Computational approaches identify a transcriptomic fingerprint of drug-induced structural cardiotoxicity.

Structural cardiotoxicity (SCT) presents a high-impact risk that is poorly tolerated in drug discovery unless significant benefit is anticipated. Therefore, we aimed to improve the mechanistic understanding of SCT. First, we combined machine learning methods with a modified calcium transient assay in human-induced pluripotent stem cell-derived cardiomyocytes to identify nine parameters that could predict SCT. Next, we applied transcriptomic profiling to human cardiac microtissues exposed to structural and non-structural cardiotoxins. Fifty-two genes expressed across the three main cell types in the heart (cardiomyocytes, endothelial cells, and fibroblasts) were prioritised in differential expression and network clustering analyses and could be linked to known mechanisms of SCT. This transcriptomic fingerprint may prove useful for generating strategies to mitigate SCT risk in early drug discovery.

Targeted discovery of unusual diterpenoids with anti-fungal activity from the root of Euphorbia lathyris.

Lathyrisone A (1), a diterpene with an undescribed tricyclic 6/6/6 fused carbon skeleton, along with spirolathyrisins B-D (3-5), three diterpenes with a rare [4.5.0] spirocyclic carbon skeleton, and one known compound (2) were isolated from the roots of Euphorbia lathyris. Their chemical structures were characterized by extensive spectroscopic analysis, X-ray crystallography, ECD and quantum chemistry calculation. A plausible biosynthetic pathway for compounds 1-5 was proposed, which suggested it is a competitive pathway for ingenol biosynthesis in the plant. The anti-fungal activities of these compounds were tested, especially, compound 2 showed stronger anti-fungal activities against Fusarium oxysporum and Alternaria alternata than the positive control fungicide thiophanate-methyl. The preliminary structure-activity relationship of compounds 1-5 was also discussed. These results not only expanded the chemical diversities of E. lathyris, but also provided a lead compound for the control of plant pathogens.

Multi-omics bioactivity profile-based chemical grouping and read-across: a case study with Daphnia magna and azo dyes.

Grouping/read-across is widely used for predicting the toxicity of data-poor target substance(s) using data-rich source substance(s). While the chemical industry and the regulators recognise its benefits, registration dossiers are often rejected due to weak analogue/category justifications based largely on the structural similarity of source and target substances. Here we demonstrate how multi-omics measurements can improve confidence in grouping via a statistical assessment of the similarity of molecular effects. Six azo dyes provided a pool of potential source substances to predict long-term toxicity to aquatic invertebrates (Daphnia magna) for the dye Disperse Yellow 3 (DY3) as the target substance. First, we assessed the structural similarities of the dyes, generating a grouping hypothesis with DY3 and two Sudan dyes within one group. Daphnia magna were exposed acutely to equi-effective doses of all seven dyes (each at 3 doses and 3 time points), transcriptomics and metabolomics data were generated from 760 samples. Multi-omics bioactivity profile-based grouping uniquely revealed that Sudan 1 (S1) is the most suitable analogue for read-across to DY3. Mapping ToxPrint structural fingerprints of the dyes onto the bioactivity profile-based grouping indicated an aromatic alcohol moiety could be responsible for this bioactivity similarity. The long-term reproductive toxicity to aquatic invertebrates of DY3 was predicted from S1 (21-day NOEC, 40 µg/L). This prediction was confirmed experimentally by measuring the toxicity of DY3 in D. magna. While limitations of this 'omics approach are identified, the study illustrates an effective statistical approach for building chemical groups.

Two-component system RstAB promotes the pathogenicity of adherent-invasive Escherichia coli in response to acidic conditions within macrophages.

