = .452, P = .703, P = .411, respectively, 2-way analysis of variance). CONCLUSION: In late gestation, CVF-decreased expression of the cysteine protease inhibitor, cystatin A, is associated with labor. Although the role and contribution of cystatin A to increased extracellular matrix remodeling has yet to be elucidated, the data that were obtained are consistent with this hypothesis. [ABSTRACT FROM AUTHOR]

The field of extracellular vesicle (EV) signalling has the potential to transform our understanding of maternal-fetal communication and affords new opportunities for non-invasive prenatal testing and therapeutic intervention. EVs have been implicated in implantation, placentation, maternal adaptation to pregnancy and complications of pregnancy, being detectable in maternal circulation as early as 6 weeks of pregnancy. EVs of differing biogenic origin, composition and bioactivity are released by cells to maintain homoeostasis. Induction of EV signalling is associated with aberrant cellular metabolism and manifests as changes in EV concentrations and/or composition. Characterizing such changes affords opportunity to develop more informative diagnostics and efficacious interventions. To develop accurate and reliable EV-based diagnostics requires: identification of disease-associated biomarkers in specific EV subpopulations; and rapid, reproducible and scalable sample processing. Conventional isolation methods face challenges due to co-isolation of particles with similar physicochemical properties. Methods targeting specific vesicle-surface epitopes and compatible with automated platforms show promise. Effective EV therapeutics require precise targeting, achieved through genetic engineering to release EVs expressing cell-targeting ligands and carrying therapeutic payloads. Unlike cell-based therapies, this approach offers advantages including: low immunogenicity; stability; and long-term storage. Although EV diagnostics and therapeutics in reproductive biology are nascent, available technologies can enhance our understanding of EV signalling between mother and fetus, its role in pregnancies and improve outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gregroy E Rice reports financial support was provided by INOVIQ Limited., (Copyright © 2024. Published by Elsevier Ltd.)

