The HY5-PIF regulatory module coordinates light and temperature control of photosynthetic gene transcription

The ability to interpret daily and seasonal alterations in light and temperature signals is essential for plant survival. This is particularly important during seedling establishment when the phytochrome photoreceptors activate photosynthetic pigment production for photoautotrophic growth. Phytochromes accomplish this partly through the suppression of phytochrome interacting factors (PIFs), negative regulators of chlorophyll and carotenoid biosynthesis. While the bZIP transcription factor long hypocotyl 5 (HY5), a potent PIF antagonist, promotes photosynthetic pigment accumulation in response to light. Here we demonstrate that by directly targeting a common promoter cis-element (G-box), HY5 and PIFs form a dynamic activation-suppression transcriptional module responsive to light and temperature cues. This antagonistic regulatory module provides a simple, direct mechanism through which environmental change can redirect transcriptional control of genes required for photosynthesis and photoprotection. In the regulation of photopigment biosynthesis genes, HY5 and PIFs do not operate alone, but with the circadian clock. However, sudden changes in light or temperature conditions can trigger changes in HY5 and PIFs abundance that adjust the expression of common target genes to optimise photosynthetic performance and growth

Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both

Importance Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival. Objective To determine clinical effectiveness and cost-effectiveness of combining docetaxel, ZA, and Sr89, all having palliative benefits and used in bony metastatic CRPC to control bone symptoms and, for docetaxel, to prolong survival. Design, Setting, and Participants The TRAPEZE trial is a 2 × 2 factorial trial comparing docetaxel alone or with ZA, Sr89, or both. A cohort of 757 participants were recruited between February 2005 and February 2012 from hospitals in the United Kingdom. Overall, 169 participants (45%) had received palliative radiotherapy, and the median (IQR) prostate-specific antigen level was 146 (51-354). Follow-ups were performed for at least 12 months. Interventions Up to 10 cycles of docetaxel alone; docetaxel with ZA; docetaxel with a single Sr89 dose after 6 cycles; or docetaxel with both ZA and Sr89. Main Outcomes and Measures Primary outcomes included clinical progression-free survival (CPFS) (pain progression, skeletal-related events [SREs], or death) and cost-effectiveness. Secondary outcomes included SRE-free interval, pain progression–free interval, total SREs, and overall survival (OS). Results Overall, of 757 participants, 349 (46%) completed docetaxel treatment. Median (IQR) age was 68 (63-73) years. Clinical progression-free survival did not reach statistical significance for either Sr89 or ZA. Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (hazard ratio [HR], 0.85; 95% CI, 0.73-0.99; P = .03) and confirmed no effect of ZA (HR, 0.98; 95% CI, 0.85-1.14; P = .81); ZA had a significant effect on SRE-free interval (HR, 0.78; 95% CI, 0.65-0.95; P = .01). For OS, there was no effect of either Sr89 (HR, 0.92; 95% CI, 0.79-1.08; P = 0.34) or ZA (HR, 0.99; 95% CI, 0.84-1.16; P = 0.91). Conclusions and Relevance Strontium-89 combined with docetaxel improved CPFS but did not improve OS, SRE-free interval, or total SREs; ZA did not improve CPFS or OS but did significantly improve median SRE-free interval and reduced total SREs by around one-third, suggesting a role as postchemotherapy maintenance therapy

Predicting Crystallization of Amorphous Drugs with Terahertz Spectroscopy.