Adherent-invasive Escherichia coli (AIEC) strain LF82, isolated from patients with Crohn's disease, invades gut epithelial cells, and replicates in macrophages contributing to chronic inflammation. In this study, we found that RstAB contributing to the colonization of LF82 in a mouse model of chronic colitis by promoting bacterial replication in macrophages. By comparing the transcriptomes of rstAB mutant- and wild-type when infected macrophages, 83 significant differentially expressed genes in LF82 were identified. And we identified two possible RstA target genes (csgD and asr) among the differentially expressed genes. The electrophoretic mobility shift assay and quantitative real-time PCR confirmed that RstA binds to the promoters of csgD and asr and activates their expression. csgD deletion attenuated LF82 intracellular biofilm formation, and asr deletion reduced acid tolerance compared with the wild-type. Acidic pH was shown by quantitative real-time PCR to be the signal sensed by RstAB to activate the expression of csgD and asr. We uncovered a signal transduction pathway whereby LF82, in response to the acidic environment within macrophages, activates transcription of the csgD to promote biofilm formation, and activates transcription of the asr to promote acid tolerance, promoting its replication within macrophages and colonization of the intestine. This finding deepens our understanding of the LF82 replication regulation mechanism in macrophages and offers new perspectives for further studies on AIEC virulence mechanisms.

Nucleoside-diphosphate kinase of uropathogenic Escherichia coli inhibits caspase-1-dependent pyroptosis facilitating urinary tract infection.

Uropathogenic Escherichia coli (UPEC) is the most common causative agent of urinary tract infection (UTI). UPEC invades bladder epithelial cells (BECs) via fusiform vesicles, escapes into the cytosol, and establishes biofilm-like intracellular bacterial communities (IBCs). Nucleoside-diphosphate kinase (NDK) is secreted by pathogenic bacteria to enhance virulence. However, whether NDK is involved in UPEC pathogenesis remains unclear. Here, we find that the lack of ndk impairs the colonization of UPEC CFT073 in mouse bladders and kidneys owing to the impaired ability of UPEC to form IBCs. Furthermore, we demonstrate that NDK inhibits caspase-1-dependent pyroptosis by consuming extracellular ATP, preventing superficial BEC exfoliation, and promoting IBC formation. UPEC utilizes the reactive oxygen species (ROS) sensor OxyR to indirectly activate the regulator integration host factor, which then directly activates ndk expression in response to intracellular ROS. Here, we reveal a signaling transduction pathway that UPEC employs to inhibit superficial BEC exfoliation, thus facilitating acute UTI.

A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy.

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

Minocycline/Amoxicillin-Based Bismuth Quadruple Therapy for Helicobacter pylori Eradication: A Pilot Study.

The common adverse effects and the complicated administration of tetracycline and metronidazole greatly affect the clinical application of the classical bismuth quadruple therapy (BQT) for Helicobacter pylori eradication. This pilot study aimed to evaluate the efficacy and safety of minocycline/amoxicillin-based BQT for H. pylori eradication. Firstly, consecutive H. pylori isolates collected at West China Hospital of Sichuan University between 2018 and 2021 were included for susceptibility testing of tetracycline and minocycline using E-test strips. Secondly, both treatment-naïve and experienced patients were included to receive a 14-day minocycline/amoxicillin-based BQT: esomeprazole 40 mg or vonoprazan 20 mg, bismuth colloidal pectin 300 mg, amoxicillin 1000 mg, and minocycline 100 mg, all given twice daily. Among a total of 101 H. pylori isolates, tetracycline resistance was 3.0%, whereas minocycline resistance was nil. A total of 114 patients (treatment-naïve/experienced, 72/42) received the minocycline/amoxicillin-based BQT. The overall intention-to-treat (ITT) and per protocol (PP) eradication rates were 94.7% (108/114) and 97.3% (108/111), respectively. The ITT and PP eradication rates were 91.7% (66/72) and 95.7% (66/69) among the treatment-naïve patients, and both were 100.0% among the treatment-experienced patients. No serious adverse event was recorded. This pilot study suggests that minocycline/amoxicillin-based BQT is an excellent therapy for H. pylori eradication.

