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BACKGROUNDThe inclusion of adolescents in TB drug trials is essential for the development of safe, child-friendly regimens for the prevention and treatment of TB. TB Trials Consortium Study 31/AIDS Clinical Trials Group A5349 (S31/A5349) enrolled adolescents as young as 12 years old. We assessed investigator and coordinator described facilitators and barriers to adolescent recruitment, enrollment, and retention.METHODSInterviews were conducted with six investigators from sites that enrolled adolescent participants and six investigators from non-enrolling sites. Additionally, two focus groups were conducted with study coordinators from enrolling sites and two focus groups with non-enrolling sites. Discussions were transcribed, analyzed, summarized, and summaries were reviewed by Community Research Advisors Group members and research group representatives for content validity.RESULTSInvestigators and coordinators attributed the successful enrollment of adolescents to the establishment and cultivation of external partnerships, flexibility to accommodate adolescents' schedules, staff engagement, recruitment from multiple locations, dedicated recruitment staff working onsite to access potential participants, creation of youth-friendly environments, and effective communications. Non-enrolling sites were mainly hindered by regulations. Suggestions for improvement in future trials focused on study planning and site preparations.CONCLUSIONProactive partnerships and collaboration with institutions serving adolescents helped identify and reduce barriers to their inclusion in this trial..

Melody is a core component of music in which discrete pitches are serially arranged to convey emotion and meaning. Perception varies along several pitch-based dimensions: (i) the absolute pitch of notes, (ii) the difference in pitch between successive notes, and (iii) the statistical expectation of each note given prior context. How the brain represents these dimensions and whether their encoding is specialized for music remains unknown. We recorded high-density neurophysiological activity directly from the human auditory cortex while participants listened to Western musical phrases. Pitch, pitch-change, and expectation were selectively encoded at different cortical sites, indicating a spatial map for representing distinct melodic dimensions. The same participants listened to spoken English, and we compared responses to music and speech. Cortical sites selective for music encoded expectation, while sites that encoded pitch and pitch-change in music used the same neural code to represent equivalent properties of speech. Findings reveal how the perception of melody recruits both music-specific and general-purpose sound representations.

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.

Abstract Background Key populations (KP), including men who have sex with men (MSM), female sex workers (FSW), and transgender women (TGW), experience a disproportionate burden of HIV, even in generalized epidemics like South Africa. Given this disproportionate burden and unique barriers to accessing health services, sustained provision of care is particularly relevant. It is unclear how the COVID-19 pandemic and its associated restrictions may have impacted this delivery. In this study, we aimed to describe patterns of engagement in HIV prevention and treatment services among KP in South Africa and assess the impact of different COVID-19 restriction levels on service delivery. Methods We leveraged programmatic data collected by the US President’s Emergency Plan for AIDS Relief (PEPFAR)-supported KP partners in South Africa. We divided data into three discrete time periods based on national COVID-19 restriction periods: (i) Pre-restriction period, (ii) High-level restriction period, and (iii) After-high level restriction period. Primary outcomes included monthly total HIV tests, new HIV cases identified, new initiations of pre-exposure prophylaxis (PrEP), and new enrollments in antiretroviral therapy (ART). We conducted interrupted time series segmented regression analyses to estimate the impact of COVID-19 restrictions on HIV prevention and treatment service utilization. Results Between January 2018 and June 2022, there were a total of 231,086 HIV tests, 27,051 HIV positive cases, 27,656 pre-exposure prophylaxis (PrEP) initiations, and 15,949 antiretroviral therapy initiations among MSM, FSW and TGW in PEPFAR-supported KP programs in South Africa. We recorded 90,457 total HIV tests during the ‘pre-restriction’ period, with 13,593 confirmed new HIV diagnoses; 26,134 total HIV tests with 2,771 new diagnoses during the ‘high-level restriction’ period; and 114,495 HIV tests with 10,687 new diagnoses during the after high-level restriction period. Our Poisson regression model estimates indicate an immediate and significant decrease in service engagement at the onset of COVID-19 restrictions, including declines in HIV testing, treatment, and PrEP use, which persisted. As programs adjusted to the new restrictions, there was a gradual rebound in service engagement, particularly among MSM and FSW. Towards the end of the high-level restriction period, with some aspects of daily life returning to normal but others still restricted, there was more variability. Some indicators continued to improve, while others stagnated or decreased. Conclusion Service provision rebounded from the initial shock created by pandemic-related restrictions, and HIV services were largely maintained for KP in South Africa. These results suggest that HIV service delivery among programs designed for KP was able to be flexible and resilient to the evolving restrictions. The results of this study can inform plans for future pandemics and large-scale disruptions to the delivery of HIV services.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values

