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Masaki Kato,1 Toshiaki Kikuchi,2 Koichiro Watanabe,3 Tomiki Sumiyoshi,4 Yoshiya Moriguchi,5 Daniel Oudin Åström,6 Michael Cronquist Christensen6 1Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan; 2Department of Neuropsychiatry, Keio University School of Medicine, Department of Neuropsychiatry, Tokyo, Japan; 3Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan; 4Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan; 5Lundbeck Japan K.K, Tokyo, Japan; 6H. Lundbeck A/S, Valby, DenmarkCorrespondence: Yoshiya Moriguchi, Medical Affairs, Lundbeck Japan, K.K, Kamiyacho Prime Place 8F, 4-1-17 Toranomon, Minato-ku, Tokyo, 105-0001, Japan, Email yomo@lundbeck.comPurpose: Goal attainment scaling (GAS) has been proposed as a person-centric, semi-quantitative measure that assimilates achievement of individually set goals into a single standardized “goal attainment score” that can be compared at the population level. We aimed to examine the reliability and validity of the Japanese version of the GAS for depression (GAS-D) tool in assessing goal attainment in people living with major depressive disorder (MDD).Patients and Methods: This was a prespecified analysis of a prospective, 24-week, multicenter, observational cohort study of employed Japanese outpatients with MDD initiating treatment with vortioxetine according to the Japanese label (JRCT1031210200). Participants were assessed using the Japanese version of the GAS-D and other clinical rating scales at baseline and Weeks 8, 12 and 24.Results: Goal attainment was significantly associated with symptom severity as assessed by the Montgomery–Åsberg Depression Rating Scale (MADRS) scale, confirming convergent validity. In particular, GAS-D scores were significantly related to MADRS total score at Weeks 12 and 24, indicating that improvements in overall symptom severity with vortioxetine treatment were likely to be reflected in the achievement of individualized treatment goals. With an intraclass correlation coefficient of 0.67 (95% CI 0.45– 0.82), the GAS-D also showed moderate test–retest reliability between Weeks 8 and 12 while proving independent of demographic characteristics.Conclusion: The results of this open-label study support the use of the GAS-D as a valid and sensitive outcome measure in the assessment of treatment response in MDD.Keywords: major depressive disorder, goal attainment scaling, goal setting, validation, vortioxetine

Abstract Background Despite accumulating evidence of an association between air pollution and renal disease, studies on the association between long-term exposure to air pollution and renal function are still contradictory. This study aimed to investigate this association in a large population with relatively low exposure and with improved estimation of renal function as well as renal injury biomarkers. Methods We performed a cross-sectional analysis in the middle-aged general population participating in the Swedish CardioPulmonary bioImaging Study (SCAPIS; n = 30 154). Individual 10-year exposure to total and locally emitted fine particulate matter (PM2.5), inhalable particulate matter (PM10), and nitrogen oxides (NOx) were modelled using high-resolution dispersion models. Linear regression models were used to estimate associations between exposures and estimated glomerular filtration rate (eGFR, combined creatinine and cystatin C) and serum levels of renal injury biomarkers (KIM-1, MCP-1, IL-6, IL-18, MMP-2, MMP-7, MMP-9, FGF-23, and uric acid), with consideration of potential confounders. Results Median long-term PM2.5 exposure was 6.2 µg/m3. Almost all participants had a normal renal function and median eGFR was 99.2 mL/min/1.73 m2. PM2.5 exposure was associated with 1.3% (95% CI 0.6, 2.0) higher eGFR per 2.03 µg/m3 (interquartile range, IQR). PM2.5 exposure was also associated with elevated serum matrix metalloproteinase 2 (MMP-2) concentration, with 7.2% (95% CI 1.9, 12.8) higher MMP-2 per 2.03 µg/m3. There was a tendency towards an association between PM10 and higher levels of uric acid, but no associations were found with the other biomarkers. Associations with other air pollutants were null or inconsistent. Conclusion In this large general population sample at low exposure levels, we found a surprising association between PM2.5 exposure and a higher renal filtration. It seems unlikely that particle function would improve renal function. However, increased filtration is an early sign of renal injury and may be related to the relatively healthy population at comparatively low exposure levels. Furthermore, PM2.5 exposure was associated with higher serum concentrations of MMP-2, an early indicator of renal and cardiovascular pathology.

IntroductionAir pollution is a significant contributor to morbidity and mortality globally and has been linked to an increased risk of dementia. Previous studies within the Betula cohort in Northern Sweden have demonstrated associations between air pollution and dementia, as well as distinctive metabolomic profiles in dementia patients compared to controls. This study aimed to investigate whether air pollution is associated with quantitative changes in metabolite levels within this cohort, and whether future dementia status would modify this association.MethodsBoth short-term and long-term exposure to air pollution were evaluated using high spatial resolution models and measured data. Air pollution from vehicle exhaust and woodsmoke were analyzed separately. Metabolomic profiling was conducted on 321 participants, including 58 serum samples from dementia patients and a control group matched for age, sex, and education level, using nuclear magnetic resonance spectroscopy.ResultsNo statistically significant associations were found between any metabolites and any measures of short-term or long-term exposure to air pollution. However, there were trends potentially suggesting associations between both long-term and short-term exposure to air pollution with lactate and glucose metabolites. Notably, these associations were observed despite the lack of correlation between long-term and short-term air pollution exposure in this cohort. There were also tendencies for associations between air pollution from woodsmoke to be more pronounced in participants that would later develop dementia, suggesting a potential effect depending on urban/rural factors.DiscussionWhile no significant associations were found, the trends observed in the data suggest potential links between air pollution exposure and changes in lactate and glucose metabolites. These findings provide some new insights into the link between air pollution and metabolic markers in a low-exposure setting. However, addressing existing limitations is crucial to improve the robustness and applicability of future research in this area. The pronounced associations in participants who later developed dementia may indicate an influence of urban/rural factors, warranting further investigation.

Planetary health is being or should be added to medical training curricula in accordance with association consensus. Several articles published in recent years have addressed concern on the implementation, and the challenges that can occur if not addressed properly. This scoping narrative literature review focuses on planetary health as a concept, as well as challenges and suggested solutions to address these challenges. Planetary health is an important concept and needs to be addressed in all medical training. We found that one main challenge is implementation without ensuring the right competences and resources. Medically trained teachers set out to understand and teach complex natural and social systems. At some institutions the time allocated to teach planetary health is limited or non-existent. Case studies and student led teaching are solutions suggested, while other argue that true interdisciplinarity by inviting experts are more in line with what we expect from other subjects. In conclusion, the roots of planetary health, the enormous health risks at stake and nature of the subject requires medical training to adopt a true inter/trans-disciplinary approach to succeed. It might not be expected for all students to become planetary health experts, but all need a general understanding of the most important aspects and values.

Study region: French part of the Moselle catchmentStudy focus: By relying on hydrological simulations forced by climate change scenarios, stakeholders can assess the magnitude of future changes in the rainfall–runoff relationship. The inclusion of human influences in water resources modelling in a non-stationary context is a way to improve the accuracy and usefulness of climate change impact studies. Here, we propose a modelling approach that explicitly considers water uses to evaluate adaptation measures for water management at the French Moselle catchment scale.New hydrological insights for the region: The results highlight the decrease in future low flows but also the change in the balance between demand and supply. Over the Moselle catchment, whatever the water use scenario considered, climate change induces lower water availability both for environmental flows and for human uses. This leads to a potential increase in the duration of water restriction of up to 8 weeks for RCP 8.5 in the long term (2070–2099) compared to 1976–2005. This study could provide water managers with more appropriate climate impact results and potentially help them to design adequate adaptation measures.