Uropathogenic Escherichia coli subverts host autophagic defenses by stalling pre-autophagosomal structures to escape lysosome exocytosis.

Urinary tract infections are primarily caused by uropathogenic Escherichia coli (UPEC). UPEC infects bladder epithelial cells (BECs) via fusiform vesicles and escapes into the cytosol by disrupting fusiform vesicle membrane using outer membrane phospholipase PldA, and establishes biofilm-like intracellular bacterial communities (IBCs) for protection from host immune clearance. Cytosolic UPEC is captured by autophagy to form autophagosomes, then transport to lysosomes, triggering the spontaneous exocytosis of lysosomes. The mechanism by which UPEC evades autophagy to recognize and form IBCs remains unclear. Here, we demonstrate that by inhibiting autophagic flux, UPEC PldA reduces the lysosome exocytosis of BECs. By reducing intracellular PI3P levels, UPEC PldA increases the accumulation of NDP52 granules and decreases the targeting of NDP52 to autophagy, hence stalling pre-autophagosome structures. Thus, our results uncover a critical role for PldA to inhibit autophagic flux, favoring UPEC escapes from lysosome exocytosis, thereby contributing to acute UTI.

100 years of anthropogenic impact causes changes in freshwater functional biodiversity.

Despite efforts from scientists and regulators, biodiversity is declining at an alarming rate. Unless we find transformative solutions to preserve biodiversity, future generations may not be able to enjoy nature's services. We have developed a conceptual framework that establishes the links between biodiversity dynamics and abiotic change through time and space using artificial intelligence. Here, we apply this framework to a freshwater ecosystem with a known history of human impact and study 100 years of community-level biodiversity, climate change and chemical pollution trends. We apply explainable network models with multimodal learning to community-level functional biodiversity measured with multilocus metabarcoding, to establish correlations with biocides and climate change records. We observed that the freshwater community assemblage and functionality changed over time without returning to its original state, even if the lake partially recovered in recent times. Insecticides and fungicides, combined with extreme temperature events and precipitation, explained up to 90% of the functional biodiversity changes. The community-level biodiversity approach used here reliably explained freshwater ecosystem shifts. These shifts were not observed when using traditional quality indices (e.g. Trophic Diatom Index). Our study advocates the use of high-throughput systemic approaches on long-term trends over species-focused ecological surveys to identify the environmental factors that cause loss of biodiversity and disrupt ecosystem functions.

Over long periods of time, environmental changes ­ such as chemical pollution and climate change ­ affect the diversity of organisms that live in an ecosystem, known as 'biodiversity'. Understanding the impact of these changes is challenging because they can happen slowly, their effect is only measurable after years, and historical records are limited. This can make it difficult to determine when specific changes happened, what might have driven them and what impact they might be having. One way to measure changes in biodiversity over time is by analysing traces of DNA shed by organisms. Plants, animals, and bacteria living in lakes leave behind genetic material that gets trapped and buried in the sediment at the bottom of lakes. Similarly, biocides ­ substances used to kill or control populations of living organisms ­ that run-off into lakes leach into the sediment and can be measured years later. Therefore, this sediment holds a record of life and environmental impacts in the lake over past centuries. Eastwood, Zhou et al. wanted to understand the relationship between environmental changes (such as the use of biocides and climate change) and shifts in lake biodiversity. To do so, the researchers studied a lake community that had experienced major environmental impacts over the last century (including nutrient pollution, chemical pollution and climate change), but which appeared to improve over the last few years of the 20^th century. Using machine learning to find connections over time between biodiversity and non-living environmental changes, Eastwood, Zhou et al. showed that, despite apparent recovery in water quality, the biodiversity of the lake was not restored to its original state. A combination of climate factors (such as rainfall levels and extreme temperatures) and biocide application (particularly insecticides and fungicides) explained up to 90% of the biodiversity changes that occurred in the lake. These changes had not been identified before using traditional techniques. The functional roles microorganisms played in the ecosystem (such as degradation and nitrogen metabolism) were also altered, suggesting that loss of biodiversity may lead to loss of ecosystem functions. The findings described by Eastwood, Zhou et al. can be used by environmental regulators to identify species or ecosystems at risk from environmental change and prioritise them for intervention. The approach can also be used to identify which chemicals pose the greatest threat to biodiversity. Additionally, the use of environmental DNA from sediment can provide rich historical biodiversity data, which can be used to train artificial intelligence-based models to improve predictions of how ecosystems will respond to complex environmental changes.