Resting-state network research is extremely influential, yet the functions of many networks remain unknown. In part, this is due to typical (e.g., univariate) analyses independently testing the function of individual regions and not examining the full set of regions that form a network whilst co-activated. Connectivity is dynamic and the function of a region may change based on its current connections. Therefore, determining the function of a network requires assessment at this network-level. Yet popular theories implicating the default mode network (DMN) in episodic memory and social cognition, rest principally upon analyses performed at the level of individual brain regions. Here we use independent component analysis to formally test the role of the DMN in episodic and social processing at the network level. As well as an episodic retrieval task, two independent datasets were employed to assess DMN function across the breadth of social cognition; a person knowledge judgement and a theory of mind task. Each task dataset was separated into networks of co-activated regions. In each, the co-activated DMN, was identified through comparison to an a priori template and its relation to the task model assessed. This co-activated DMN did not show greater activity in episodic or social tasks than high-level baseline conditions. Thus, no evidence was found to support hypotheses that the co-activated DMN is involved in explicit episodic or social tasks at a network-level. The networks associated with these processes are described. Implications for prior univariate findings and the functional significance of the co-activated DMN are considered., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Knowledge about the consequences of stroke on high-level vision comes primarily from single case studies of patients selected based on their behavioural profiles, typically patients with specific stroke syndromes like pure alexia or prosopagnosia. There are, however, no systematic, detailed, large-scale evaluations of the more typical clinical behavioural and lesion profiles of impairments in high-level vision after posterior cerebral artery stroke. We present behavioural and lesion data from the Back of the Brain project, to date the largest ( N = 64) and most detailed examination of patients with cortical posterior cerebral artery strokes selected based on lesion location. The aim of the current study was to relate behavioural performance with faces, objects and written words to lesion data through two complementary analyses: (i) a multivariate multiple regression analysis to establish the relationships between lesion volume, lesion laterality and the presence of a bilateral lesion with performance and (ii) a voxel-based correlational methodology analysis to establish whether there are distinct or separate regions within the posterior cerebral artery territory that underpin the visual processing of words, faces and objects. Behaviourally, most patients showed more general deficits in high-level vision ( n = 22) or no deficits at all ( n = 21). Category-selective deficits were rare ( n = 6) and were only found for words. Overall, total lesion volume was most strongly related to performance across all three domains. While behavioural impairments in all domains were observed following unilateral left and right as well as bilateral lesions, the regions most strongly related to performance mainly confirmed the pattern reported in more selective cases. For words, these included a left hemisphere cluster extending from the occipital pole along the fusiform and lingual gyri; for objects, bilateral clusters which overlapped with the word cluster in the left occipital lobe. Face performance mainly correlated with a right hemisphere cluster within the white matter, partly overlapping with the object cluster. While the findings provide partial support for the relative laterality of posterior brain regions supporting reading and face processing, the results also suggest that both hemispheres are involved in the visual processing of faces, words and objects., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Semantic control allows us to focus semantic activation on currently relevant aspects of knowledge, even in the face of competition or when the required information is weakly encoded. Diverse cortical regions, including left prefrontal and posterior temporal cortex, are implicated in semantic control, however; the relative contribution of these regions is unclear. For the first time, we compared semantic aphasia (SA) patients with damage restricted to temporoparietal cortex (TPC; N = 8) to patients with infarcts encompassing prefrontal cortex (PF+; N = 22), to determine if prefrontal lesions are necessary for semantic control deficits. These SA groups were also compared with semantic dementia (SD; N = 10), characterised by degraded semantic representations. We asked whether TPC cases with semantic impairment show controlled retrieval deficits equivalent to PF+ cases or conceptual degradation similar to patients with SD. Independent of lesion location, the SA subgroups showed similarities, whereas SD patients showed a qualitatively distinct semantic impairment. Relative to SD, both TPC and PF+ SA subgroups: (1) showed few correlations in performance across tasks with differing control demands, but a strong relationship between tasks of similar difficulty; (2) exhibited attenuated effects of lexical frequency and concept familiarity, (3) showed evidence of poor semantic regulation in their verbal output - performance on picture naming was substantially improved when provided with a phonological cue, and (4) showed effects of control demands, such as retrieval difficulty, which were equivalent in severity across TPC and PF+ groups. These findings show that semantic impairment in SA is underpinned by damage to a distributed semantic control network, instantiated across anterior and posterior cortical areas., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: While benefits of greenness to health have been reported, findings specific to child respiratory health are inconsistent., Methods: We utilized a prospective birth cohort followed from birth to age 7 years (n = 617). Residential surrounding greenness was quantified via Normalized Difference Vegetation Index (NDVI) within 200, 400, and 800 m distances from geocoded home addresses at birth, age 7 years, and across childhood. Respiratory health outcomes were assessed at age 7 years, including asthma and lung function [percent predicted forced expiratory volume in the first second (%FEV 1 ), percent predicted forced vital capacity (%FVC), and percent predicted ratio of forced expiratory volume in the first second to forced vital capacity (%FEV 1 /FVC)]. We assessed associations using linear and logistic regression models adjusted for community deprivation, household income, and traffic-related air pollution. We tested for effect measure modification by atopic status., Results: We noted evidence of positive confounding as inverse associations were attenuated upon adjustment in the multivariable models. We found evidence of effect measure modification of NDVI and asthma within 400 m at age 7 years by atopic status (p = 0.04), whereby children sensitized to common allergens were more likely to develop asthma as exposure to greenness increased (OR = 1.3, 95% CI: 0.9, 2.0) versus children not sensitized to common allergens (OR = 0.8, 95% CI: 0.5, 1.2). We found consistently positive associations between NDVI and %FEV 1 and %FVC which similarly evidenced positive confounding upon adjustment. In the adjusted regression models, NDVI at 7 years of age was associated with %FEV 1 (200 m: β = 2.1, 95% CI: 0.1, 3.3; 400 m: β = 1.6, 95% CI: 0.3, 2.9) and %FVC (200 m: β = 1.8, 95% CI: 0.7, 3.0; 400 m: β = 1.6, 95% CI: 0.3, 2.8; 800 m: β = 1.5, 95% CI: 0.1, 2.8). Adjusted results for %FEV 1 /FVC were non-significant except exposure at birth in the 400 m buffer (β = 0.81, 95% CI: 0.1, 1.5). We found no evidence of effect measure modification of NDVI by atopic status for objective measures of lung function., Conclusion: Sensitivity to allergens may modify the effect of greenness on risk for asthma in children but greenness is likely beneficial for concurrent lung function regardless of allergic status., (© 2022. The Author(s).)

