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Abstract Objective Tuberous sclerosis complex (TSC) results from overactivity of the mechanistic target of rapamycin (mTOR). Sirolimus and everolimus are mTOR inhibitors that treat most facets of TSC but are understudied in infants. We sought to understand the safety and potential efficacy of preventative sirolimus in infants with TSC. Methods We conducted a phase 1 clinical trial of sirolimus, treating five patients until 12 months of age. Enrolled infants had to be younger than 6 months of age with no history of seizures and no clinical indication for sirolimus treatment. Adverse events (AEs), tolerability, and blood concentrations of sirolimus measured by tandem mass spectrometry were tracked through 12 months of age, and clinical outcomes (seizure characteristics and developmental profiles) were tracked through 24 months of age. Results There were 92 AEs, with 34 possibly, probably, or definitely related to treatment. Of those, only two were grade 3 (both elevated lipids) and all AEs were resolved by the age of 24 months. During the trial, 94% of blood sirolimus trough levels were in the target range (5–15 ng/mL). Treatment was well tolerated, with less than 8% of doses held because of an AE (241 of 2941). Of the five patients, three developed seizures (but were well controlled on medications) at 24 months of age. Of the five patients, four had normal cognitive development for age. One was diagnosed with possible autism spectrum disorder. Interpretation These results suggest that sirolimus is both safe and well tolerated by infants with TSC in the first year of life. Additionally, the preliminary work suggests a favorable efficacy profile compared with previous TSC cohorts not exposed to early sirolimus treatment. Results support sirolimus being studied as preventive treatment in TSC, which is now underway in a prospective phase 2 clinical trial (TSC‐STEPS).

Abstract Background Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific. Methods The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community. Results At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to “screen” for TAND at least annually, to “act” using appropriate next steps for evaluation and treatment, and to “repeat” the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families. Conclusions The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a “TAND toolkit” of “what to seek” and “what to do” when difficulties are identified in TAND clusters.

Abstract Background Tuberous sclerosis complex (TSC) is a rare and complex genetic disorder, associated with tumor growth in various organ systems, epilepsy, and a range of neuropsychiatric manifestations including intellectual disability. With improving patient-centered care and targeted therapies, patient-reported outcome measures (PROMs) are needed to measure the impact of TSC manifestations on daily functioning. The aim of this study was to develop a TSC-specific PROM for adults that captures the impact of TSC on physical functions, mental functions, activity and participation, and the social support individuals with TSC receive, called the TSC-PROM. Methods COSMIN methodology was used to develop a self-reported and proxy-reported version. Development and validation consisted of the following studies: PROM development, content validity, structural validity, internal consistency, and construct validity. The International Classification of Functioning and Disability was used as a framework. Content validity was examined by a multidisciplinary expert group and cognitive interview study. Structural and construct validity, and internal consistency were examined in a large cohort, using confirmatory factor analysis, hypotheses testing, and Cronbach’s alpha. Results The study resulted in an 82-item self version and 75-item proxy version of the TSC-PROM with four subscales (physical functions 18 and 19 items, mental functions 37 and 28 items, activities and participation 13 and 14 items, social support 13 items, for self version and proxy version respectively). Sufficient results were found for structural validity with sufficient unidimensionality for each subscale. With regard to construct validity, 82% of the hypotheses were met for the self version and 59% for the proxy version. The PROM showed good internal consistency (Cronbach’s alpha 0.78–0.97). Conclusions We developed a PROM for adults with TSC, named TSC-PROM, showing sufficient evidence for reliability and validity that can be used in clinical and research settings to systematically gain insight into their experiences. It is the first PROM in TSC that addresses the impact of specific TSC manifestations on functioning, providing a valuable, patient-centered addition to the current clinical outcomes.

Two-dimensional materials have recently gained significant awareness. A representative of such materials, black phosphorous (BP), earned attention based on its comprehensive application potential. The presented study focuses on the mode of cellular response underlying the BP interaction with Chlamydomonas reinhardtii as an algal model organism. We observed noticeable ROS formation and changes in outer cellular topology after 72 h of incubation at 5 mg/L BP. Transcriptome profiling was employed to examine C. reinhardtii response after exposure to 25 mg/L BP for a deeper understanding of the associated processes. The RNA sequencing has revealed a comprehensive response with abundant transcript downregulation. The mode of action was attributed to cell wall disruption, ROS elevation, and chloroplast disturbance. Besides many other dysregulated genes, the cell response involved the downregulation of GH9 and gametolysin within a cell wall, pointing to a shift to discrete manipulation with resources. The response also included altered expression of the PRDA1 gene associated with redox governance in chloroplasts implying ROS disharmony. Altered expression of the Cre-miR906–3p, Cre-miR910, and Cre-miR914 pointed to those as potential markers in stress response studies.