Abstract The repeated use of small doses of psychedelics (also referred to as “microdosing”) to facilitate benefits in mental health, cognition, and mood is a trending practice. Placebo-controlled studies however have largely failed to demonstrate strong benefits, possibly because of large inter-individual response variability. The current study tested the hypothesis that effects of low doses of LSD on arousal, attention and memory depend on an individual’s cognitive state at baseline. Healthy participants (N = 53) were randomly assigned to receive repeated doses of LSD (15 mcg) or placebo on 4 occasions divided over 2 weeks. Each treatment condition also consisted of a baseline and a 1-week follow-up visit. Neurophysiological measures of arousal (resting state EEG), pre-attentive processing (auditory oddball task), and perceptual learning and memory (visual long-term potentiation (LTP) paradigm) were assessed at baseline, dosing session 1 and 4, and follow-up. LSD produced stimulatory effects as reflected by a reduction in resting state EEG delta, theta, and alpha power, and enhanced pre-attentive processing during the acute dosing sessions. LSD also blunted the induction of LTP on dosing session 4. Stimulatory effects of LSD were strongest in individuals with low arousal and attention at baseline, while inhibitory effects were strongest in high memory performers at baseline. Decrements in delta EEG power and enhanced pre-attentive processing in the LSD treatment condition were still present during the 1-week follow-up. The current study demonstrates across three cognitive domains, that acute responses to low doses of LSD depend on the baseline state and provides some support for LSD induced neuroadaptations that sustain beyond treatment.

Background: We aimed to determine the timeliness of rabies post-exposure prophylaxis (PEP) and the proportion of individuals with an adequate antibody response post-PEP among those attending the Belgian national reference center. Methods: Retrospective analysis of patient records who attended our center from 2018 to 2023. Delay was defined as rabies immunoglobulin (RIG) and vaccine initiation beyond 2 calendar days after exposure. Antibodies were measured by rapid fluorescent focus inhibition test (RFFIT) after PEP in high-risk exposures. A titer ≥0.5 IU/ml was considered adequate. Results: We reviewed 317 patient records. Among individuals with inland exposure (n = 103), 85 % timely received PEP. Among travelers exposed abroad (n = 214), administration of RIG and vaccine initiation were timely in 30 % and 50 % of cases, respectively. An adequate antibody response was detected in 99.5 % (195/196) individuals. Conclusion: Substantial PEP delays among travelers were observed. The robust antibody responses suggest that routine serological follow-up is not necessary for all patients.