Human Papillomavirus (HPV) vaccine coverage was

Abstract Background Measured or modeled levels of outdoor air pollution are being used as proxies for individual exposure in a growing number of epidemiological studies. We studied the accuracy of such approaches, in comparison with measured individual levels, and also combined modeled levels for each subject’s workplace with the levels at their residence to investigate the influence of living and working in different places on individual exposure levels. Methods A GIS-based dispersion model and an emissions database were used to model concentrations of NO2 at the subject’s residence. Modeled levels were then compared with measured levels of NO2. Personal exposure was also modeled based on levels of NO2 at the subject’s residence in combination with levels of NO2 at their workplace during working hours. Results There was a good agreement between measured façade levels and modeled residential NO2 levels (rs = 0.8, p > 0.001); however, the agreement between measured and modeled outdoor levels and measured personal exposure was poor with overestimations at low levels and underestimation at high levels (rs = 0.5, p > 0.001 and rs = 0.4, p > 0.001) even when compensating for workplace location (rs = 0.4, p > 0.001). Conclusion Modeling residential levels of NO2 proved to be a useful method of estimating façade concentrations. However, the agreement between outdoor levels (both modeled and measured) and personal exposure was, although significant, rather poor even when compensating for workplace location. These results indicate that personal exposure cannot be fully approximated by outdoor levels and that differences in personal activity patterns or household characteristics should be carefully considered when conducting exposure studies. This is an important finding that may help to correct substantial bias in epidemiological studies.

Abstract Background The relationship between fish intake and stroke incidence has been inconsistent in previous Swedish studies. Here, we report the risk of stroke and fish intake in a cohort from southern Sweden. Findings Data were obtained from an already available population based case-control study where the cases were defined as incident first-time ischemic stroke patients. Complete data on all relevant variables were obtained for 2722 controls and 2469 cases. The data were analyzed with logistic regression analysis. Stroke risk decreased with fat fish intake ([greater than or equal to] 1/week versus Conclusions The results suggest fat fish intake to decrease ischemic stroke risk and lean fish intake to increase women's stroke risk. The inconsistent relationship between fish intake and stroke risk reported in previous studies is further stressed by the results of this study.

Abstract Background Long-term exposure to air pollution is a hypothesized risk factor for ischemic stroke. In a large case-control study with a complete study base, we investigated whether hospital admissions for ischemic stroke were associated with residential concentrations of outdoor NOx, as a proxy for exposure to air pollution, in the region of Scania, Southern Sweden. Methods We used a two-phase case-control study design, including as first-phase controls all individuals born between 1923 and 1965 and residing in Scania in 2002 (N = 556 912). We defined first-phase cases as first-time ischemic stroke patients residing in Scania and registered in the Swedish stroke register between 2001 and 2005 (N = 4 904) and second-phase cases as cases for whom we had information on smoking status, diabetes, and medication for hypertension (N = 4 375). For the controls, information on these covariables was collected from a public health survey, resulting in 4 716 second-phase controls. With a geographical information system and an emission database, individual residential outdoor annual mean NOx concentration was modelled. The data were analyzed with logistic regression. Results We found no evident association between NOx and ischemic stroke. For example, the odds ratio for ischemic stroke associated with the NOx category 20–30 μg/m3 compared to the reference category of 3 was 0.95 (95% CI 0.86–1.06). Conclusion In this study area, with generally low levels of air pollution, using a complete study base, high-quality ascertainment of cases, and individually modelled exposure, we did not observe any clear association between NOx and ischemic stroke hospital admissions.

Abstract Background Blood lead concentrations (B-Pb) were measured in 3 879 Swedish school children during the period 1978–2007. The objective was to study the effect of the proximity to lead sources based on the children's home and school location. Methods The children's home address and school location were geocoded and their proximity to a lead smelter and major roads was calculated using geographical information system (GIS) software. All the statistical analyses were carried out using means of generalized log-linear modelling, with natural-logarithm-transformed B-Pb, adjusted for sex, school year, lead-exposing hobby, country of birth and, in the periods 1988–1994 and 1995–2007, parents' smoking habits. Results The GIS analysis revealed that although the emission from the smelter and children's B-Pb levels had decreased considerably since 1978, proximity to the lead smelter continued to affect levels of B-Pb, even in recent years (geometric mean: near smelter: 22.90 μg/l; far from smelter 19.75 μg/l; p = 0.001). The analysis also revealed that proximity to major roads noticeably affected the children's B-Pb levels during the period 1978–1987 (geometric mean near major roads: 44.26 μg/l; far from roads: 38.32 μg/l; p = 0.056), due to the considerable amount of lead in petrol. This effect was, however, not visible after 1987 due to prohibition of lead in petrol. Conclusion The results show that proximity to the lead smelter still has an impact on the children's B-Pb levels. This is alarming since it could imply that living or working in the vicinity of a former lead source could pose a threat years after reduction of the emission. The analysis also revealed that urban children exposed to lead from traffic were only affected during the early period, when there were considerable amounts of lead in petrol, and that the prohibition of lead in petrol in later years led to reduced levels of lead in the blood of urban children.

Abstract Background We plan to conduct a case-control study to investigate whether exposure to nitrogen dioxide (NO2) increases the risk of stroke. In case-control studies, selective participation can lead to bias and loss of efficiency. A two-phase design can reduce bias and improve efficiency by combining information on the non-participating subjects with information from the participating subjects. In our planned study, we will have access to individual disease status and data on NO2 exposure on group (area) level for a large population sample of Scania, southern Sweden. A smaller sub-sample will be selected to the second phase for individual-level assessment on exposure and covariables. In this paper, we simulate a case-control study based on our planned study. We develop a two-phase method for this study and compare the performance of our method with the performance of other two-phase methods. Methods A two-phase case-control study was simulated with a varying number of first- and second-phase subjects. Estimation methods: Method 1: Effect estimation with second-phase data only. Method 2: Effect estimation by adjusting the first-phase estimate with the difference between the adjusted and unadjusted second-phase estimate. The first-phase estimate is based on individual disease status and residential address for all study subjects that are linked to register data on NO2-exposure for each geographical area. Method 3: Effect estimation by using the expectation-maximization (EM) algorithm without taking area-level register data on exposure into account. Method 4: Effect estimation by using the EM algorithm and incorporating group-level register data on NO2-exposure. Results The simulated scenarios were such that, unbiased or marginally biased (< 7%) odds ratio (OR) estimates were obtained with all methods. The efficiencies of method 4, are generally higher than those of methods 1 and 2. The standard errors in method 4 decreased further when the case/control ratio is above one in the second phase. For all methods, the standard errors do not become substantially reduced when the number of first-phase controls is increased. Conclusion In the setting described here, method 4 had the best performance in order to improve efficiency, while adjusting for varying participation rates across areas.

Abstract Background Numerous studies have shown that exposure to air pollutants in the area of residence and the socio-economic status of an individual may be related. Therefore, when conducting an epidemiological study on the health effect of air pollution, socio-economy may act as a confounding factor. In this paper we examine to what extent socio-economic status and concentrations of NO2 in the county/region of Scania, southern Sweden, are associated and if such associations between these factors differ when studying them at county or city level. To perform this study we used high-resolution census data and modelled the annual exposure to NO2 using an emission database, a dispersion modelling program and a geographical information system (GIS). Results The results from this study confirm that socio-economic status and the levels of NO2 in the area of residence are associated in some cities. The associations vary considerably between cities within the same county (Scania). Even for cities of similar sizes and population bases the associations observed are different. Studying the cities together or separately yields contradictory results, especially when education is used as a socio-economic indicator. Conclusion Four conclusions have been drawn from the results of this study. 1) Adjusting for socio-economy is important when investigating the health effects of air pollution. 2) The county of Scania seems to be heterogeneous regarding the association between air pollution and socio-economy. 3) The relationship between air pollution and socio-economy differs in the five cities included in our study, depending on whether they are analysed separately or together. It is therefore inadvisable to determine and analyse associations between socio-economy and exposure to air pollutants on county level. This study indicates that the size and choice of study area is of great importance. 4) The selection of socio-economic indices (in this study: country of birth and education level) is important.