Abstract Background Tuberous sclerosis complex (TSC)–associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed, under-treated and under-researched. We performed a comprehensive scoping review of all TAND research to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND research. Methods The study was conducted in accordance with stages outlined within the Arksey and O’Malley scoping review framework. Ten research questions relating to study characteristics, research design and research content of TAND levels and clusters were examined. Results Of the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal studies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in 2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults (16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA (89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low–middle income countries (LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non-pharmacological, and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the autism spectrum disorder–like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the least (53/200; 27%). Conclusions Despite the recent increase in TAND research, studies that represent participants across the lifespan, LMIC research sites and non-pharmacological interventions were identified as future priorities. The quality of cohort studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In human studies, the academic level in particular warrants further investigation. Remote technologies could help to address many of the TAND knowledge gaps identified.

Abstract Background Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric difficulties, appropriately termed TSC-Associated Neuropsychiatric Disorders (TAND). The objectives of the study were to analyze the rates of TAND symptoms in a cohort of patients seen at the TSC Center of Excellence at Cincinnati Children’s Hospital and to identify clinically meaningful profiles based on TAND symptoms. Methods Data from the TAND Checklist was obtained from participants seen at the TSC Center of Excellence at Cincinnati Children’s Hospital Medical Center from June 2015 to August 2018. Cluster and factor analyses for each TAND symptom were performed. Factor scores were then calculated for participants, and a K-means cluster analysis of these scores was used to empirically identify distinct overall TAND symptom profiles occurring in TSC. Results A total of 1545 checklists was completed for 668 participants (37% adults and 63% children). Approximately 90% of participants reported at least one TAND symptom with an average of 12 symptoms (out of 29). Symptom rates ranged between 5 and 60%. The most common symptoms were neuropsychologic symptoms. A seven-cluster and seven-factor solution were found to be optimal. K-means cluster analysis resulted in a seven-profile solution, ranging from low to high symptom burden. Conclusion This study is the first to identify natural phenotypic profiles of TAND symptoms. Study of specific TAND subpopulations with shared profiles may facilitate better understanding of the underlying biology of TAND and better assessment of more targeted treatments.

IntroductionTuberous Sclerosis Complex (TSC) is a multi-system genetic disorder with various TSC-Associated Neuropsychiatric Disorders (TAND) that significantly impact the mental health and wellbeing of individuals with TSC and their caregivers. TAND represents the number one concern to families worldwide, yet is highly under-identified and under-treated. The clinician-administered TAND-Checklist (Lifetime version, TAND-L) has improved identification of TAND in clinical settings. However, many individuals with TSC and their caregivers still have difficulty accessing suitable support for diagnosis and evidence-informed interventions. The TANDem study is a community-based participatory research project with a broad range of TSC stakeholders aimed at reducing the TAND identification and treatment gap.ObjectivesParticipatory research identified three priority next steps: 1) development and validation of a self-report, quantified version of the TAND Checklist (TAND-SQ) and building the TAND-SQ into a smartphone application, 2) generation of consensus clinical recommendations for the identification and treatment of TAND, to be incorporated as a TAND toolkit on the app, and 3) establishment of a global TAND consortium through networking, capacity-building and public engagement activities.MethodsTANDem is a four-year project, and includes 24 consortium members from 10 countries representing all World Health Organization regions. Collaborators represent five stakeholder groups (family representatives, technology experts, clinical experts, non-profit organisations and researchers). Here we outline the project study protocol in detail, describing the scientific rationale, the project aims and objectives, the methods involved in participant recruitment, multi-site and multi-phase data collection, data analysis, ethical considerations including informed consent, data protection, privacy and confidentiality considerations related to the European Union General Data Protection Regulation and the USA Health Insurance Portability and Accountability Act. The expected outcomes and potential impact on the TSC community, implementation and dissemination of results, as well as future scale-up and scale-out plans are also discussed.ConclusionsThe TANDem project has the potential to transform the global TSC community by empowering families living with TSC through an easily accessible digital solution to allow them to document their own TAND needs linked to an evidence-informed toolkit to enhance personalised healthcare, and by providing healthcare professionals with consensus clinical recommendations to prevent, identify and manage TAND manifestations.