Many social animals can recognize other individuals by their vocalizations. This requires a memory system capable of mapping incoming acoustic signals to one of many known individuals. Using the zebra finch, a social songbird that uses songs and distance calls to communicate individual identity (Elie and Theunissen, 2018), we tested the role of two cortical-like brain regions in a vocal recognition task. We found that the rostral region of the Cadomedial Nidopallium (NCM), a secondary auditory region of the avian pallium, was necessary for maintaining auditory memories for conspecific vocalizations in both male and female birds, whereas HVC (used as a proper name), a premotor areas that gates auditory input into the vocal motor and song learning pathways in male birds (Roberts and Mooney, 2013), was not. Both NCM and HVC have previously been implicated for processing the tutor song in the context of song learning (Sakata and Yazaki-Sugiyama, 2020). Our results suggest that NCM might not only store songs as templates for future vocal imitation but also songs and calls for perceptual discrimination of vocalizers in both male and female birds. NCM could therefore operate as a site for auditory memories for vocalizations used in various facets of communication. We also observed that new auditory memories could be acquired without intact HVC or NCM but that for these new memories NCM lesions caused deficits in either memory capacity or auditory discrimination. These results suggest that the high-capacity memory functions of the avian pallial auditory system depend on NCM.SIGNIFICANCE STATEMENT Many aspects of vocal communication require the formation of auditory memories. Voice recognition, for example, requires a memory for vocalizers to identify acoustical features. In both birds and primates, the locus and neural correlates of these high-level memories remain poorly described. Previous work suggests that this memory formation is mediated by high-level sensory areas, not traditional memory areas such as the hippocampus. Using lesion experiments, we show that one secondary auditory brain region in songbirds that had previously been implicated in storing song memories for vocal imitation is also implicated in storing vocal memories for individual recognition. The role of the neural circuits in this region in interpreting the meaning of communication calls should be investigated in the future.

Abstract Purpose Few studies have compared patient characteristics, clinical management, and outcome of patients with COVID-19 between the different epidemic waves. In this study, we describe patient characteristics, treatment, and outcome of patients admitted for COVID-19 in the Antwerp University Hospital over the first three epidemic waves of 2020–2021. Methods Retrospective observational study of COVID-19 patients in a Belgian tertiary referral hospital. All adult patients with COVID-19, hospitalized between February 29, 2020, and June 30, 2021, were included. Standardized routine medical data was collected from patient records. Risk factors were assessed with multivariable logistic regression. Results We included 722 patients, during the first (n = 179), second (n = 347) and third (n = 194) wave. We observed the lowest disease severity at admission during the first wave, and more elderly and comorbid patients during the second wave. Throughout the subsequent waves we observed an increasing use of corticosteroids and high-flow oxygen therapy. In spite of increasing number of complications throughout the subsequent waves, mortality decreased each wave (16.6%,15.6% 11.9% in 1st, 2nd and 3rd wave respectively). C-reactive protein above 150 mg/L was predictive for the need for intensive care unit admission (odds ratio (OR) 3.77, 95% confidence interval (CI) 2.32–6.15). A Charlson comorbidity index ≥ 5 (OR 5.68, 95% CI 2.54–12.70) and interhospital transfers (OR 3.78, 95% CI 2.05–6.98) were associated with a higher mortality. Conclusions We observed a reduction in mortality each wave, despite increasing comorbidity. Evolutions in patient management such as high-flow oxygen therapy on regular wards and corticosteroid use may explain this favorable evolution.

Abstract Background Patients undergoing dialysis have an impaired health-related quality of life (HRQOL). There are conflicting data from small series on whether patient-related factors such as educational level have an impact on experienced HRQOL. The aim of this study was to investigate the association between educational level and HRQOL in dialysis patients. Methods In a single-center retrospective cross-sectional study HRQOL was measured using the Kidney Disease Quality of Life Short Form-36 (KDQOL-SF36) in prevalent chronic dialysis patients. Educational level was categorized into low, intermediate and high subgroups. Univariate and multivariate regression analyses were performed to assess the effects of age, gender, ethnicity, and dialysis vintage on the association between HRQOL and educational level. Results One hundred twenty-nine chronic dialysis patients were included. Patients with an intermediate educational level had significantly higher odds of a higher emotional well-being than patients with a low educational level 4.37 (1.-89–10.13). A similar trend was found for a high educational level (OR 4.13 (1.04–16.42), p = 0.044) The odds for women compared to men were 2.83 (1.32–6.06) for better general health and 2.59 (1.15–5,84) for emotional well-being. There was no interaction between gender and educational level for both subdomains. Each year of increasing age significantly decreased physical functioning (OR 0.94 (0.91–0.97)). Conclusions Educational level and sex were associated with emotional well-being, since patients with intermediate and high educational level and females had better emotional well-being in comparison to patients with low educational level and males. Physical functioning decreased with increasing age.