Secondary metal doped cuprous-cyanoimidazole frameworks for triple-mode detection of dopamine.

BACKGROUNDS: Metal-organic framework-based nanozymes enable several opportunities for designing novel analysis methods for the detection of pesticides, heavy metal ions, and biomolecules; however, practical applications are still limited by a complicated synthesis route, lower catalytic activity, and single detection mode. Dopamine (DA) is a crucial catecholamine substance in the human body that acts as a neurotransmitter regulating a variety of physiological functions of the central nervous system. Therefore, it is highly significant to explore simple nanozymes synthesis methods for constructing a multiple analysis system to detection DA. RESULTS: Herein, we elaborately selected cobalt ions as the secondary metal doping in cuprous-cyanoimidazole frameworks (CuCo-CIFs) with a mass-production strategy. CuCo-CIFs possess intrinsic peroxidase-like activity that can convert hydrogen peroxide into various reactive oxygen species (i.e., 1O2, OH·, O2·-) and thereby oxidize colorless 3,3',5,5'-tetramethylbenzidine (TMB) and DA to blue oxTMB and orange polydopamine (PDA), respectively. The absorption of the detection system increases at 460 nm while decreases at 652 nm as the concentration of DA increases under near-neutral pH (6.1), resulting in a color transition from blue to orange. Consequently, an unprecedented triple-mode analysis system of DA monitored by naked eyes, ratiometric-absorption, and scanometric was constructed. The limit of detection for the ratiometric-absorption and scanometric mode can reach 20 nM and 28 nM, respectively. CuCo-CIFs were successfully used for the rapid and accurate detection of DA in practical samples. SIGNIFICANCE: As a simple, low-cost, multi-mode colorimetric platform, this kind of nanozyme detection with peroxidase-like activity exhibits significant potential for the detection of DA. Our work not only expands the applications of MOFs in analytical fields but also addresses the general challenges faced by nanozyme-based colorimetric detection systems of DA. This work provides valuable insights for the rational application of nanozyme and the design of new analysis systems.

The hologenome of Daphnia magna reveals possible DNA methylation and microbiome-mediated evolution of the host genome.

Properties that make organisms ideal laboratory models in developmental and medical research are often the ones that also make them less representative of wild relatives. The waterflea Daphnia magna is an exception, by both sharing many properties with established laboratory models and being a keystone species, a sentinel species for assessing water quality, an indicator of environmental change and an established ecotoxicology model. Yet, Daphnia's full potential has not been fully exploited because of the challenges associated with assembling and annotating its gene-rich genome. Here, we present the first hologenome of Daphnia magna, consisting of a chromosomal-level assembly of the D. magna genome and the draft assembly of its metagenome. By sequencing and mapping transcriptomes from exposures to environmental conditions and from developmental morphological landmarks, we expand the previously annotates gene set for this species. We also provide evidence for the potential role of gene-body DNA-methylation as a mutagen mediating genome evolution. For the first time, our study shows that the gut microbes provide resistance to commonly used antibiotics and virulence factors, potentially mediating Daphnia's environmental-driven rapid evolution. Key findings in this study improve our understanding of the contribution of DNA methylation and gut microbiota to genome evolution in response to rapidly changing environments.

Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant.

Background: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. Methods: A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. Results: The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). Conclusions: Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.