During the last decade, there has been great interest in elucidating the biological role of extracellular vesicles (EVs), particularly, their hormone-like role in cell-to-cell communication. The field of endocrinology is uniquely placed to provide insight into the functions of EVs, which are secreted from all cells into biological fluids and carry endocrine signals to engage in paracellular and distal interactions. EVs are a heterogeneous population of membrane-bound vesicles of varying size, content, and bioactivity. EVs are specifically packaged with signaling molecules, including lipids, proteins, and nucleic acids, and are released via exocytosis into biofluid compartments. EVs regulate the activity of both proximal and distal target cells, including translational activity, metabolism, growth, and development. As such, EVs signaling represents an integral pathway mediating intercellular communication. Moreover, as the content of EVs is cell-type specific, it is a "fingerprint" of the releasing cell and its metabolic status. Recently, changes in the profile of EV and bioactivity have been described in several endocrine-related conditions including diabetes, obesity, cardiovascular diseases, and cancer. The goal of this statement is to highlight relevant aspects of EV research and their potential role in the field of endocrinology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Fast periodic visual stimulation (FPVS) allows the recording of objective brain responses of human face categorization (i.e., generalizable face-selective responses) with high signal-to-noise ratio. This approach has been successfully employed in a number of scalp electroencephalography (EEG) studies but has not been used with magnetoencephalography (MEG) yet, let alone with combined MEG/EEG recordings and distributed source estimation. Here, we presented various natural images of faces periodically (1.2 Hz) among natural images of objects (base frequency 6 Hz) whilst recording simultaneous EEG and MEG in 15 participants. Both measurement modalities showed face-selective responses at 1.2 Hz and harmonics across participants, with high and comparable signal-to-noise ratio (SNR) in about 3 min of stimulation. The correlation of face categorization responses between EEG and two MEG sensor types was lower than between the two MEG sensor types, indicating that the two sensor modalities provide independent information about the sources of face-selective responses. Face-selective EEG responses were right-lateralized as reported previously, and were numerically but non-significantly right-lateralized in MEG data. Distributed source estimation based on combined EEG/MEG signals confirmed a more bilateral face-selective response in visual brain regions located anteriorly to the common response to all stimuli at 6 Hz and harmonics. Conventional sensor and source space analyses of evoked responses in the time domain further corroborated this result. Our results demonstrate that FPVS in combination with simultaneously recorded EEG and MEG may serve as an efficient localizer paradigm for human face categorization., (Copyright © 2021. Published by Elsevier Inc.)

Proteomics has gone through tremendous development during recent decades [...].

Conceptual knowledge allows the categorisation of items according to their meaning beyond their physical similarities. This ability to respond to different stimuli (e.g., a leek, a cabbage, etc.) based on similar semantic representations (e.g., belonging to the vegetable category) is particularly important for language processing, because word meaning and the stimulus form are unrelated. The neural basis of this core human ability is debated and is complicated by the strong reliance of most neural measures on explicit tasks, involving many non-semantic processes. Here we establish an implicit method, i.e., fast periodic visual stimulation (FPVS) coupled with electroencephalography (EEG), to study neural conceptual categorisation processes with written word stimuli. Fourteen neurotypical participants were presented with different written words belonging to the same semantic category (e.g., different animals) alternating at 4 Hz rate. Words from a different semantic category (e.g., different cities) appeared every 4 stimuli (i.e., at 1 Hz). Following a few minutes of recording, objective electrophysiological responses at 1 Hz, highlighting the human brain's ability to implicitly categorize stimuli belonging to distinct conceptual categories, were found over the left occipito-temporal region. Topographic differences were observed depending on whether the periodic change involved living items, associated with relatively more ventro-temporal activity as compared to non-living items associated with relatively more dorsal posterior activity. Overall, this study demonstrates the validity and high sensitivity of an implicit frequency-tagged marker of word-based semantic memory abilities., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