There is a controversy about the extent to which the primary and secondary dielectric relaxations influence the crystallization of amorphous organic compounds below the glass transition temperature. Recent studies also point to the importance of fast molecular dynamics on picosecond-to-nanosecond time scales with respect to the glass stability. In the present study we provide terahertz spectroscopy evidence on the crystallization of amorphous naproxen well below its glass transition temperature and confirm the direct role of Johari-Goldstein (JG) secondary relaxation as a facilitator of the crystallization. We determine the onset temperature Tβ above which the JG relaxation contributes to the fast molecular dynamics and analytically quantify the level of this contribution. We then show there is a strong correlation between the increase in the fast molecular dynamics and onset of crystallization in several chosen amorphous drugs. We believe that this technique has immediate applications to quantify the stability of amorphous drug materials.JS and JAZ would like to acknowledge the UK Engineering and Physical Sciences Research Council for funding (EP/J007803/1).This is the final version of the article. It first appeared from ACS at http://dx.doi.org/10.1021/acs.molpharmaceut.5b0033

Health-related quality of life at 5 years of age for children born very preterm with congenital anomalies: a multi-national cohort study

Background: This study aimed to investigate the health-related quality of life (HRQoL) at 5 years of age of European children born very preterm across multi-dimensional outcomes by presence and severity of congenital anomalies. Methods: The study used data from a European cohort of children born very preterm (<32 weeks of gestation) and followed up to 5 years of age (N = 3493). Multilevel Ordinary Least Squares (OLS) regression were used to explore the associations between the presence and severity of congenital anomalies. Results: The mean total PedsQL™ GCS score for children with a mild congenital anomaly was lower than the respective value for children without a congenital anomaly by 3.7 points (p < 0.05), controlling for socioeconomic variables only; this effect was attenuated when accumulatively adjusting for perinatal characteristics (3.3 points (p < 0.05)) and neonatal morbidities (3.1 (p < 0.05)). The mean total PedsQL™ GCS scores for children who had a severe congenital anomaly were lower by 7.1 points (p < 0.001), 6.6 points (p < 0.001) and 6.0 points (p < 0.001) when accumulatively adjusting for socioeconomic, perinatal and neonatal variables, respectively. Conclusion: This study revealed that the presence and severity of congenital anomalies are significant predictors of HRQoL outcomes in children born very preterm. Impact: Children born very preterm with congenital anomalies experience poorer health-related quality of life (HRQoL) than their very preterm counterparts born without congenital anomalies. Increased severity of these anomalies compounds the negative impacts on HRQoL. Our findings can be used by stakeholders for clinical and planning purposes. © The Author(s) 2024.We appreciate all the participants that completed the parental questionnaires. The entire SHIPS study team reviewed and approved the final version for publication. Funding/Support This study was supported by a grant from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No 633724. Prof Petrou receives support as a UK National Insitute for Health and Care Research (NIHR) Senior Investigator (NF-SI-0616-10103) and from the NIHR Applied Research Collaboration Oxford and Thames Valley at the Oxford Health NHS Foundation Trust. The European Union’s Horizon 2020 Research and Innovation Programme and the NIHR Applied Research Collaboration Oxford and Thames Valley at the Oxford Health NHS Foundation Trust had no role in the design and conduct of the study

Health-related quality of life at 5 years of age for children born very preterm with congenital anomalies: a multi-national cohort study

\ua9 The Author(s) 2024.Background: This study aimed to investigate the health-related quality of life (HRQoL) at 5 years of age of European children born very preterm across multi-dimensional outcomes by presence and severity of congenital anomalies. Methods: The study used data from a European cohort of children born very preterm (&lt;32 weeks of gestation) and followed up to 5 years of age (N = 3493). Multilevel Ordinary Least Squares (OLS) regression were used to explore the associations between the presence and severity of congenital anomalies. Results: The mean total PedsQL™ GCS score for children with a mild congenital anomaly was lower than the respective value for children without a congenital anomaly by 3.7 points (p &lt; 0.05), controlling for socioeconomic variables only; this effect was attenuated when accumulatively adjusting for perinatal characteristics (3.3 points (p &lt; 0.05)) and neonatal morbidities (3.1 (p &lt; 0.05)). The mean total PedsQL™ GCS scores for children who had a severe congenital anomaly were lower by 7.1 points (p &lt; 0.001), 6.6 points (p &lt; 0.001) and 6.0 points (p &lt; 0.001) when accumulatively adjusting for socioeconomic, perinatal and neonatal variables, respectively. Conclusion: This study revealed that the presence and severity of congenital anomalies are significant predictors of HRQoL outcomes in children born very preterm. Impact: Children born very preterm with congenital anomalies experience poorer health-related quality of life (HRQoL) than their very preterm counterparts born without congenital anomalies. Increased severity of these anomalies compounds the negative impacts on HRQoL. Our findings can be used by stakeholders for clinical and planning purposes