Evaluation of a Molecular Mosprie Assay for Detection of Helicobacter pylori and Resistance to Clarithromycin and Levofloxacin.

BACKGROUND: Helicobacter pylori eradication regimens should be guided by antimicrobial susceptibility testing. The objective of this study was to evaluate the molecular-based Mosprie assay for detecting H. pylori resistance to clarithromycin and levofloxacin using gastric biopsies. METHODS: A total of 185 culture-positive frozen gastric biopsies were included for Mosprie assay and also for 23S rRNA and gyrA gene sequencing. The susceptibility results by the Mosprie assay were compared with the E-test results retrospectively retrieved. The discordant results were analyzed by sequencing of the 23S rRNA and gyrA genes. RESULTS: Susceptibility concordance between the Mosprie assay and E-test for clarithromycin and levofloxacin was 97.30% (180/185) and 88.11% (163/185), respectively. The full agreement between clarithromycin genotypes by Mosprie assay and the 23S rRNA sequencing results was observed in the 5 samples with discordant Mosprie assay and E-test results. However, for levofloxacin, of the 16 discordant samples with resistant phenotype but a susceptible genotype by Mosprie assay, 6 were found to have levofloxacin resistance-related gyrA gene mutations. CONCLUSIONS: The rapid and reliable Mosprie assay can be recommended for H. pylori susceptibility testing of clarithromycin and levofloxacin on gastric biopsies. Future technical improvements are needed in detecting levofloxacin resistance-associated gene mutations.

Bioprinting of Human Neural Tissues Using a Sustainable Marine Tunicate-Derived Bioink for Translational Medicine Applications.

Bioprinting of nervous tissue is a major challenge in the bioprinting field due to its soft consistency and complex architecture. The first step in efficient neural bioprinting is the design and optimization of printable bioinks which favor the growth and differentiation of neural tissues by providing the mechanophysiological properties of the native tissue microenvironment. However, till date, limited studies have been conducted to make tissue specific bioinks. Here, we report a novel bioink formulation specifically designed for bioprinting and differentiation of neural stem cells (NSCs) to peripheral neurons, using a marine tunicate-derived hydrogel and Matrigel. The formulation resulted in seamless bioprinting of NSCs with minimal processing time from bioink preparation to in vitro culture. The tissues exhibited excellent post-printing viability and cell proliferation along with a precise peripheral nerve morphology on in vitro differentiation. The cultured tissues showed significant cell recovery after subjecting to a freeze-thaw cycle of -80 to 37°C, indicating the suitability of the method for developing tissues compatible for long-term storage and transportation for clinical use. The study provides a robust method to use a sustainable bioink for three-dimensional bioprinting of neural tissues for translational medicine applications.

Comparisons of unmanipulated haploidentical donor, unrelated cord blood donor and matched unrelated donor hematopoietic stem cell transplantation in pediatric acquired severe aplastic anemia: a single center study.

We retrospectively analyzed the outcomes of 240 pediatric SAA patients who underwent unmanipulated alternative HSCT between September 2012 and November 2020 at our center. The incidence of GF (PGF + SGF) was higher in the UCBD cohort compared to the MUD and HID cohorts [(13.5% ± 6.5%) vs (0%), and (1.6% ± 5.3%), respectively, p = .0001]. The incidence of platelet engraftment within 180 days post-HSCT was lower in the UCBD cohort (82.4% ± 2.3%) compared to the HID group (96.2% ± 1.3%) and the MUD group (97.4% ± 0.5%) (p = .020). the median duration time for platelet engraftment in the UCBD cohort was 29 days, longer than in HID cohort 14 days and the MUD cohort 13 days (p = .005). UCBD cohort had a lower 3-year failure-free survival (FFS) (70.5% ± 8.4%) compared to the HID cohort (81.1% ± 4.3%) and the MUD cohort (92.5% ± 3.1%) (p = .030) and lower 3-year GVHD/relapse free survival (GRFS) (63.3% ± 9.5.4%) compared to the HID cohort (75.5% ± 6.8%) and MUD cohort (87.9% ± 4.5%) (p = .002). UCBD-HSCT had inferior FFS and GRFS compared to an HSCT with an HID or MUD in pediatric patients with acquired SAA. A UCBD-HSCT had a higher GF and lower incidence of platelet engraftment and longer platelet engraftment time.