Background Health agency refers to one’s capacity to form health-related goals, experience control, and possess the means to pursue them. Low socioeconomic status (SES) is linked to impaired health agency and increased risk of adverse pregnancy outcomes, potentially due to a reduced tendency to seek care. Better healthcare availability may not improve their pregnancy outcomes, and therefore improved understanding of maternal health agency is paramount. Methods Semi-structured interviews were conducted with 15 participants who either had children or desired to have them. Low SES was determined by neighborhood median income and educational attainment. A thematic content analyses was conducted. Results Two themes emerged: 1) Origin and development of personal goals, and 2) Awareness and competence. Participant’s goals stemmed from cultural norms, personal narratives, and intuition. Integrated goals were those participants valued highly, were aware of, and strived for. Four subthemes were identified in goal-awareness and competence. Internal conflict due to discrepancies between goals and behavior resulted in the need to balance the burdens and benefits of behavior change. Conclusion Maternal health agency is a modifiable outcome dependent on goal-awareness and various factors. Impaired agency seemed to stem from lack of goal-awareness rather than an inability to meet established pillars.

ABSTRACTEpigenetic modifications, including DNA methylation, are proposed mechanisms explaining the impact of parental exposures to foetal development and lifelong health. Micronutrients including folate, choline, and vitamin B12 provide methyl groups for the one-carbon metabolism and subsequent DNA methylation processes. Placental DNA methylation changes in response to one-carbon moieties hold potential targets to improve obstetrical care. We conducted a systematic review on the associations between one-carbon metabolism and human placental DNA methylation. We included 22 studies. Findings from clinical studies with minimal ErasmusAGE quality score 5/10 (n = 15) and in vitro studies (n = 3) are summarized for different one-carbon moieties. Next, results are discussed per study approach: (1) global DNA methylation (n = 9), (2) genome-wide analyses (n = 4), and (3) gene specific (n = 14). Generally, one-carbon moieties were not associated with global methylation, although conflicting outcomes were reported specifically for choline. Using genome-wide approaches, few differentially methylated sites associated with S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), or dietary patterns. Most studies taking a gene-specific approach indicated site-specific relationships depending on studied moiety and genomic region, specifically in genes involved in growth and development including LEP, NR3C1, CRH, and PlGF; however, overlap between studies was low. Therefore, we recommend to further investigate the impact of an optimized one-carbon metabolism on DNA methylation and lifelong health.

ABSTRACTEfficacy of cancer immunotherapies relies on correct recognition of tumor antigens by lymphocytes, eliciting thus functional responses capable of eliminating tumor cells. Therefore, important efforts have been carried out in antigen identification, with the aim of understanding mechanisms of response to immunotherapy and to design safer and more efficient strategies. In addition to classical tumor-associated antigens identified during the last decades, implementation of next-generation sequencing methodologies is enabling the identification of neoantigens (neoAgs) arising from mutations, leading to the development of new neoAg-directed therapies. Moreover, there are numerous non-classical tumor antigens originated from other sources and identified by new methodologies. Here, we review the relevance of neoAgs in different immunotherapies and the results obtained by applying neoAg-based strategies. In addition, the different types of non-classical tumor antigens and the best approaches for their identification are described. This will help to increase the spectrum of targetable molecules useful in cancer immunotherapies.

The categorization of animal vocalizations into distinct behaviorally relevant groups for communication is an essential operation that must be performed by the auditory system. This auditory object recognition is a difficult task that requires selectivity to the group identifying acoustic features and invariance to renditions within each group. We find that small ensembles of auditory neurons in the forebrain of a social songbird can code the bird's entire vocal repertoire (∼10 call types). Ensemble neural discrimination is not, however, correlated with single unit selectivity, but instead with how well the joint single unit tunings to characteristic spectro-temporal modulations span the acoustic subspace optimized for the discrimination of call types. Thus, akin to face recognition in the visual system, call type recognition in the auditory system is based on a sparse code representing a small number of high-level features and not on highly selective grandmother neurons.