Objective Sickle cell disease (SCD) is the most frequent monogenic disease worldwide. Psychological and behavioural factors are often reported as playing a significant role in predicting SCD health outcomes. When focusing on adaptation to a specific health condition and its treatment, the Common Sense Model of Health and Illness (CSM) has proven to be of heuristic value. In other health conditions, illness outcomes are directly influenced by illness perception. Therefore, the aim of this study is to explore the psychometric proprieties of the Revised Illness Perception Questionnaire (IPQ-R). Design We performed a cross-sectional assessment on 517 adult patients with sickle cell disease and collected the results of 406 IPQ-R. With these data, we verified the factor structure of the Belief scale and proposed modifications to improve its fit to the data with a confirmatory factor analysis. In addition, we explored the factorial structure of the Causal attribution scale with an exploratory factor analysis. Results The initial model showed poor fit with the data. After structural modifications, elimination of two items with a low loading (model 2), covariance added between items (model 3) and items reallocation (model 4), the last model proposed presented a correct fit with the data. Before doing this model specification, we reviewed and compiled the nine studies that explored the psychometric properties of the IPQ-R in order to highlight all the modifications made by the other authors who have adapted the IPQ-R to a specific population and to allow a comparison with our own modifications. Conclusion Considering previous findings, this research suggests further work is needed on the structure of the dimensions of the IPQ-R.

Abstract In breast cancer, nerve presence has been correlated with more invasive disease and worse prognosis, yet the mechanisms by which different types of peripheral nerves drive tumor progression remain poorly understood. In this study, we identified sensory nerves as more abundant in human triple-negative breast cancer (TNBC) tumors. Co-injection of sensory neurons isolated from the dorsal root ganglia (DRG) of adult female mice with human TNBC cells in immunocompromised mice increased the number of lung metastases. Direct in vitro co-culture of human TNBC cells with the dorsal root ganglia (DRG) of adult female mice revealed that TNBC cells adhere to sensory neuron fibers leading to an increase in migration speed. Species-specific RNA sequencing revealed that co-culture of TNBC cells with sensory nerves upregulates the expression of genes associated with cell migration and adhesion in cancer cells. We demonstrated that lack of the semaphorin receptor PlexinB3 in cancer cells attenuate their adhesion to and migration on sensory nerves. Together, our results identify a mechanism by which nerves contribute to breast cancer migration and metastasis by inducing a shift in TNBC cell gene expression and support the rationale for disrupting neuron-cancer cell interactions to target metastasis.

Abstract Early mouse development is characterized by structural and epigenetic changes while cells progress towards differentiation. At blastocyst stage, the segregation of the three primordial lineages is accompanied by establishment of differential patterns of DNA methylation and post-translational modifications of histones, such as H3K27me3. Here, we analysed the dynamics of H3K27me3 at pericentromeric heterochromatin (PCH) during early development. We also followed the localization of EZH2 and BEND3, previously shown in ESCs to drive PRC2 to hypomethylated PCH. We show that the location of H3K27me3 at PCH, in addition to H3K9me3, is a defining feature of embryonic cells in vivo. Moreover, it may play an important role in structuring PCH and preserving genomic integrity at a time of globally relaxed chromatin. At peri-implantation stages, while DNA methylation is still low, EZH2 and then H3K27me3, leave PCH in epiblast progenitors at the time of their spatial segregation from primitive endoderm cells, while BEND3 remains there up to implantation. The comparison with stem cells (ESCs and TSCs) reveals that the epigenetic marks (i.e. H3K9me3 and H3K27me3) of PCH are reset during in vitro derivation and only partially restored thereafter. This highlights possible divergences between in vitro and “in embryo” epigenetic regulation regarding constitutive heterochromatin.

The app-based COVID Symptom Study was launched in Sweden in April 2020 to contribute to real-time COVID-19 surveillance using daily symptom reports from study participants. Here, the authors show how syndromic surveillance can be used to estimate regional COVID-19 prevalence and to predict later COVID-19 hospital admissions.

The increasing air temperature in a changing climate will impact actual evaporation and have consequences for water resource management in energy-limited regions. In many hydrological models, evaporation is assessed using a preliminary computation of potential evaporation (PE), which represents the evaporative demand of the atmosphere. Therefore, in impact studies, the quantification of uncertainties related to PE estimation, which can arise from different sources, is crucial. Indeed, a myriad of PE formulations exist, and the uncertainties related to climate variables cascade into PE computation. To date, no consensus has emerged on the main source of uncertainty in the PE modeling chain for hydrological studies. In this study, we address this issue by setting up a multi-model and multi-scenario approach. We used seven different PE formulations and a set of 30 climate projections to calculate changes in PE. To estimate the uncertainties related to each step of the PE calculation process, namely Representative Concentration Pathway (RCP) scenarios, general circulation models (GCMs), regional climate models (RCMs) and PE formulations, an analysis of variance (ANOVA) decomposition was used. Results show that mean annual PE will increase across France by the end of the century (from +40 to +130 mm y−1). In ascending order, uncertainty contributions by the end of the century are explained by PE formulations (below 10 %), RCPs (above 20 %), RCMs (30 %–40 %) and GCMs (30 %–40 %). However, under a single scenario, the contribution of the PE formulation is much higher and can reach up to 50 % of the total variance. All PE formulations show similar future trends, as climatic variables are co-dependent with respect to temperature. While no PE formulation stands out from the others, the Penman–Monteith formulation may be preferred in hydrological impact studies, as it is representative of the PE formulations' ensemble mean and allows one to account for the coevolution of climate and environmental drivers.

Abstract Parkinson’s disease (PD) is typically considered an age-related disease, but the age at disease onset can vary by decades between patients. Aging and aging-associated diseases can affect the movement system independently of PD, and advanced age has previously been proposed to be associated with a more severe PD phenotype with accelerated progression. In this work, we investigated how interactions between PD progression and aging affect a wide range of outcomes related to PD motor and nonmotor symptoms as well as Health Related Quality of Life (HRQoL) and treatment characteristics. This population-based cohort study is based on 1436 PD patients from southern Sweden followed longitudinally for up to approximately 7.5 years from enrollment (3470 visits covering 2285 patient years, average follow-up time 1.7 years). Higher age at onset was generally associated with faster progression of motor symptoms, with a notable exception of dyskinesia and other levodopa-associated motor fluctuations that had less severe trajectories for patients with higher age at onset. Mixed results were observed for emergence of non-motor symptoms, while higher age at onset was generally associated with worse HRQoL trajectories. Accounting for these identified age-associated differences in disease progression could positively impact patient management and drug development efforts.

Abstract Background Alzheimer’s disease (AD) and other dementias currently represent the fifth most common cause of death in the world, according to the World Health Organization, with a projected future increase as the proportion of the elderly in the population is growing. Air pollution has emerged as a plausible risk factor for AD, but studies estimating dementia cases attributable to exposure to fine particulate matter (PM2.5) air pollution and resulting monetary estimates are lacking. Methods We used data on average population-weighted exposure to ambient PM2.5 for the entire population of Sweden above 30 years of age. To estimate the annual number of dementia cases attributable to air pollution in the Swedish population above 60 years of age, we used the latest concentration response functions (CRF) between PM2.5 exposure and dementia incidence, based on ten longitudinal cohort studies, for the population above 60 years of age. To estimate the monetary burden of attributable cases, we calculated total costs related to dementia, including direct and indirect lifetime costs and intangible costs by including quality-adjusted life years (QALYs) lost. Two different monetary valuations of QALYs in Sweden were used to estimate the monetary value of reduced quality-of-life from two different payer perspectives. Results The annual number of dementia cases attributable to PM2.5 exposure was estimated to be 820, which represents 5% of the annual dementia cases in Sweden. Direct and indirect lifetime average cost per dementia case was estimated to correspond € 213,000. A reduction of PM2.5 by 1 μg/m3 was estimated to yield 101 fewer cases of dementia incidences annually, resulting in an estimated monetary benefit ranging up to 0.01% of the Swedish GDP in 2019. Conclusion This study estimated that 5% of annual dementia cases could be attributed to PM2.5 exposure, and that the resulting monetary burden is substantial. These findings suggest the need to consider airborne toxic pollutants associated with dementia incidence in public health policy decisions.