Background: Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to grow in multiple organ systems. Nonfunctional pancreatic neuroendocrine tumors (PNETs) are a rare clinical feature of TSC with no specific guidelines outlined for clinical management at this time. Our purpose is to calculate the frequency of nonfunctional PNETs as well as characterize the presentation, current clinical management, and assess the impact of systemic mammalian target of rapamycin (mTOR) on nonfunctional PNETs in TSC.Methods: This retrospective chart review was performed by a query of the TS Alliance's Natural History Database and the Cincinnati Children's Hospital TSC Database for patients with nonfunctional PNET. Clinical data from these two groups was summarized for patients identified to have a nonfunctional PNET and compared to previously reported cases with TSC and nonfunctional PNETs.Results: Our calculated frequency of nonfunctional PNETs is 0.65%. We identified 16 individuals, nine males and seven females, with a median age of 18.0 years (interquartile range: −15.5 to 25.5). Just over half (56.3%, n = 9) of the patients provided results from genetic testing. Six had pathogenic variants in TSC2 whereas three had pathogenic variants in TSC1. The average age at PNET diagnosis was 15.0 years (range: 3–46 years). Almost all individuals were diagnosed with a PNET during routine TSC surveillance, 56.3% (n = 9) by MRI, 12.5% (n = 2) by CT, 25% (n = 4) by ultrasound, and 6.2% (n = 1) through a surgical procedure. Follow up after diagnosis involved 68.8% (n = 11) having serial imaging and nine of the sixteen individuals proceeding with surgical removal of the PNET. Eight individuals had a history of using systemic mTOR inhibitors. Tumor growth rate was slightly less in individuals taking an mTOR inhibitor (−0.8 mm/yr, IQR: −2.3 to 2.2) than those without (1.6 mm/yr; IQR: −0.99 to 5.01, p > 0.05).Conclusions: Nonfunctional PNETs occurred at younger ages in our TSC cohort and more commonly compared to ages and prevalence reported for the general population. PNETs in patients on systemic mTOR inhibitors had lower rates of growth. The outcome of this study provides preliminary evidence supporting the use of mTOR inhibitor therapy in conjunction with serial imaging as medical management for nonfunctional PNETs as an alternative option to invasive surgical removal.

Two-dimensional materials have recently gained significant awareness. A representative of such materials, black phosphorous (BP), earned attention based on its comprehensive application potential. The presented study focuses on the mode of cellular response underlying the BP interaction with Chlamydomonas reinhardtii as an algal model organism. We observed noticeable ROS formation and changes in outer cellular topology after 72 h of incubation at 5 mg/L BP. Transcriptome profiling was employed to examine C. reinhardtii response after exposure to 25 mg/L BP for a deeper understanding of the associated processes. The RNA sequencing has revealed a comprehensive response with abundant transcript downregulation. The mode of action was attributed to cell wall disruption, ROS elevation, and chloroplast disturbance. Besides many other dysregulated genes, the cell response involved the downregulation of GH9 and gametolysin within a cell wall, pointing to a shift to discrete manipulation with resources. The response also included altered expression of the PRDA1 gene associated with redox governance in chloroplasts implying ROS disharmony. Altered expression of the Cre-miR906–3p, Cre-miR910, and Cre-miR914 pointed to those as potential markers in stress response studies. • In BP-treated cultures, numerous transcriptomic and metabolomic pathways were altered in C. reinhardtii. • Microscopic analysies revealed cell wall damage after interaction with BP. • After annotation, 452 annotated transcripts were obtained, including 319 downregulated DEGs and 133 upregulated DEGs. • The BP caused significant CO 2 metabolic activity and photosynthesis downregulation. • Also, overexpression of Cre-miR906-3p was observed in treated samples. [ABSTRACT FROM AUTHOR]