Ovarian cancer (OC) is one of the most diagnosed gynecological cancers in women. Due to the lack of effective early stage screening, women are more often diagnosed at an advanced stage; therefore, it is associated with poor patient outcomes. There are a lack of tools to identify patients at the highest risk of developing this cancer. Moreover, early detection strategies, therapeutic approaches, and real-time monitoring of responses to treatment to improve survival and quality of life are also inadequate. Tumor development and progression are dependent upon cell-to-cell communication, allowing cancer cells to re-program cells not only within the surrounding tumor microenvironment, but also at distant sites. Recent studies established that extracellular vesicles (EVs) mediate bi-directional communication between normal and cancerous cells. EVs are highly stable membrane vesicles that are released from a wide range of cells, including healthy and cancer cells. They contain tissue-specific signaling molecules (e.g., proteins and miRNA) and, once released, regulate target cell phenotypes, inducing a pro-tumorigenic and immunosuppressive phenotype to contribute to tumor growth and metastasis as well as proximal and distal cell function. Thus, EVs are a "fingerprint" of their cell of origin and reflect the metabolic status. Additionally, via the capacity to evade the immune system and remain stable over long periods in circulation, EVs can be potent therapeutic agents. This review examines the potential role of EVs in the different aspects of the tumor microenvironment in OC, as well as their application in diagnosis, delivery of therapeutic agents, and disease monitoring.

Hypoxia is a key regulator of cancer progression and chemoresistance. Ambiguity remains about how cancer cells adapt to hypoxic microenvironments and transfer oncogenic factors to surrounding cells. In this study, we determined the effects of hypoxia on the bioactivity of sEVs in a panel of ovarian cancer (OvCar) cell lines. The data obtained demonstrate a varying degree of platinum resistance induced in OvCar cells when exposed to low oxygen tension (1% oxygen). Using quantitative mass spectrometry (Sequential Window Acquisition of All Theoretical Fragment Ion Mass Spectra, SWATH) and targeted multiple reaction monitoring (MRM), we identified a suite of proteins associated with glycolysis that change under hypoxic conditions in cells and sEVs. Interestingly, we identified a differential response to hypoxia in the OvCar cell lines and their secreted sEVs, highlighting the cells' heterogeneity. Proteins are involved in metabolic reprogramming such as glycolysis, including putative hexokinase (HK), UDP-glucuronosyltransferase 1-6 (UD16), and 6-phosphogluconolactonase (6 PGL), and their presence correlates with the induction of platinum resistance. Furthermore, when normoxic cells were exposed to sEVs from hypoxic cells, platinum-resistance increased significantly ( p < 0.05). Altered chemoresistance was associated with changes in glycolysis and fatty acid synthesis. Finally, sEVs isolated from a clinical cohort ( n = 31) were also found to be enriched in glycolysis-pathway proteins, especially in patients with recurrent disease. These data support the hypothesis that hypoxia induces changes in sEVs composition and bioactivity that confers carboplatin resistance on target cells. Furthermore, we propose that the expression of sEV-associated glycolysis-pathway proteins is predictive of ovarian cancer recurrence and is of clinical utility in disease management.

The purpose of this study was to explore an important research goal in cognitive and clinical neuroscience: What are the neurocomputational mechanisms that make cognitive systems "well engineered" and thus resilient across a range of performance demands and to mild levels of perturbation or even damage? A new hypothesis called 'variable neuro-displacement' suggests that cognitive systems are formed with dynamic, spare processing capacity, which balances energy consumption against performance requirements and can be resilient to changes in performance demands. Here, we tested this hypothesis by investigating the neural dynamics of the semantic system by manipulating performance demand. The performance demand was manipulated with two levels of task difficulty (easy vs. hard) in two different ways (stimulus type and response timing). We found that the demanding semantic processing increased regional activity in both the domain-specific semantic representational system (anterior temporal lobe) and the parallel executive control networks (prefrontal, posterior temporal, and parietal regions). Functional connectivity between these regions was also increased during demanding semantic processing and these increases were related to better semantic task performance. Our results suggest that semantic cognition is made resilient by flexible, dynamic changes including increased regional activity and functional connectivity across both domain-specific and domain-general systems. It reveals the intrinsic resilience-related mechanisms of semantic cognition, mimicking alterations caused by perturbation or brain damage. Our findings provide a strong implication that the intrinsic mechanisms of a well-engineered semantic system might be attributed to the compensatory functional alterations in the impaired brain.