Speech processing requires extracting meaning from acoustic patterns using a set of intermediate representations based on a dynamic segmentation of the speech stream. Using whole brain mapping obtained in fMRI, we investigate the locus of cortical phonemic processing not only for single phonemes but also for short combinations made of diphones and triphones. We find that phonemic processing areas are much larger than previously described: they include not only the classical areas in the dorsal superior temporal gyrus but also a larger region in the lateral temporal cortex where diphone features are best represented. These identified phonemic regions overlap with the lexical retrieval region, but we show that short word retrieval is not sufficient to explain the observed responses to diphones. Behavioral studies have shown that phonemic processing and lexical retrieval are intertwined. Here, we also have identified candidate regions within the speech cortical network where this joint processing occurs.

IntroductionMaternal obesity poses risks for both mother and offspring during pregnancy, with underlying mechanisms remaining largely unexplored. Obesity is associated with microbial gut dysbiosis and low-grade inflammation, and also the diet has a major impact on these parameters. This study aimed to investigate how maternal obesity and diet contribute to changes in immune responses, exploring potential associations with gut microbiota dysbiosis and adverse pregnancy outcomes in mice.MethodsBefore mating, C57BL/6 mice were assigned to either a high-fat-diet (HFD) or low-fat-diet (LFD) to obtain obese (n=17) and lean (n=10) mice. To distinguish between the effects of obesity and diet, 7 obese mice were switched from the HFD to the LFD from day 7 until day 18 of pregnancy (“switch group”), which was the endpoint of the study. T helper (Th) cell subsets were studied in the spleen, mesenteric lymph nodes (MLN) and Peyer’s patches (PP), while monocyte subsets and activation status were determined in maternal blood (flow cytometry). Feces were collected before and during pregnancy (day 7,14,18) for microbiota analysis (16S rRNA sequencing). Pregnancy outcome included determination of fetal and placental weight.ResultsObesity increased splenic Th1 and regulatory T cells, MLN Th1 and PP Th17 cells and enhanced IFN-γ and IL-17A production by splenic Th cells upon ex vivo stimulation. Switching diet decreased splenic and PP Th2 cells and classical monocytes, increased intermediate monocytes and activation of intermediate/nonclassical monocytes. Obesity and diet independently induced changes in the gut microbiota. Various bacterial genera were increased or decreased by obesity or the diet switch. These changes correlated with the immunological changes. Fetal weight was lower in the obese than the lean group, while placental weight was lower in the switch than the obese group. DiscussionThis study demonstrates that obesity and diet independently impact peripheral and intestinal immune responses at the end of pregnancy. Simultaneously, both factors affect specific bacterial gut genera and lead to reduced fetal or placental weight. Our data suggest that switching diet during pregnancy to improve maternal health is not advisable and it supports pre/probiotic treatment of maternal obesity-induced gut dysbiosis to improve maternal immune responses and pregnancy outcome.

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Abstract Human naïve pluripotent stem cells (hnPSCs) can generate integrated models of blastocysts termed blastoids upon switch to inductive medium. However, the underlying mechanisms remain obscure. Here we report that self-renewing hnPSCs spontaneously and efficiently give rise to blastoids upon three dimensional (3D) suspension culture. The spontaneous blastoids mimic early stage human blastocysts in terms of structure, size, and transcriptome characteristics and are capable of progressing to post-implantation stages. This property is conferred by the glycogen synthase kinase-3 (GSK3) signalling inhibitor IM-12 present in 5iLAF self-renewing medium. IM-12 upregulates oxidative phosphorylation-associated genes that underly the capacity of hnPSCs to generate blastoids spontaneously. Starting from day one of self-organization, hnPSCs at the boundary of all 3D aggregates dedifferentiate into E5 embryo-like intermediates. Intermediates co-express SOX2/OCT4 and GATA6 and by day 3 specify trophoblast fate, which coincides with cavity and blastoid formation. In summary, spontaneous blastoid formation results from 3D culture triggering dedifferentiation of hnPSCs into earlier embryo-like intermediates which are then competent to segregate blastocyst fates.