Summary The pharmaceutical industry faces a growing demand and recurrent shortages in many anticancer plant drugs given their extensive use in human chemotherapy. Efficient alternative strategies of supply of these natural products such as bioproduction by microorganisms are needed to ensure stable and massive manufacturing. Here, we developed and optimized yeast cell factories efficiently converting tabersonine to vindoline, a precursor of the major anticancer alkaloids vinblastine and vincristine. First, fine‐tuning of heterologous gene copies restrained side metabolites synthesis towards vindoline production. Tabersonine to vindoline bioconversion was further enhanced through a rational medium optimization (pH, composition) and a sequential feeding strategy. Finally, a vindoline titre of 266 mg l−1 (88% yield) was reached in an optimized fed‐batch bioreactor. This precursor‐directed synthesis of vindoline thus paves the way towards future industrial bioproduction through the valorization of abundant tabersonine resources.

Summary: Patients with severe COVID-19 show an altered immune response that fails to control the viral spread and suffer from exacerbated inflammatory response, which eventually can lead to death. A major challenge is to develop an effective treatment for COVID-19. NF-κB is a major player in innate immunity and inflammatory process. By a high-throughput screening approach, we identified FDA-approved compounds that inhibit the NF-κB pathway and thus dampen inflammation. Among these, we show that Auranofin prevents post-translational modifications of NF-κB effectors and their recruitment into activating complexes in response to SARS-CoV-2 infection or cytokine stimulation. In addition, we demonstrate that Auranofin counteracts several steps of SARS-CoV-2 infection. First, it inhibits a raft-dependent endocytic pathway involved in SARS-CoV-2 entry into host cells; Second, Auranofin alters the ACE2 mobility at the plasma membrane. Overall, Auranofin should prevent SARS-CoV-2 infection and inflammatory damages, offering new opportunities as a repurposable drug candidate to treat COVID-19.

BackgroundMood disorders are commonly diagnosed and staged using clinical features that rely merely on subjective data. The concept of digital phenotyping is based on the idea that collecting real-time markers of human behavior allows us to determine the digital signature of a pathology. This strategy assumes that behaviors are quantifiable from data extracted and analyzed through digital sensors, wearable devices, or smartphones. That concept could bring a shift in the diagnosis of mood disorders, introducing for the first time additional examinations on psychiatric routine care.ObjectiveThe main objective of this review was to propose a conceptual and critical review of the literature regarding the theoretical and technical principles of the digital phenotypes applied to mood disorders.MethodsWe conducted a review of the literature by updating a previous article and querying the PubMed database between February 2017 and November 2021 on titles with relevant keywords regarding digital phenotyping, mood disorders and artificial intelligence.ResultsOut of 884 articles included for evaluation, 45 articles were taken into account and classified by data source (multimodal, actigraphy, ECG, smartphone use, voice analysis, or body temperature). For depressive episodes, the main finding is a decrease in terms of functional and biological parameters [decrease in activities and walking, decrease in the number of calls and SMS messages, decrease in temperature and heart rate variability (HRV)], while the manic phase produces the reverse phenomenon (increase in activities, number of calls and HRV).ConclusionThe various studies presented support the potential interest in digital phenotyping to computerize the clinical characteristics of mood disorders.

Abstract Background Sickle cell disease (SCD) as other chronic medical conditions is commonly complicated by depression or other psychiatric symptoms. Results reported in studies present a large variation. Thus, synthetic data are needed to understand impact of depression in adults with SCD. The aim of this literature review is to analyse the methodology used in the studies assessing depression and discuss the different prevalence levels reported. Methods Studies involving adults with SCD from 1999 to 2018 were included when providing data on prevalence of depression. It was defined by a psychometric assessment, a structured interview, or a medical record review. PRISMA recommendations were followed. Results 36 studies are included accordingly to our methodology. Prevalence variation is large, from 0% to more than 85%. We find that the type of assessment tool used plays a major role in this between studies variation. Also, methodological issues arise with respect to psychometric assessment. Moreover, differences emerge between continents, setting of recruitment or time of assessment. Conclusion All these issues are discussed to provide insight on depression in adults with sickle cell disease. Trial Registration PROSPERO Registration CRD42018100684.

Abstract Background Few studies have assessed the mental health of principals, or studied associations with both organizational and social work environment factors and occupational balance. The purpose of the present study was therefore to investigate associations between supporting and demanding organizational and social work environment factors, occupational balance and stress symptoms in principals. Methods A total of 4309 surveys (2316 from the first round, 1992 from the second round), representing 2781 Swedish principals who had responded to at least one of two surveys, were included in the present study. The surveys include questions about socio-demographic factors, occupational balance, overtime work, and supporting and demanding organizational and social work environment factors, as well as questions about personal stress and exhaustion. Generalized Estimating Equations (GEE) models were used to specify a repeated measures model with a dichotomous outcome (binary logistic regression) and multiple independent factors. Data from two surveys were combined, taking into account dependent observations due to the fact that many study subjects had participated in both surveys. Results Associations were found between occupational balance (Q1: OR 2.52, 95% CI 2.03–3.15; Q2: OR 4.95, 95% CI 3.86–6.35; Q3: OR 9.29, 95% CI 6.99–12.34), overtime work (Once a week: OR 1.51, 95% CI 1.10–2.08; Sometimes a week: OR 1.31, 95% CI 1.03–1.66), supportive private life (OR 1.50, 95% CI 1.36–1.66), supportive colleagues at the leadership level (OR 1.24, 95% CI 1.14–1.36), supportive management (OR 1.17, 95% CI 1.07–1.28) and no or negligible stress symptoms. In addition, role demands (OR 0.72, 95% CI 0.63–0.83), having a container function (OR 0.72, 95% CI 0.64–0.82), collaboration with employees (OR 0.77, 95% CI 0.66–0.89), role conflicts (OR 0.75, 95% CI 0.66–0.89) and having a buffer function (OR 0.86, 95% CI 0.77–0.97) were associated with lower likelihood to rate no or negligible stress symptoms. Conclusions The occupational balance of principals is strongly associated with no or negligible stress symptoms, and thus is a promising venue for promoting well-being. Improvements should be made to several factors in the organizational and social work environments to improve principals’ chances of having occupational balance, and therefore better mental health.

Air pollution poses a threat to human health, with pregnant women and their developing fetuses being particularly vulnerable. A high dual burden of ambient and indoor air pollution exposure has been identified in Ethiopia, but studies investigating their effects on adverse birth outcomes are currently lacking. This study explores the association between ambient air pollution (NOX and NO2) and indoor air pollution (cooking fuel type) and fetal and neonatal death in Adama, Ethiopia. A prospective cohort of mothers and their babies was used, into which pregnant women were recruited at their first antenatal visit (n = 2085) from November 2015 to February 2018. Previously developed land-use regression models were utilized to assess ambient concentrations of NOX and NO2 at the residential address, whereas data on cooking fuel type was derived from questionnaires. Birth outcome data was obtained from self-reported questionnaire responses during the participant's postnatal visit or by phone if an in-person meeting was not possible. Binary logistic regression was employed to assess associations within the final study population (n = 1616) using both univariate and multivariate models; the latter of which adjusted for age, education, parity, and HIV status. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were reported. Within the cohort, 69 instances of fetal death (n = 16 miscarriages; n = 53 stillbirths) and 16 cases of neonatal death were identified. The findings suggest a tendency towards an association between ambient NOX and NO2 exposure during pregnancy and an increased risk of fetal death overall as well as stillbirth, specifically. However, statistical significance was not observed. Results for indoor air pollution and neonatal death were inconclusive. As limited evidence on the effects of exposure to ambient air pollution on adverse birth outcomes exists in Sub-Saharan Africa and Ethiopia, additional studies with larger study populations should be conducted.