The organisational principles of the visual ventral stream are still highly debated, particularly the relative association/dissociation between word and face recognition and the degree of lateralisation of the underlying processes. Reports of dissociations between word and face recognition stem from single case-studies of category selective impairments, and neuroimaging investigations of healthy participants. Despite the historical reliance on single case-studies, more recent group studies have highlighted a greater commonality between word and face recognition. Studying individual patients with rare selective deficits misses (a) important variability between patients, (b) systematic associations between task performance, and (c) patients with mild, severe and/or non-selective impairments; meaning that the full spectrum of deficits is unknown. The Back of the Brain project assessed the range and specificity of visual perceptual impairment in 64 patients with posterior cerebral artery stroke recruited based on lesion localization and not behavioural performance. Word, object, and face processing were measured with comparable tests across different levels of processing to investigate associations and dissociations across domains. We present two complementary analyses of the extensive behavioural battery: (1) a data-driven analysis of the whole patient group, and (2) a single-subject case-series analysis testing for deficits and dissociations in each individual patient. In both analyses, the general organisational principle was of associations between words, objects, and faces even following unilateral lesions. The majority of patients either showed deficits across all domains or in no domain, suggesting a spectrum of visuo-perceptual deficits post stroke. Dissociations were observed, but they were the exception and not the rule: Category-selective impairments were found in only a minority of patients, all of whom showed disproportionate deficits for words. Interestingly, such selective word impairments were found following both left and right hemisphere lesions. This large-scale investigation of posterior cerebral artery stroke patients highlights the bilateral representation of visual perceptual function., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Exposure to an adverse prenatal environment can influence fetal development and result in long-lasting changes in the offspring. However, the association between maternal exposure to stressful events during pregnancy and the achievement of pre-reading skills in the offspring is unknown. Here we examined the association between prenatal exposure to the Chilean high-magnitude earthquake that occurred on February 27th, 2010 and the development of early reading precursors skills (listening comprehension, print knowledge, alphabet knowledge, vocabulary, and phonological awareness) in children at kindergarten age. This multilevel retrospective cohort study including 3280 children, of whom 2415 were unexposed and 865 were prenatally exposed to the earthquake shows substantial evidence that maternal exposure to an unambiguously stressful event resulted in impaired pre-reading skills and that a higher detrimental effect was observed in those children who had been exposed to the earthquake during the first trimester of gestation. In addition, females were more significantly affected by the exposure to the earthquake than their male peers in alphabet knowledge; contrarily, males were more affected than females in print knowledge skills. These findings suggest that early intervention programs for pregnant women and/or children exposed to prenatal stress may be effective strategies to overcome impaired pre-reading skills in children.

Background: Aggregate exposure, the combined exposures to a single chemical from all pathways, is a critical children's health issue., Objective: The primary objective is to develop a tool to illustrate potential differences in aggregate exposure at various childhood lifestages and the adult lifestage., Methods: We developed ExpoKids (an R-based tool) using oral exposure estimates across lifestages generated by US EPA's Exposure Factors Interactive Resource for Scenarios Tool (ExpoFIRST)., Results: ExpoKids is applied to illustrate aggregate oral exposure, for ten media, as average daily doses (ADD) and lifetime average daily doses (LADD) in five graphs organized across seven postnatal childhood lifestages and the adult lifestage. This data visualization tool conveys ExpoFIRST findings, from available exposure data, to highlight the relative contributions of media and lifestages to chemical exposure. To evaluate the effectiveness of ExpoKids, three chemical case examples (di[2-ethylhexyl] phthalate [DEHP], manganese, and endosulfan) were explored. Data available from the published literature and databases for each case example were used to explore research questions regarding media and lifestage contributions to aggregate exposure., Significance: These illustrative case examples demonstrate ExpoKids' versatile application to explore a diverse set of children's health risk assessment and management questions by visually depicting specific media and lifestage contributions to aggregate exposure.

Background: Gestational diabetes mellitus (GDM) is increasing worldwide and women with a history of GDM are at risk of developing type 2 diabetes which is a risk factor for periodontitis. The aim of this study was to explore the association between the concentrations of matrix metalloproteinase (MMP)-8 and -9 in gingival crevicular fluid (GCF) during early pregnancy with the periodontal diagnosis and the risk of GDM development., Methods: A prospective cohort study, including 314 women, enrolled at 11 to 14 weeks of pregnancy was conducted. A complete maternal/obstetric and periodontal exam was performed, and GCF samples were obtained for the MMP-8 and -9 determination by Multiplex Elisa Assays. Mann-Whitney test; Spearman's correlation and log-binomial regression model estimated the association between MMPs concentration in GCF and GDM., Results: Fourteen percent of the pregnancies were diagnosed with GDM. An increase in the concentration of MMP-8 and -9 in women with periodontitis stage III and IV compared to periodontitis stage I was observed (99.31 ng/mL [IQR: 85.32] versus 71.95 ng/mL [IQR: 54.04], and 262.4 ng/mL [IQR: 312.55] versus 114.1 ng/mL [IQR: 184.94], respectively). Women who developed GDM showed increased concentrations of MMP-8 and -9 in GCF since the beginning of pregnancy (P = 0.0381; P = 0.0302, respectively). MMP-8 concentration in GCF was associated with GDM (RR: 1.19; P = 0.045; CI 95% 1.00 to 1.40; and RR: 1.20; P = 0.063; CI 95% 0.99 to 1.45 in the adjusted model)., Conclusion(s): GCF concentrations of MMP-8 and -9 at early of pregnancy are increased in women with severe periodontitis and associated with the GDM development., (© 2020 American Academy of Periodontology.)