Poplar species such as aspen (Populus tremula L.) play a very important role in the forest formation process not only in Eastern European regions. Unfortunately, such aspen stands are often severely affected by fungal diseases, causing mainly core rot. In this study, the indirect effects of thinning on the phytosanitary condition of aspen by promotion of tree growth were investigated. Two thinning methods, manual (thinning from below) and mechanical thinning (schematic), were applied to young stands dominated by Eurasian aspen to study their effects on tree growth and health. All trees were measured at breast height and diameter frequency distribution was determined twice, i.e. three and 24 years after the beginning of the experiment. In addition, during the second measurement, tree-ring samples were obtained from individual trees to evaluate growth and wood decay damage. Neither manual nor mechanical thinning of aspen significantly increased its growth at the stand level, but positive effects on individual trees were observed in plots where mechanical thinning was applied. The thicker the trees, the less decayed they were. The analysis suggests that thinning in general should not be used to increase stand production, but the positive effects of mechanical thinning on individual aspens can be recommended to promote the growth of individual vigorous trees.

BackgroundA low socioeconomic status is associated with a vulnerable health status (VHS) through the accumulation of health-related risk factors, such as poor lifestyle behaviors (eg, inadequate nutrition, chronic stress, and impaired health literacy). For pregnant women, a VHS translates into a high incidence of adverse pregnancy outcomes and therefore pregnancy-related inequity. We hypothesize that stimulating adequate pregnancy preparation, targeting lifestyle behaviors and preconception care (PCC) uptake, can reduce these inequities and improve the pregnancy outcomes of women with a VHS. A nudge is a behavioral intervention aimed at making healthy choices easier and more attractive and may therefore be a feasible way to stimulate engagement in pregnancy preparation and PCC uptake, especially in women with a VHS. To support adequate pregnancy preparation, we designed a mobile health (mHealth) app, Pregnant Faster, that fits the preferences of women with a VHS and uses nudging to encourage PCC consultation visits and engagement in education on healthy lifestyle behaviors. ObjectiveThis study aimed to test the feasibility of Pregnant Faster by determining usability and user satisfaction, the number of visited PCC consultations, and the course of practical study conduction. MethodsWomen aged 18-45 years, with low-to-intermediate educational attainment, who were trying to become pregnant within 12 months were included in this open cohort. Recruitment took place through social media, health care professionals, and distribution of flyers and posters from September 2021 until June 2022. Participants used Pregnant Faster daily for 4 weeks, earning coins by reading blogs on pregnancy preparation, filling out a daily questionnaire on healthy lifestyle choices, and registering for a PCC consultation with a midwife. Earned coins could be spent on rewards, such as fruit, mascara, and baby products. Evaluation took place through the mHealth App Usability Questionnaire (MAUQ), an additional interview or questionnaire, and assessment of overall study conduction. ResultsDue to limited inclusions, the inclusion criterion “living in a deprived neighborhood” was dropped. This resulted in the inclusion of 47 women, of whom 39 (83%) completed the intervention. In total, 16 (41%) of 39 participants visited a PCC consultation, with their main motivation being obtaining personalized information. The majority of participants agreed with 16 (88.9%) of 18 statements of the MAUQ, indicating high user satisfaction. The mean rating was 7.7 (SD 1.0) out of 10. Points of improvement included recruitment of the target group, simplification of the log-in system, and automation of manual tasks. ConclusionsNudging women through Pregnant Faster to stimulate pregnancy preparation and PCC uptake has proven feasible, but the inclusion criteria must be revised. A substantial number of PCC consultations were conducted, and this study will therefore be continued with an open cohort of 400 women, aiming to establish the (cost-)effectiveness of an updated version, named Pregnant Faster 2. International Registered Report Identifier (IRRID)RR2-10.2196/45293