Abstract Objective To evaluate the safety of mTOR inhibitors (sirolimus or everolimus) in infants and very young children with tuberous sclerosis complex (TSC) under two years of age. Methods Study design was retrospective to capture medical record data from 52 international TSC Centres who initiated treatment with sirolimus or everolimus in TSC children before the age of two years. Data collection included demographic and clinical information including reason(s) for initiating treatment with mTOR inhibitors, treatment duration, dosing, and corresponding serum trough levels, response to treatment, and adverse events (AE). Results 19 of 52 (37%) TSC Centres reported treatment of at least one child with TSC under the age of two years with everolimus or sirolimus. Treatment-related data were provided for 45 patients meeting inclusion criteria. Everolimus was utilised 87% of the time, compared to 24% for sirolimus (5 subjects, 11%, were treated separately with both). Refractory epilepsy (45%) was the most common primary reason for initiating treatment and treatment was initiated on average at 11.6 ± 7.6 months of age. At least one AE, suspected or definitely treatment-related, occurred in 35 of 45 (78%) treated subjects. Most AEs were mild (Grade 1) or moderate (Grade 2) in severity and most commonly related to infections. Severe AE (Grade 3) was reported in 7 subjects (20%) and no life-threatening AE (Grade 4) or death/disability (Grade 5) was reported. Treatment was discontinued due to an AE in 9 of 45 (20%). Conclusions Everolimus, and to a lesser extent sirolimus, are increasingly being used to treat TSC infants and very young children for multiple TSC-associated clinical indications. While AEs were common, most were not severe and did not prevent continued treatment in the majority of this younger population. Highlights • Infants and very young children with TSC are increasingly treated with mTOR inhibitors for TSC-associated medical conditions. • Treatment with both everolimus and sirolimus is being utilised. • Treatment is generally well-tolerated without unexpected or major concerning side effects. [ABSTRACT FROM AUTHOR]

Microalgae and cyanobacteria are among the most important primary producers and are responsible for the production of 50–80% of the oxygen on Earth. They can be significantly affected by plastic pollution, as the vast majority of plastic waste ends up in rivers and then the oceans. This research focuses on green microalgae Chlorella vulgaris (C. vulgaris) , Chlamydomonas reinhardtii (C. reinhardtii), filamentous cyanobacterium Limnospira (Arthrospira) maxima (L.(A.) maxima) and how they are affected by environmentally relevant PET-MPs (polyethylene-terephtalate microplastics). Manufactured PET-MPs have asymmetric shape, size between 3 and 7 μm and were used in concentrations ranging from 5 mg/L to 80 mg/L. The highest inhibitory rate of growth was found in C. reinhardtii (−24%). Concentration-dependent changes in chlorophyll a composition were found in C. vulgaris and C. reinhardtii , not in L. (A.) maxima. Furthermore, cell damage was detected in all three organisms by CRYO-SEM (shriveling, cell wall disruption), but the cyanobacterium was the least damaged. A PET-fingerprint was detected on the surface of all tested organisms using FTIR, indicating the adherence of PET-MPs. The highest rate of PET-MPs adsorption was detected in L. (A.) maxima. Specifically, characteristic spectra were observed at ∼721, 850, 1100, 1275, 1342, and 1715 cm−1 which are specific for functional groups of PET-MPs. Nitrogen and carbon content significantly increased in L. (A.) maxima under exposure to 80 mg/L due to the PET-MPs adherence and mechanical stress. In all three tested organisms, weak exposure-related ROS generation was detected. In general, cyanobacteria seem to be more resistant to the effects of MPs. However, organisms in the aquatic environment are exposed to MPs over a longer time scale, so it is important to use the present findings for further longer-term experiments on environmentally relevant organisms. [Display omitted] • Concentration-dependent decrease in chlorophyll a composition in eukaryotes (C. vulgaris, C. reinhardtii). • Slightly inhibitory effect on growth and mechanical damage observed in eukaryotic species. • Cell surface showed high interaction rate with the PET-MPs in L. (A.) maxima. • Increase in L. (A.) maxima carbon and nitrogen content after exposure to high concentrations of PET-MPs. [ABSTRACT FROM AUTHOR]