Glioblastomas (GBMs) are highly invasive brain tumours, but the underlying mechanisms of GBM invasion are unclear. Here, the authors perform an RNA interference screen and identify AN1-Type Zinc Finger protein 3 (ZFAND3) as a regulator of GBM invasion, and find that it acts through the transcriptional regulation of invasion-related genes.

Background: Associations between air pollution and chronic kidney disease (CKD) have been reported, but studies at low exposure levels and relevant exposure time windows are still warranted. This study investigated clinical CKD at low air pollution levels in the Swedish Malmö Diet and Cancer Cohort in different exposure time windows. Methods: This study included 30,396 individuals, aged 45–74 at enrollment 1991–1996. Individual annual average residential outdoor PM2.5, PM10, nitrogen oxides (NOx), and black carbon (BC) were assigned using dispersion models from enrollment to 2016. Diagnoses of incident CKD were retrieved from national registries. Cox proportional hazards models were used to obtain hazard ratios (HRs) for CKD in relation to three time-dependent exposure time windows: exposure at concurrent year (lag 0), mean exposure in the 1–5 or 6–10 preceding years (lag 1–5 and lag 6–10), and baseline exposure. Results: During the study period, the average annual residential exposures were 16 μg/m3 for PM10, 11 μg/m3 for PM2.5, 26 μg/m3 for NOx, and 0.97 μg/m3 for BC. For lag 1–5 and lag 6–10 exposure, significantly elevated HRs for incident CKD were found for total PM10:1.13 (95% CI: 1.01–1.26) and 1.22 (1.06–1.41); NOx: 1.19 (1.07–1.33) and 1.13 (1.02–1.25) and BC: 1.12 (1.03–1.22) and 1.11 (1.02–1.21) per interquartile range increase in exposure. For total PM2.5 the positive associations of 1.12 (0.97–1.31) and 1.16 (0.98–1.36) were not significant. For baseline or lag 0 exposure there were significant associations only for NOx and BC, not for PM. Conclusion: Residential exposure to outdoor air pollution was associated with increased risk of incident CKD at relatively low exposure levels. Average long-term exposure was more clearly associated with CKD than current exposure or exposure at recruitment. Our findings imply that the health effects of low-level air pollution on CKD are considerable.

Summary: Background: There is a critical need to better understand the mechanisms that drive local cell invasion and metastasis to develop new therapeutics targeting metastatic disease. Bioelectricity is an important mediator of cellular processes and changes in the resting membrane potential (RMP) are associated with increased cancer cell invasion. However, whether the RMP can be used to target invading cancer cells is unknown. Methods: We employed both genetic and pharmacological manipulation of potassium channel activity and characterized the effects on breast cancer cell migration and invasion in vitro, and metastasis in an animal model of breast cancer. Findings: Our data demonstrate that altering the RMP of triple-negative breast cancer (TNBC) cells by manipulating potassium channel expression increases in vitro invasion, in vivo tumour growth and metastasis, and is accompanied by changes in gene expression associated with cell adhesion. Interpretation: We describe a novel mechanism for RMP-mediated cell migration involving cadherin-11 and the MAPK pathway. Importantly, we identify a new strategy to target metastatic TNBC in vivo by repurposing an FDA-approved potassium channel blocker. Our results demonstrate that bioelectricity regulates cancer cell invasion and metastasis which could lead to a new class of therapeutics for patients with metastatic disease. Funding: This work was supported by the National Institutes of Health (R00-CA207866 to M.J.O.), Tufts University (Start-up funds from the School of Engineering to M.J.O., Tufts Collaborates Award to M.J.O. and M.L.), Allen Discovery centre program (Paul G. Allen Frontiers Group (12,171) to M.L.), and Breast Cancer Alliance Young Investigator Grant to M.J.O, Laidlaw Scholar funding to D.S. M.L. also gratefully acknowledges support of the Barton Family Foundation.

Introduction: Asthma is a complex, heterogeneous disease and one of the most common chronic diseases among children. Exposure to ambient air pollution in early life and childhood may influence asthma aetiology, but it is uncertain which specific components of air pollution and exposure windows are of importance. The role of socio-economic status (SES) is also unclear. The aims of the present study are, therefore, to investigate how various exposure windows of different pollutants affect risk-induced asthma in early life and to explore the possible effect SES has on that relationship. Methods: The study population was constructed using register data on all singleton births in the greater Stockholm area between 2006 and 2013. Exposure to ambient black carbon (BC), fine particulate matter (PM2.5), primary organic carbon (pOC) secondary organic aerosols (SOA), secondary inorganic aerosols, and oxidative potential at the residential address was modelled as mean values for the entire pregnancy period, the first year of life and the first three years of life. Swedish national registers were used to define the outcome: asthma diagnosis assessed at hospital during the first six years of life. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were modelled with Cox proportional hazards model with age as the underlying time-scale, adjusting for relevant potential confounding variables. Results: An increased risk for developing childhood asthma was observed in association with exposure to PM2.5, pOC and SOA during the first three years of life. With an interquartile range increase in exposure, the HRs were 1.06 (95% CI: 1.01–1.10), 1.05 (95% CI: 1.02–1.09) and 1.02 (95% CI: 1.00–1.04), for PM2.5, pOC and SOA, respectively, in the fully adjusted models. Exposure during foetal life or the first year of life was not associated with asthma risk, and the other pollutants were not statistically significantly associated with increased risk. Furthermore, the increase in risk associated with PM2.5 and the components BC, pOC and SOA were stronger in areas with lower SES. Conclusion: Our results suggest that exposure to air pollution during the first three years of life may increase the risk for asthma in early childhood. The findings further imply a possible increased vulnerability to air pollution-attributed asthma among low SES children.

Study region: This study focused mainly on Burkina Faso in West Africa. Study focus: This study aims to identify environmental variables that best explain the geographic variations of the flow intermittency regime, focusing on intermittency duration. Discharge data from 49 gauging stations were considered, mostly over large rivers. The mean number of dry months (Ndry¯) was used as a predictor to define four classes of flow intermittency, for which the potential explanatory environmental variables were assessed based on correlation analysis and principal component analysis (PCA). New hydrological insights for the region: The first two components (PCs) account for 82 % of the total variance with PC1 (52 %), and most of the catchments with similar flow intermittency are ordered according to PC2 (30 %), predominantly related to catchment permeability. Moreover, permeability was highly correlated with Ndry¯ (r = - 0.75). Results suggest that catchment permeability and catchment areas are the most critical variables in determining flow intermittency classes in Burkina Faso, as the effect of precipitation can be overruled by the ones of permeability, catchment area, and Strahler order. This study is a first step in understanding the controls of river intermittency in data-scarce and poorly gauged regions of West Africa. The identified variables could be used as input in statistical models to predict and map river intermittency and provide valuable information for stream conservation.

Cellular communication is important in all aspects of tissue and organism functioning, from the level of single cells, two discreet populations, and distant tissues of the body. Long distance communication networks integrate individual cells into tissues to maintain a complex organism during development, but when communication between cells goes awry, disease states such as cancer emerge. Herein we discuss the growing body of evidence suggesting that communication methods known to be employed by neurons, also exist in other cell types. We identify three major areas of long-distance communication: bioelectric signaling, tunneling nanotubes (TNTs), and macrophage modulation of networks, and draw comparisons about how these systems operate in the context of development and cancer. Bioelectric signaling occurs between cells through exchange of ions and tissue-level electric fields, leading to changes in biochemical gradients and molecular signaling pathways to control normal development and tumor growth and invasion in cancer. TNTs transport key morphogens and other cargo long distances, mediating electrical coupling, tissue patterning, and malignancy of cancer cells. Lastly macrophages maintain long distance signaling networks through trafficking of vesicles during development, providing communication relays and priming favorable microenvironments for cancer metastasis. By drawing comparisons between non-neural long distance signaling in the context of development and cancer we aim to encourage crosstalk between the two fields to cultivate new hypotheses and potential therapeutic strategies.