Calcium-dependent activator protein for secretion 2 (CAPS2; also referred to as CADPS2) is a dense core vesicle-associated protein that promotes the activity-dependent release of neuropeptides including neurotrophins. Addictive drugs appear to prime neurotrophin release in multiple brain regions, but mechanistic factors are still being elucidated. Here, experimenters administered cocaine to adolescent mice at doses that potentiated later cocaine self-administration. Experimenter-administered cocaine elevated the CAPS2 protein content in the orbitofrontal cortex (OFC; but not striatum) multiple weeks after drug exposure. Meanwhile, proteins that are sensitive to brain-derived neurotrophic factor (BDNF) release and binding (phosphorylated protein kinase B and phosphoinositide 3-kinase, and GABAAα1 levels) did not differ between cocaine-exposed and naive mice in the OFC. This pattern is consistent with evidence that CAPS2 primes stimulated release of neurotrophins like BDNF, rather than basal levels. Thus, cocaine administered at behaviorally relevant doses elevates CAPS2 protein content in the OFC, and the effects are detected long after cocaine exposure., (© 2021 S. Karger AG, Basel.)

Contemporary neuroscientific accounts suggest that ventral anterior temporal lobe (ATL) acts as a bilateral heteromodal semantic hub, which is particularly critical for the specific-level knowledge needed to recognise unique entities, such as familiar landmarks and faces. There may also be graded functional differences between left and right ATL, relating to effects of modality (linguistic versus non-linguistic) and category (e.g., knowledge of people and places). Individual differences in intrinsic connectivity from left and right ATL might be associated with variation in semantic categorisation performance across these categories and modalities. We recorded resting-state fMRI in 74 individuals and, in a separate session, examined semantic categorisation. People with greater connectivity between left and right ATL were more efficient at categorising landmarks (e.g., Eiffel Tower), especially when these were presented visually. In addition, participants who showed stronger connectivity from right than left ATL to medial occipital cortex showed more efficient semantic categorisation of landmarks regardless of modality of presentation. These results can be interpreted in terms of graded differences in the patterns of connectivity across left and right ATL, which give rise to a bilateral yet partially segregated semantic 'hub'. More specifically, right ATL connectivity supports the efficient semantic categorisation of landmarks., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cumulative risk assessment (CRA) addresses the combined risk associated with chemical and non-chemical exposures. Although CRA approaches are utilized in environmental and ecological contexts, they are rarely applied in workplaces. In this perspectives article, we strive to raise awareness among occupational health and safety (OHS) professionals and foster the greater adoption of a CRA perspective in practice. Specifically, we provide an overview of CRA literature as well as preliminary guidance on when to consider a CRA approach in occupational settings and how to establish reasonable boundaries. Examples of possible workplace co-exposures and voluntary risk management actions are discussed. We also highlight important implications for workplace CRA research and practice. In particular, future needs include simple tools for identifying combinations of chemical and non-chemical exposures, uniform risk management guidelines, and risk communication materials. Further development of practical CRA methods and tools are essential to meet the needs of complex and changing work environments.