Building an adverse outcome pathway network for COVID-19

The COVID-19 pandemic generated large amounts of data on the disease pathogenesis leading to a need for organizing the vast knowledge in a succinct manner. Between April 2020 and February 2023, the CIAO consortium exploited the Adverse Outcome Pathway (AOP) framework to comprehensively gather and systematically organize published scientific literature on COVID-19 pathology. The project considered 24 pathways relevant for COVID-19 by identifying essential key events (KEs) leading to 19 adverse outcomes observed in patients. While an individual AOP defines causally linked perturbed KEs towards an outcome, building an AOP network visually reflect the interrelatedness of the various pathways and outcomes. In this study, 17 of those COVID-19 AOPs were selected based on quality criteria to computationally derive an AOP network. This primary network highlighted the need to consider tissue specificity and helped to identify missing or redundant elements which were then manually implemented in the final network. Such a network enabled visualization of the complex interactions of the KEs leading to the various outcomes of the multifaceted COVID-19 and confirmed the central role of the inflammatory response in the disease. In addition, this study disclosed the importance of terminology harmonization and of tissue/organ specificity for network building. Furthermore the unequal completeness and quality of information contained in the AOPs highlighted the need for tighter implementation of the FAIR principles to improve AOP findability, accessibility, interoperability and re-usability. Finally, the study underlined that describing KEs specific to SARS-CoV-2 replication and discriminating physiological from pathological inflammation is necessary but requires adaptations to the framework. Hence, based on the challenges encountered, we proposed recommendations relevant for ongoing and future AOP-aligned consortia aiming to build computationally biologically meaningful AOP networks in the context of, but not limited to, viral diseases.info:eu-repo/semantics/publishedVersio

Associations of language barriers with very preterm children’s behavioural and socio-emotional problems across Europe

\ua9 The Author(s) 2024. Background: Very preterm birth (&lt;32 weeks gestation, VP), immigrant background, and language barriers are all independently associated with a high risk for mental health problems in childhood, but research has neglected the long-term development of immigrant children born VP. We assessed whether behavioural and socio-emotional problems of 5-year-old children born VP growing up across different language contexts in the European Union are associated with an immigrant background and linguistic distance of families’ mother tongue (L1) to the host countries’ official languages. Methods: Data are from a population-based cohort including all VP births in 2011/12 in 11 European countries; a total of 3,067 children were followed up at 2 and 5 years of age. Behavioural and socio-emotional difficulties were assessed using the parent-reported Strengths and Difficulties Questionnaire (SDQ). Results: Mixed-effects models showed that a larger linguistic distance of children’s L1 to the host countries’ official language was associated with higher SDQ total scores (0.02 [0.01, 0.03]), after adjusting for a wide range of social risks, biological, and perinatal clinical factors. Conclusion: Language barriers in the form of linguistic distance between VP children’s L1 and countries’ official languages play a critically important role for the behavioural and socio-emotional development of immigrant children born VP. Impact: Immigrant children born very preterm across Europe face systemic inequalities such as language barriers. Language barriers can be operationalised as a continuous linguistic distance score between children’s mother tongues and countries’ official languages. Linguistic distance plays an important role for the behavioural and socio-emotional development of immigrant children born VP. Research, policy, and practice need to better account for language barriers to increase equity in health and education

Global Profiling of Rice and Poplar Transcriptomes Highlights Key Conserved Circadian-Controlled Pathways and cis-Regulatory Modules