While air pollution data in Ethiopia is limited, existing studies indicate high levels of both ambient and household air pollution; rapid urbanization also threatens the preservation of urban green spaces. In this study, environmental injustice, or the disproportionate burden of environmental exposures on persons of lower socioeconomic status (SES), was explored among women in Ethiopia using a mother and child cohort from the city of Adama. Land-use regression models were previously developed for modeling ambient nitrogen dioxide (NO2) and nitrogen oxides (NOx) throughout Adama, while household air pollution (cooking fuel type) and the presence of green space were assessed through questionnaires and home visits, respectively. The odds of being exposed to these environmental factors were analyzed in association with two SES indicators, education and occupation, using logistic regression. Our results indicate the presence of environmental injustice in Adama, as women with lower SES shouldered a higher burden of air pollution exposure and enjoyed less urban green space than their higher SES counterparts. These findings encourage the prioritization of air quality control and urban planning resources toward policy action within lower SES areas. From a societal perspective, our results also support more upstream interventions, including investment in educational and occupational opportunities. Still, a human rights approach is emphasized, as governments are responsible for protecting the right to a clean environment, especially for those disproportionately exposed. To the best of our knowledge, this is the first study on environmental injustice in Ethiopia, and the first in Sub-Saharan Africa to investigate the inequalities of ambient and household air pollution exposure as well as urban green space access in the same cohort.

Anti-programmed death 1 (PD-1) is a revolutionary treatment for many cancers. The response to anti-PD-1 relies on several properties of tumor and immune cells, including the expression of PD-L1 and PD-1. Despite the impressive clinical benefit achieved with anti-PD-1 in several cancers in adults, the use of this therapy for high-risk neuroblastoma remains modest. Here, we evaluated the therapeutic benefit of anti-PD-1 in combination with JQ1 in a highly relevant TH-MYCN neuroblastoma transgenic mouse model. JQ1 is a small molecule inhibitor of the extra-terminal domain (BET) family of bromodomain proteins, competitively binding to bromodomains. Using several neuroblastoma cell lines in vitro, we showed that JQ1 inhibited hypoxia-dependent induction of HIF-1α and decreased the expression of the well-known HIF-1α downstream target gene CA9. Using MRI relaxometry performed on TH-MYCN tumor-bearing mice, we showed that JQ1 decreases R2* in tumors, a parameter associated with intra-tumor hypoxia in pre-clinical settings. Decreasing hypoxia by JQ1 was associated with improved blood vessel quality and integrity, as revealed by CD31 and αSMA staining on tumor sections. By analyzing the immune landscape of TH-MYCN tumors in mice, we found that JQ1 had no major impact on infiltrating immune cells into the tumor microenvironment but significantly increased the percentage of CD8+ PD-1+, conventional CD4+ PD-1+, and Treg PD-1+ cells. While anti-PD-1 monotherapy did not affect TH-MYCN tumor growth, we showed that combinatorial therapy associating JQ1 significantly decreased the tumor volume and improved the therapeutic benefit of anti-PD-1. This study provided the pre-clinical proof of concept needed to establish a new combination immunotherapy approach that may create tremendous enthusiasm for treating high-risk childhood neuroblastoma.

Summary: Tumor organoids and patient-derived orthotopic xenografts (PDOXs) are some of the most valuable pre-clinical tools in cancer research. In this protocol, we describe efficient derivation of organoids and PDOX models from glioma patient tumors. We provide detailed steps for organoid culture, intracranial implantation, and detection of tumors in the brain. We further present technical adjustments for standardized functional assays and drug testing.For complete details on the use and execution of this protocol, please refer to Golebiewska et al. (2020).

Background: Studies have shown that ambient air pollution is linked to preeclampsia (PE), possibly via generation of oxidative stress in the placenta. Telomere length and mitochondrial DNA copy number (mtDNAcn) are sensitive to oxidative stress damage.Objective: To study the association between prenatal exposure to ambient nitrogen oxides (NOx, a marker for traffic-related air pollution), and PE, as well as potential mediation effects by placental telomere length and mtDNAcn.Methods: This is a cross-sectional study of 42 preeclamptic and 95 arbitrarily selected normotensive pregnant women with gestational ambient NOx exposure assessment in southern Scania, Sweden. Hourly concentrations of NOx were estimated at the residential addresses by a Gaussian-plume dispersion model with 100 × 100 m spatial resolutions and aggregated into trimester-specific mean concentrations. Placental relative mtDNAcn and telomere length were measured using qPCR. Linear and logistic regression models were used to investigate associations, adjusted for perinatal and seasonal characteristics.Results: Exposure was categorized into low and high exposures by median cut-offs during first [11.9 μg/m3; interquartile range (IQR) 7.9, 17.9], second (11.6 μg/m3; IQR: 7.1, 21.1), third trimesters (11.9 μg/m3; IQR: 7.7, 19.5) and entire pregnancy (12.0 μg/m3; IQR: 7.6, 20.1). Increased risk of PE was found for high prenatal NOx exposure during the first trimester (OR 4.0; 95% CI: 1.4, 11.1; p = 0.008), and entire pregnancy (OR 3.7; 95% CI: 1.3, 10.4; p = 0.012). High exposed group during the first trimester had lower placental relative mtDNAcn compared with low exposed group (−0.20; 95% CI: −0.36, −0.04; p = 0.01). Changes in relative mtDNAcn did not mediate the association between prenatal NOx exposure and PE. No statistically significant association was found between placental relative telomere length, prenatal NOx exposure and PE.Conclusion: In this region with relatively low levels of air pollution, ambient NOx exposure during the first trimester was associated with reduced placental relative mtDNAcn and an increased risk of PE. However, we did not find any evidence that mtDNAcn or TL mediated the association between air pollution and PE. Future research should further investigate the role of mtDNAcn for pregnancy complications in relation to exposure to ambient air pollution during pregnancy.

Malignant brain tumors remain uniformly fatal, even with the best-to-date treatment. For Glioblastoma (GBM), the most severe form of brain cancer in adults, the median overall survival is roughly over a year. New therapeutic options are urgently needed, yet recent clinical trials in the field have been largely disappointing. This is partially due to inappropriate preclinical model systems, which do not reflect the complexity of patient tumors. Furthermore, clinically relevant patient-derived models recapitulating the immune compartment are lacking, which represents a bottleneck for adequate immunotherapy testing. Emerging 3D organoid cultures offer innovative possibilities for cancer modeling. Here, we review available GBM organoid models amenable to a large variety of pre-clinical applications including functional bioassays such as proliferation and invasion, drug screening, and the generation of patient-derived orthotopic xenografts (PDOX) for validation of biological responses in vivo. We emphasize advantages and technical challenges in establishing immunocompetent ex vivo models based on co-cultures of GBM organoids and human immune cells. The latter can be isolated either from the tumor or from patient or donor blood as peripheral blood mononuclear cells (PBMCs). We also discuss the challenges to generate GBM PDOXs based on humanized mouse models to validate efficacy of immunotherapies in vivo. A detailed characterization of such models at the cellular and molecular level is needed to understand the potential and limitations for various immune activating strategies. Increasing the availability of immunocompetent GBM models will improve research on emerging immune therapeutic approaches against aggressive brain cancer.

All cells possess an electric potential across their plasma membranes and can generate and receive bioelectric signals. The cellular resting membrane potential (RMP) can regulate cell proliferation, differentiation and apoptosis. Current approaches to measure the RMP rely on patch clamping, which is technically challenging, low-throughput and not widely available. It is therefore critical to develop simple strategies to measure, manipulate and characterize the RMP. Here, we present a simple methodology to study the RMP of non-excitable cells and characterize the contribution of individual ions to the RMP using a voltage-sensitive dye. We define protocols using extracellular solutions in which permeable ions (Na+, Cl− and K+) are substituted with non-permeable ions [N-Methyl-D-glucamine (NMDG), gluconate, choline, SO42−]. The resulting RMP modifications were assessed with both patch clamp and a voltage sensitive dye. Using an epithelial and cancer cell line, we demonstrate that the proposed ionic solutions can selectively modify the RMP and help determine the relative contribution of ionic species in setting the RMP. The proposed method is simple and reproducible and will make the study of bioelectricity more readily available to the cell biology community. This article has an associated First Person interview with the first author of the paper.