Spontaneous abortion is a common complication in early pregnancy, with an incidence of around 20%. Ultrasound scan and measurement of human chorionic gonadotropin are used to identify patients at risk of spontaneous abortion; however, there is a clinical need to find new biomarkers to prospectively identify patients before the onset of clinical symptoms. Here, we aim to investigate potential biomarkers of spontaneous abortion taken in the first clinical appointment of pregnancy. A case-control study was conducted based on a prospectively collected cohort in which cases and controls were retrospectively stratified based on pregnancy outcome: normal healthy pregnancies (controls = 33) and pregnancies that ended in spontaneous abortion (cases = 10). We evaluated extracellular vesicles isolated by precipitation with ExoQuick™ and protein concentrations of tissue plasminogen activator, leptin, and adiponectin measured by ELISA. The extracellular vesicles showed the typical morphology and membrane proteins: CD63, Alix, and Flotilin-1. The size distributions of the isolated extracellular vesicles were 112 ± 27 and 118 ± 28 nm in diameter for controls and spontaneous abortion, respectively, and the total amount of extracellular vesicles did not show any difference between controls and the spontaneous abortion group. The tissue plasminogen activator showed a significant difference ( p = 0.0004) between both groups, although neither adiponectin nor leptin revealed significant changes, indicating that women who had spontaneous abortions have significantly higher levels of tissue plasminogen activator than women who had normal pregnancies.

Small extracellular vesicles (sEVs) released from the extravillous trophoblast (EVT) are known to regulate uterine spiral artery remodeling during early pregnancy. The bioactivity and release of these sEVs differ under differing oxygen tensions and in aberrant pregnancy conditions. Whether the placental cell-derived sEVs released from the hypoxic placenta contribute to the pathophysiology of preeclampsia is not known. We hypothesize that, in response to low oxygen tension, the EVT packages a specific set of proteins in sEVs and that these released sEVs interact with endothelial cells to induce inflammation and increase maternal systemic blood pressure. Using a quantitative MS/MS approach, we identified 507 differentially abundant proteins within sEVs isolated from HTR-8/SVneo cells (a commonly used EVT model) cultured at 1% (hypoxia) compared with 8% (normoxia) oxygen. Among these differentially abundant proteins, 206 were up-regulated and 301 were down-regulated (P < 0.05), and they were mainly implicated in inflammation-related pathways. In vitro incubation of hypoxic sEVs with endothelial cells, significantly increased (P < 0.05) the release of GM-CSF, IL-6, IL-8, and VEGF, when compared with control (i.e. cells without sEVs) and normoxic sEVs. In vivo injection of hypoxic sEVs into pregnant rats significantly increased (P < 0.05) mean arterial pressure with increases in systolic and diastolic blood pressures. We propose that oxygen tension regulates the release and bioactivity of sEVs from EVT and that these sEVs regulate inflammation and maternal systemic blood pressure. This novel oxygen-responsive, sEVs signaling pathway, therefore, may contribute to the physiopathology of preeclampsia., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Objective: Amniotic fluid cytokines have been implicated in the mechanisms of preterm labor and birth. Cytokines can be packaged within or on the surface of extracellular vesicles. The main aim of this study was to test whether the protein abundance internal to and on the surface of extracellular vesicles changes in the presence of sterile intra-amniotic inflammation and proven intra-amniotic infection in women with preterm labor as compared to the women with preterm labor without either intra-amniotic inflammation or proven intra-amniotic infection., Study Design: Women who had an episode of preterm labor and underwent an amniocentesis for the diagnosis of intra-amniotic infection or intra-amniotic inflammation were classified into three groups: 1) preterm labor without either intra-amniotic inflammation or proven intra-amniotic infection, 2) preterm labor with sterile intra-amniotic inflammation, and 3) preterm labor with intra-amniotic infection. The concentrations of 38 proteins were determined on the extracellular vesicle surface, within the vesicles, and in the soluble fraction of amniotic fluid., Results: 1) Intra-amniotic inflammation, regardless of detected microbes, was associated with an increased abundance of amniotic fluid cytokines on the extracellular vesicle surface, within vesicles, and in the soluble fraction. These changes were most prominent in women with proven intra-amniotic infection. 2) Cytokine changes on the surface of extracellular vesicles were correlated with those determined in the soluble fraction; yet the magnitude of the increase was significantly different between these compartments. 3) The performance of prediction models of early preterm delivery based on measurements on the extracellular vesicle surface was equivalent to those based on the soluble fraction., Conclusions: Differential packaging of amniotic fluid cytokines in extracellular vesicles during preterm labor with sterile intra-amniotic inflammation or proven intra-amniotic infection is reported herein for the first time. The current study provides insights into the biology of the intra-amniotic fluid ad may aid in the development of biomarkers for obstetrical disease., Competing Interests: The authors have declared that no competing interests exist.