There is increasing interest in forensic ancestry tests, which are part of a growing number of DNA analyses that can enhance routine profiling by obtaining additional genetic information about unidentified DNA donors. Nearly all ancestry tests use single nucleotide polymorphisms (SNPs), but these currently rely on SNaPshot single base extension chemistry that can fail to detect mixed DNA. Insertion-deletion polymorphism (Indel) tests have been developed using dye-labeled primers that allow direct capillary electrophoresis detection of PCR products (PCR-to-CE). PCR-to-CE maintains the direct relationship between input DNA and signal strength as each marker is detected with a single dye, so mixed DNA is more reliably detected. We report the results of a collaborative inter-laboratory exercise of 19 participants (15 from the EDNAP European DNA Profiling group) that assessed a 34-plex SNP test using SNaPshot and a 46-plex Indel test using PCR-to-CE. Laboratories were asked to type five samples with different ancestries and detect an additional mixed DNA sample. Statistical inference of ancestry was made by participants using the Snipper online Bayes analysis portal plus an optional PCA module that analyzes the genotype data alongside calculation of Bayes likelihood ratios . Exercise results indicated consistent genotyping performance from both tests, reaching a particularly high level of reliability for the Indel test. SNP genotyping gave 93.5% concordance (compared to the organizing laboratory’s data) that rose to 97.3% excluding one laboratory with a large number of miscalled genotypes. Indel genotyping gave a higher concordance rate of 99.8% and a reduced no-call rate compared to SNP analysis. All participants detected the mixture from their Indel peak height data and successfully assigned the correct ancestry to the other samples using Snippe r, with the exception of one laboratory with SNP miscalls that incorrectly assigned ancestry of two samples and did not obtain informative likelihood ratios for a third. Therefore, successful ancestry assignments were achieved by participants in 92 of 95 Snipper analyses. This exercise demonstrates that ancestry inference tests based on binary marker sets can be readily adopted by laboratories that already have well-established CE regimes in place. The Indel test proved to be easy to use and allowed all exercise participants to detect the DNA mixture as well as achieving complete and concordant profiles in nearly all cases. Lastly, two participants successfully ran parallel next-generation sequencing analyses (each using different systems) and achieved high levels of genotyping concordance using the exercise PCR primer mixes unmodified. [ABSTRACT FROM AUTHOR]

Abstract: The IrisPlex system is a DNA-based test system for the prediction of human eye colour from biological samples and consists of a single forensically validated multiplex genotyping assay together with a statistical prediction model that is based on genotypes and phenotypes from thousands of individuals. IrisPlex predicts blue and brown human eye colour with, on average, >94% precision accuracy using six of the currently most eye colour informative single nucleotide polymorphisms (HERC2 rs12913832, OCA2 rs1800407, SLC24A4 rs12896399, SLC45A2 (MATP) rs16891982, TYR rs1393350, and IRF4 rs12203592) according to a previous study, while the accuracy in predicting non-blue and non-brown eye colours is considerably lower. In an effort to vigorously assess the IrisPlex system at the international level, testing was performed by 21 laboratories in the context of a collaborative exercise divided into three tasks and organised by the European DNA Profiling (EDNAP) Group of the International Society of Forensic Genetics (ISFG). Task 1 involved the assessment of 10 blood and saliva samples provided on FTA cards by the organising laboratory together with eye colour phenotypes; 99.4% of the genotypes were correctly reported and 99% of the eye colour phenotypes were correctly predicted. Task 2 involved the assessment of 5 DNA samples extracted by the host laboratory from simulated casework samples, artificially degraded, and provided to the participants in varying DNA concentrations. For this task, 98.7% of the genotypes were correctly determined and 96.2% of eye colour phenotypes were correctly inferred. For Tasks 1 and 2 together, 99.2% (1875) of the 1890 genotypes were correctly generated and of the 15 (0.8%) incorrect genotype calls, only 2 (0.1%) resulted in incorrect eye colour phenotypes. The voluntary Task 3 involved participants choosing their own test subjects for IrisPlex genotyping and eye colour phenotype inference, while eye photographs were provided to the organising laboratory and judged; 96% of the eye colour phenotypes were inferred correctly across 100 samples and 19 laboratories. The high success rates in genotyping and eye colour phenotyping clearly demonstrate the reproducibility and the robustness of the IrisPlex assay as well as the accuracy of the IrisPlex model to predict blue and brown eye colour from DNA. Additionally, this study demonstrates the ease with which the IrisPlex system is implementable and applicable across forensic laboratories around the world with varying pre-existing experiences. [Copyright &y& Elsevier]