INTRODUCTION:Schizophrenia is a condition that places a significant burden on individuals with the condition, their family, and society. A large proportion of those treated for schizophrenia do not experience treatment response and are referred to as having "treatment-resistant schizophrenia" (TRS). Expert opinion has long held that the prevalence of TRS among individuals with schizophrenia is 30%, but the basis of this estimate is unclear. This article presents a model developed for estimating the prevalence of TRS in the United States 2014. METHODS:An incidence-prevalence-mortality model was developed to estimate the prevalence of TRS in the United States. The model was populated with data from public health agencies and published literature. Prevalence in 2014 was modelled using a Markov cohort simulation for each birth cohort between 1930 to 2014. RESULTS:Using different scenarios for baseline incidence, relative risks of mortality, it was estimated that approximately 22% of individuals with schizophrenia would be considered treatment-resistant in 2014. DISCUSSION:The results suggests that prevalence of TRS may be somewhat lower than the 30% often reported, however this is highly dependent on the definition of treatment resistance. Methods such as this may help answer epidemiological and health policy questions as well as test the influence of key underlying assumptions.

Air pollution is responsible for one in eight premature deaths worldwide, and thereby a major threat to human health. Health impact assessments of hypothetic changes in air pollution concentrations can be used as a mean of assessing the health impacts of policy, plans and projects, and support decision-makers in choices to prevent disease.The aim of this study was to estimate health impacts attributable to a hypothetical decrease in air pollution concentrations in the city of Malmö in Southern Sweden corresponding to a policy on-road transportations without tail-pipe emissions in the municipality. We used air pollution data modelled for each of the 326,092 inhabitants in Malmö by a Gaussian dispersion model combined with an emission database with >40,000 sources. The dispersion model calculates Nitrogen Oxides (NOx) (later transformed into Nitrogen Dioxide (NO2)) and particulate matter with an aerodynamic diameter

Plant specialized metabolites are widely used in the pharmaceutical industry, including the monoterpene indole alkaloids (MIAs) vinblastine and vincristine, which both display anticancer activity. Both compounds can be obtained through the chemical condensation of their precursors vindoline and catharanthine extracted from leaves of the Madagascar periwinkle. However, the extensive use of these molecules in chemotherapy increases precursor demand and results in recurrent shortages, explaining why the development of alternative production approaches, such microbial cell factories, is mandatory. In this context, the precursor-directed biosynthesis of vindoline from tabersonine in yeast-expressing heterologous biosynthetic genes is of particular interest but has not reached high production scales to date. To circumvent production bottlenecks, the metabolic flux was channeled towards the MIA of interest by modulating the copy number of the first two genes of the vindoline biosynthetic pathway, namely tabersonine 16-hydroxylase and tabersonine-16-O-methyltransferase. Increasing gene copies resulted in an optimized methoxylation of tabersonine and overcame the competition for tabersonine access with the third enzyme of the pathway, tabersonine 3-oxygenase, which exhibits a high substrate promiscuity. Through this approach, we successfully created a yeast strain that produces the fourth biosynthetic intermediate of vindoline without accumulation of other intermediates or undesired side-products. This optimization will probably pave the way towards the future development of yeast cell factories to produce vindoline at an industrial scale.

The biosynthetic pathway of preakuammicine, a monoterpene precursor of the anti-cancer agent vinblastine, has remained largely unexplored. Here, the authors provide transcriptomic and biochemical data to identify two enzymes that, in tandem, convert strictosidine to akuammicine, the stable shunt product of preakuammicine.

The low pathogenicity and replicative potential of HIV-2 are still poorly understood. We investigated whether HIV-2 reservoirs might follow the peculiar distribution reported in models of attenuated HIV-1/SIV infections, i.e. limited infection of central-memory CD4 T lymphocytes (TCM). Antiretroviral-naive HIV-2 infected individuals from the ANRS-CO5 (12 non-progressors, 2 progressors) were prospectively included. Peripheral blood mononuclear cells (PBMCs) were sorted into monocytes and resting CD4 T-cell subsets (naive [TN], central- [TCM], transitional- [TTM] and effector-memory [TEM]). Reactivation of HIV-2 was tested in 30-day cultures of CD8-depleted PBMCs. HIV-2 DNA was quantified by real-time PCR. Cell surface markers, co-receptors and restriction factors were analyzed by flow-cytometry and multiplex transcriptomic study. HIV-2 DNA was undetectable in monocytes from all individuals and was quantifiable in TTM from 4 individuals (median: 2.25 log10 copies/106 cells [IQR: 1.99-2.94]) but in TCM from only 1 individual (1.75 log10 copies/106 cells). HIV-2 DNA levels in PBMCs (median: 1.94 log10 copies/106 PBMC [IQR = 1.53-2.13]) positively correlated with those in TTM (r = 0.66, p = 0.01) but not TCM. HIV-2 reactivation was observed in the cells from only 3 individuals. The CCR5 co-receptor was distributed similarly in cell populations from individuals and donors. TCM had a lower expression of CXCR6 transcripts (p = 0.002) than TTM confirmed by FACS analysis, and a higher expression of TRIM5 transcripts (p = 0.004). Thus the low HIV-2 reservoirs differ from HIV-1 reservoirs by the lack of monocytic infection and a limited infection of TCM associated to a lower expression of a potential alternative HIV-2 co-receptor, CXCR6 and a higher expression of a restriction factor, TRIM5. These findings shed new light on the low pathogenicity of HIV-2 infection suggesting mechanisms close to those reported in other models of attenuated HIV/SIV infection models.

The lesser periwinkle Vinca minor accumulates numerous monoterpene indole alkaloids (MIAs) including the vasodilator vincamine. While the biosynthetic pathway of MIAs has been largely elucidated in other Apocynaceae such as Catharanthus roseus, the counterpart in V. minor remains mostly unknown, especially for reactions leading to MIAs specific to this plant. As a consequence, we generated a comprehensive V. minor transcriptome elaborated from eight distinct samples including roots, old and young leaves exposed to low or high light exposure conditions. This optimized resource exhibits an improved completeness compared to already published ones. Through homology-based searches using C. roseus genes as bait, we predicted candidate genes for all common steps of the MIA pathway as illustrated by the cloning of a tabersonine/vincadifformine 16-O-methyltransferase (Vm16OMT) isoform. The functional validation of this enzyme revealed its capacity of methylating 16-hydroxylated derivatives of tabersonine, vincadifformine and lochnericine with a Km 0.94 ± 0.06 µM for 16-hydroxytabersonine. Furthermore, by combining expression of fusions with yellow fluorescent proteins and interaction assays, we established that Vm16OMT is located in the cytosol and forms homodimers. Finally, a gene co-expression network was performed to identify candidate genes of the missing V. minor biosynthetic steps to guide MIA pathway elucidation.

Background and objectives: Despite global warming, the climate in Northern Europe is generally cold, and the large number of deaths due to non-optimal temperatures is likely due to cold temperatures. The aim of the current study is to investigate the association between cold temperatures and all-cause mortality, as well as cause-specific mortality, in Tallinn and Riga in North-Eastern Europe. Materials and Methods: We used daily information on deaths from state death registries and minimum temperatures from November to March over the period 1997−2015 in Tallinn and 2009−2015 in Riga. The relationship between the daily minimum temperature and mortality was investigated using the Poisson regression, combined with a distributed lag non-linear model considering lag times of up to 21 days. Results: We found significantly higher all-cause mortality owing to cold temperatures both in Tallinn (Relative Risk (RR) = 1.28, 95% Confidence Interval (CI) 1.01−1.62) and in Riga (RR = 1.41, 95% CI 1.11−1.79). In addition, significantly increased mortality due to cold temperatures was observed in the 75+ age group (RR = 1.64, 95% CI 1.17−2.31) and in cardiovascular mortality (RR = 1.83, 95% CI 1.31−2.55) in Tallinn and in the under 75 age group in Riga (RR = 1.58, 95% CI 1.12−2.22). In this study, we found no statistically significant relationship between mortality due to respiratory or external causes and cold days. The cold-related attributable fraction (AF) was 7.4% (95% CI -3.7−17.5) in Tallinn and 8.3% (95% CI -0.5−16.3) in Riga. This indicates that a relatively large proportion of deaths in cold periods can be related to cold in North-Eastern Europe, where winters are relatively harsh.