Summary: Preeclampsia (PE) is a hypertensive pregnancy disorder with increased risk of maternal and fetal morbidity and mortality. Abnormal extravillous trophoblast (EVT) development and function is considered to be the underlying cause of PE, but has not been previously modeled in vitro. We previously derived induced pluripotent stem cells (iPSCs) from placentas of PE patients and characterized abnormalities in formation of syncytiotrophoblast and responses to changes in oxygen tension. In this study, we converted these primed iPSC to naïve iPSC, and then derived trophoblast stem cells (TSCs) and EVT to evaluate molecular mechanisms underlying PE. We found that primed (but not naïve) iPSC-derived PE-EVT have reduced surface HLA-G, blunted invasive capacity, and altered EVT-specific gene expression. These abnormalities correlated with promoter hypermethylation of genes associated with the epithelial-mesenchymal transition pathway, specifically in primed-iPSC derived PE-EVT. Our findings indicate that abnormal epigenetic regulation might play a role in PE pathogenesis.

Information about the resistance and adaptive potential of tree species and provenances is needed to select suitable planting material in times of rapidly changing climate conditions. In this study, we evaluate growth responses to climatic fluctuations and extreme events for 12 provenances of northern red oak (Quercus rubra L.) that were tested across three trial sites with distinct environmental conditions in Germany. Six provenances each were sourced from the natural distribution in North America and from introduced stands in Germany. We collected increment cores of 16 trees per provenance and site. Dendroecological methods were used to compare provenance performance and establish climate-growth relationships to identify the main growth limiting factors. To evaluate the provenance response to extreme drought and frost events, three site-specific drought years were selected according to the Standardized Precipitation Evapotranspiration Index (SPEI) and 2010 as a year with an extreme late frost event. Resistance indices for these years were calculated and assessed in relation to overall growth performance. We observed a high variation in growth and in the climate sensitivity between sites depending on the prevailing climatic conditions, as well as a high intra-specific variation. Overall, summer drought and low temperatures in the early growing season appear to constrain the growth of red oak. The resistance of provenances within sites and extreme years showed considerable rank changes and interaction effects. We did not find a trade-off between growth and resistance to late frost, namely, fast growing provenances had a high frost hardiness. Further, there was no evidence for a trade-off between growth and drought hardiness. Still, responses to drought or late frost differ between provenances, pointing to dissimilar adaptive strategies. Provenances from introduced (i.e. German) stands represent suitable seed sources, as they combine a higher growth and frost hardiness compared to their North American counterparts. Drought hardiness was slightly higher in the slow-growing provenances. The results provide a better understanding of the variable adaptive strategies between provenances and help to select suitable planting material for adaptive forest management.

The breadth and complexity of natural behaviors inspires awe. Understanding how our perceptions, actions, and internal thoughts arise from evolved circuits in the brain has motivated neuroscientists for generations. Researchers have traditionally approached this question by focusing on stereotyped behaviors, either natural or trained, in a limited number of model species. This approach has allowed for the isolation and systematic study of specific brain operations, which has greatly advanced our understanding of the circuits involved. At the same time, the emphasis on experimental reductionism has left most aspects of the natural behaviors that have shaped the evolution of the brain largely unexplored. However, emerging technologies and analytical tools make it possible to comprehensively link natural behaviors to neural activity across a broad range of ethological contexts and timescales, heralding new modes of neuroscience focused on natural behaviors. Here we describe a three-part roadmap that aims to leverage the wealth of behaviors in their naturally occurring distributions, linking their variance with that of underlying neural processes to understand how the brain is able to successfully navigate the everyday challenges of animals' social and ecological landscapes. To achieve this aim, experimenters must harness one challenge faced by all neurobiological systems, namely variability, in order to gain new insights into the language of the brain.