Circadian clocks provide an adaptive advantage through anticipation of daily and seasonal environmental changes. In plants, the central clock oscillator is regulated by several interlocking feedback loops. It was shown that a substantial proportion of the Arabidopsis genome cycles with phases of peak expression covering the entire day. Synchronized transcriptome cycling is driven through an extensive network of diurnal and clock-regulated transcription factors and their target cis-regulatory elements. Study of the cycling transcriptome in other plant species could thus help elucidate the similarities and differences and identify hubs of regulation common to monocot and dicot plants.Using a combination of oligonucleotide microarrays and data mining pipelines, we examined daily rhythms in gene expression in one monocotyledonous and one dicotyledonous plant, rice and poplar, respectively. Cycling transcriptomes were interrogated under different diurnal (driven) and circadian (free running) light and temperature conditions. Collectively, photocycles and thermocycles regulated about 60% of the expressed nuclear genes in rice and poplar. Depending on the condition tested, up to one third of oscillating Arabidopsis-poplar-rice orthologs were phased within three hours of each other suggesting a high degree of conservation in terms of rhythmic gene expression. We identified clusters of rhythmically co-expressed genes and searched their promoter sequences to identify phase-specific cis-elements, including elements that were conserved in the promoters of Arabidopsis, poplar, and rice.Our results show that the cycling patterns of many circadian clock genes are highly conserved across poplar, rice, and Arabidopsis. The expression of many orthologous genes in key metabolic and regulatory pathways is diurnal and/or circadian regulated and phased to similar times of day. Our results confirm previous findings in Arabidopsis of three major classes of cis-regulatory modules within the plant circadian network: the morning (ME, GBOX), evening (EE, GATA), and midnight (PBX/TBX/SBX) modules. Identification of identical overrepresented motifs in the promoters of cycling genes from different species suggests that the core diurnal/circadian cis-regulatory network is deeply conserved between mono- and dicotyledonous species

Building an Adverse Outcome Pathway network for COVID-19

Data availability statement: The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.Supplementary material: The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fsysb.2024.1384481/full#supplementary-material .The COVID-19 pandemic generated large amounts of data on the disease pathogenesis leading to a need for organizing the vast knowledge in a succinct manner. Between April 2020 and February 2023, the CIAO consortium exploited the Adverse Outcome Pathway (AOP) framework to comprehensively gather and systematically organize published scientific literature on COVID-19 pathology. The project considered 24 pathways relevant for COVID-19 by identifying essential key events (KEs) leading to 19 adverse outcomes observed in patients. While an individual AOP defines causally linked perturbed KEs towards an outcome, building an AOP network visually reflect the interrelatedness of the various pathways and outcomes. In this study, 17 of those COVID-19 AOPs were selected based on quality criteria to computationally derive an AOP network. This primary network highlighted the need to consider tissue specificity and helped to identify missing or redundant elements which were then manually implemented in the final network. Such a network enabled visualization of the complex interactions of the KEs leading to the various outcomes of the multifaceted COVID-19 and confirmed the central role of the inflammatory response in the disease. In addition, this study disclosed the importance of terminology harmonization and of tissue/organ specificity for network building. Furthermore the unequal completeness and quality of information contained in the AOPs highlighted the need for tighter implementation of the FAIR principles to improve AOP findability, accessibility, interoperability and re-usability. Finally, the study underlined that describing KEs specific to SARS-CoV-2 replication and discriminating physiological from pathological inflammation is necessary but requires adaptations to the framework. Hence, based on the challenges encountered, we proposed recommendations relevant for ongoing and future AOP-aligned consortia aiming to build computationally biologically meaningful AOP networks in the context of, but not limited to, viral diseases.This work was supported by funding from the JRC Exploratory project CIAO (Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway Framework, https://www.ciao-covid.net/). DJ would like to acknowledge funding from the US National Science Foundation (EF-2133763). PN also acknowledges funding from The Swedish Fund for Research without Animals (grants F2021-0005 and F2022-0003). SH acknowledges funding received from Health Canada’s Genomics Research and Development Initiative. ST acknowledges funding received from Japan Agency for Medical Research and Development (AMED) Grant Number JP21mk0101216, JP22mk0101216, JP23mk0101216, Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 21K12133