The effects of copper nanoparticles (Cu-NPs), including their stability in the medium, were studied with the green unicellular algae Chlamydomonas reinhardtii (CC-125). Cu-NPs were synthesized and characterized. Cu-NP particles were uniform, regular, and largely spherical, and they had smooth surfaces; the average size was estimated to be 137.4 ± 2.1 nm. Chlamydomonas cells were cultivated for 96 h under controlled conditions in the presence of Cu-NPs, according to OECD guidelines, and then subjected to toxicological bioassays. Based on scanning electron microscopy (SEM) observations, the effects of Cu-NPs resulted in part from the dissolution of nanoparticles (NPs) and the action of copper itself, which shows the importance of studying NP stability in the testing environment. In this assay, deleterious effects were enhanced by increasing Cu-NP concentrations (5, 10, 25, 50, and 100 mg/L). Concentrations higher than 25 mg/L exhibited extreme toxicity. We confirmed the known toxic effects of metal NPs, namely, growth inhibition, reduction of chlorophyll levels in cells, cell penetration and increased ROS production. Attention was also paid to select underexplored metabolites, which were studied with a LC-MS/MS system. Treatments caused changes in metabolites profiles, and levels of p-hydroxybenzaldehyde and protocatechuic acid were especially enhanced, suggesting their positive roles in the antioxidant defence response. Furthermore, a repeatable increase in suberic acid levels was observed for various stress conditions tested, and we expect that this was the result of lipid peroxidation. [Display omitted] • Structure of Cu-nanoparticles was changed under growth medium. • Osmoprotectant glycine betaine in Chlamydomonas cells increased significantly. • p-Hydroxybenzaldehyde, protocatechuic acid positively contributed to ROS generation. • Increased suberic acid content were attributed to the consequences of lipid peroxidation. • Decreased malic acids and asparagine accumulation may signalized dysregulation of nitrogen metabolism. [ABSTRACT FROM AUTHOR]

Renal cysts occur in approximately 50% of patients with tuberous sclerosis complex, but their clinical significance and response to treatment are unknown. Abdominal imaging of 15 patients with tuberous sclerosis complex-associated renal cystic disease who had received mammalian target of rapamycin inhibitor therapy for other tuberous sclerosis complex-related indications was evaluated. Reductions in cyst number, sum diameter, and volume were observed. [ABSTRACT FROM AUTHOR]

Over decades, synthetic dyes have become increasingly dominated by azo dyes posing a significant environmental risk due to their toxicity. Microalgae-based systems may offer an alternative for treatment of azo dye effluents to conventional physical-chemical methods. Here, microalgae were tested to decolorize industrial azo dye wastewater (ADW). Chlorella sorokiniana showed the highest decolorization efficiency in a preliminary screening test. Subsequently, the optimization of the experimental design resulted in 70% decolorization in a photobioreactor. Tolerance of this strain was evidenced using multiple approaches (growth and chlorophyll content assays, scanning electron microscopy (SEM), and antioxidant level measurements). Raman microspectroscopy was employed for the quantification of ADW-specific compounds accumulated by the microalgal biomass. Finally, RNA-seq revealed the transcriptome profile of C. sorokiniana exposed to ADW for 72 h. Activated DNA repair and primary metabolism provided sufficient energy for microalgal growth to overcome the adverse toxic conditions. Furthermore, several transporter genes, oxidoreductases-, and glycosyltransferases-encoding genes were upregulated to effectively sequestrate and detoxify the ADW. This work demonstrates the potential utilization of C. sorokiniana as a tolerant strain for industrial wastewater treatment, emphasizing the regulation of its molecular mechanisms to cope with unfavorable growth conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Recently, more accessible transcriptomic approaches have provided a new and deeper understanding of environmental toxicity. The present study focuses on the transcriptomic profiles of green microalgae Chlamydomonas reinhardtii exposed to new industrially promising material, TiO 2 nanotubes (NTs), as an example of a widely used one-dimensional nanomaterial. The first algal in vitro assay included 2.5 and 7.5 mg/L TiO 2 NTs, resulting in a dose-dependent negative effect on biological endpoints. At a working concentration of 7.5 mg/L, RNA-sequencing showed a mainly negative effect on the cells. In summary, the results indicated metabolic disruption, such as ATP loss, damage to mitochondria and chloroplasts, loss of solutes due to permeated membranes, and cell wall damage. Moreover, apoptosis-induced transcripts were detected. Interestingly, reactivation of transposons was observed. In signalling and transcription pathways, including chromatin remodelling and locking, the annotated genes were downregulated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)