The Madagascar periwinkle (Catharanthus roseus) synthesizes the highly valuable monoterpene indole alkaloids (MIAs) through a long metabolic route initiated by the 2C-methyl-D-erythritol 4-phosphate (MEP) pathway. In leaves, a complex compartmentation of the MIA biosynthetic pathway occurs at both the cellular and subcellular levels, notably for some gene products of the MEP pathway. To get a complete overview of the pathway organization, we cloned four genes encoding missing enzymes involved in the MEP pathway before conducting a systematic analysis of transcript distribution and protein subcellular localization. RNA in situ hybridization revealed that all MEP pathway genes were coordinately and mainly expressed in internal phloem-associated parenchyma of young leaves, reinforcing the role of this tissue in MIA biosynthesis. At the subcellular level, transient cell transformation and expression of fluorescent protein fusions showed that all MEP pathway enzymes were targeted to plastids. Surprisingly, two isoforms of 1-deoxy-D-xylulose 5-phosphate synthase and 1-deoxy-D-xylulose 5-phosphate reductoisomerase initially exhibited an artifactual aggregated pattern of localization due to high protein accumulation. Immunogold combined with transmission electron microscopy, transient transformations performed with a low amount of transforming DNA and fusion/deletion experiments established that both enzymes were rather diffuse in stroma and stromules of plastids as also observed for the last six enzymes of the pathway. Taken together, these results provide new insights into a potential role of stromules in enhancing MIA precursor exchange with other cell compartments to favor metabolic fluxes towards the MIA biosynthesis.

BackgroundHeatwaves are a critical public health problem. There will be an increase in the frequency and severity of heatwaves under changing climate. However, evidence about the impacts of climate change on heatwave-related mortality at a global scale is limited.Methods and findingsWe collected historical daily time series of mean temperature and mortality for all causes or nonexternal causes, in periods ranging from January 1, 1984, to December 31, 2015, in 412 communities within 20 countries/regions. We estimated heatwave-mortality associations through a two-stage time series design. Current and future daily mean temperature series were projected under four scenarios of greenhouse gas emissions from 1971-2099, with five general circulation models. We projected excess mortality in relation to heatwaves in the future under each scenario of greenhouse gas emissions, with two assumptions for adaptation (no adaptation and hypothetical adaptation) and three scenarios of population change (high variant, median variant, and low variant). Results show that, if there is no adaptation, heatwave-related excess mortality is expected to increase the most in tropical and subtropical countries/regions (close to the equator), while European countries and the United States will have smaller percent increases in heatwave-related excess mortality. The higher the population variant and the greenhouse gas emissions, the higher the increase of heatwave-related excess mortality in the future. The changes in 2031-2080 compared with 1971-2020 range from approximately 2,000% in Colombia to 150% in Moldova under the highest emission scenario and high-variant population scenario, without any adaptation. If we considered hypothetical adaptation to future climate, under high-variant population scenario and all scenarios of greenhouse gas emissions, the heatwave-related excess mortality is expected to still increase across all the countries/regions except Moldova and Japan. However, the increase would be much smaller than the no adaptation scenario. The simple assumptions with respect to adaptation as follows: no adaptation and hypothetical adaptation results in some uncertainties of projections.ConclusionsThis study provides a comprehensive characterisation of future heatwave-related excess mortality across various regions and under alternative scenarios of greenhouse gas emissions, different assumptions of adaptation, and different scenarios of population change. The projections can help decision makers in planning adaptation and mitigation strategies for climate change.

OBJECTIVES:There is highly suggestive evidence for an effect of air pollution exposure on dementia-related outcomes, but evidence is not yet present to clearly pinpoint which pollutants are the probable causal agents. The aims of this study was to assess the longitudinal association between exposures of fine ambient particulate matter (PM2.5) from residential wood burning, and vehicle exhaust, with dementia. METHOD:We used data from the Betula study, a longitudinal study of dementia in Umeå, Northern Sweden. The study size was 1 806 and the participants were followed from study entry (1993-1995) to 2010. Modelled levels of source-specific fine particulate matter at the residential address were combined with information on wood stoves or wood boilers, and with validated data on dementia diagnosis and individual-level characteristics from the Betula study. Cox proportional hazards models were used to estimate Hazard Ratios (HRs) and their 95% CIs for dementia incidence (vascular dementia and Alzheimer's disease), adjusted for individual-level characteristics. RESULTS:The emission of PM2.5 from local residential wood burning was associated with dementia incidence with a hazard ratio of 1.55 for a 1 μg/m3 increase in PM2.5 (95% Confidence Interval (CI): 1.00-2.41, p-value 0.05). Study participants with an address in an area with the highest quartile of PM2.5 from residential wood burning and who also had a wood-burning stove were more likely to develop dementia than those in the lower three quartiles without a wood-burning stove with hazard ratios of 1.74 (CI: 1.10-2.75, p-value 0.018). Particulate matter from traffic exhaust seemed to be associated with dementia incidence with hazard ratios of 1.66, (CI: 1.16-2.39), p-value 0.006, and 1.41 (CI: 0.97-2.23), p-value 0.07, in the third and fourth quartiles, respectively. CONCLUSIONS:If the associations we observed are causal, then air pollution from residential wood burning, and air pollution from traffic, might be independent important risk factors for dementia.

It is often argued that urban areas play a significant role in catchment hydrology, but previous studies reported disparate results of urbanization impacts on stream flow. This might stem either from the difficulty to quantify the historical flow changes attributed to urbanization only (and not climate variability) or from the inability to decipher what type of urban planning is more critical for flows. In this study, we applied a hydrological model on 43 urban catchments in the United States to quantify the flow changes attributable to urbanization. Then, we tried to relate these flow changes to the changes of urban/impervious areas of the catchments. We argue that these spatial changes of urban areas can be more precisely characterized by landscape metrics, which enable analysing the patterns of historical urban growth. Landscape metrics combine the richness (the number) and evenness (the spatial distribution) of patch types represented on the landscape. Urbanization patterns within the framework of patch analysis have been widely studied but, to our knowledge, previous research works had not linked them to catchments hydrological behaviours. Our results showed that the catchments with larger impervious areas and larger mean patch areas are likely to have larger increase of runoff yield.

Cytokinin signaling is a key regulatory pathway of many aspects in plant development and environmental stresses. Herein, we initiated the identification and functional characterization of the five CHASE-containing histidine kinases (CHK) in the economically important Malus domestica species. These cytokinin receptors named MdCHK2, MdCHK3a/MdCHK3b, and MdCHK4a/MdCHK4b by homology with Arabidopsis AHK clearly displayed three distinct profiles. The three groups exhibited architectural variations, especially in the N-terminal part including the cytokinin sensing domain. Using a yeast complementation assay, we showed that MdCHK2 perceives a broad spectrum of cytokinins with a substantial sensitivity whereas both MdCHK4 homologs exhibit a narrow spectrum. Both MdCHK3 homologs perceived some cytokinins but surprisingly they exhibited a basal constitutive activity. Interaction studies revealed that MdCHK2, MdCHK4a, and MdCHK4b homodimerized whereas MdCHK3a and MdCHK3b did not. Finally, qPCR analysis and bioinformatics approach pointed out contrasted expression patterns among the three MdCHK groups as well as distinct sets of co-expressed genes. Our study characterized for the first time the five cytokinin receptors in apple tree and provided a framework for their further functional studies.