Solid-Phase Synthesis of Red Fluorescent Carbon Dots for the Dual-Mode Detection of Hexavalent Chromium and Cell Imaging.

The excellent optical properties and biocompatibility of red fluorescence carbon dots (R-CDs) provide a new approach for the effective analysis of hexavalent chromium Cr(VI) in environmental and biological samples. However, the application of R-CDs is still limited by low yield and unfriendly synthesis route. In this study, we developed a new type of R-CDs based on a simple and green solid-phase preparation strategy. The synthesized R-CDs can emit bright red fluorescence with an emission wavelength of 625 nm and also have an obvious visible light absorption capacity. Furthermore, the absorption and fluorescence signals of the R-CDs aqueous solution are sensitive to Cr(VI), which is reflected in color change and fluorescence quenching. Based on that, a scanometric and fluorescent dual-mode analysis system for the rapid and accurate detection of Cr(VI) was established well within the limit of detection at 80 nM and 9.1 nM, respectively. The proposed methods also possess high specificity and were applied for the detection of Cr(VI) in real water samples. More importantly, the synthesized R-CDs with good biocompatibility were further successfully applied for visualizing intracellular Cr(VI) in Hela cells.

Historical exposure to chemicals reduces tolerance to novel chemical stress in Daphnia (waterflea).

Until the last few decades, anthropogenic chemicals used in most production processes have not been comprehensively assessed for their risk and impact on wildlife and humans. They are transported globally and usually end up in the environment as unintentional pollutants, causing long-term adverse effects. Modern toxicology practices typically use acute toxicity tests of unrealistic concentrations of chemicals to determine their safe use, missing pathological effects arising from long-term exposures to environmentally relevant concentrations. Here, we study the transgenerational effect of environmentally relevant concentrations of five chemicals on the priority list of international regulatory frameworks on the keystone species Daphnia magna. We expose Daphnia genotypes resurrected from the sedimentary archive of a lake with a known history of chemical pollution to the five chemicals to understand how historical exposure to chemicals influences adaptive responses to novel chemical stress. We measure within- and transgenerational plasticity in fitness-linked life history traits following exposure of "experienced" and "naive" genotypes to novel chemical stress. As the revived Daphnia originate from the same genetic pool sampled at different times in the past, we are able to quantify the long-term evolutionary impact of chemical pollution by studying genome-wide diversity and identifying functional pathways affected by historical chemical stress. Our results suggest that historical exposure to chemical stress causes reduced genome-wide diversity, leading to lower cross-generational tolerance to novel chemical stress. Lower tolerance is underpinned by reduced gene diversity at detoxification, catabolism and endocrine genes in experienced genotypes. We show that these genes sit within pathways that are conserved and potential chemical targets in other species, including humans.

A 'Relay'-Type Drug-Eluting Nerve Guide Conduit: Computational Fluid Dynamics Modeling of the Drug Eluting Efficiency of Various Drug Release Systems.

Nerve guidance conduits (NGCs) are tubular scaffolds that act as a bridge between the proximal and distal ends of the native nerve to facilitate the nerve regeneration. The application of NGCs is mostly limited to nerve defects less than 3 mm due to the lack of sufficient cells in the lumen. The development of drug-release-system-embedded NGCs has the potential to improve the nerve regeneration performance by providing long-term release of growth factors. However, most of the past works only focused on one type of drug release system, limiting the variation in drug release system types and features. Therefore, in this study, computer-aided design (CAD) models were constructed and Computational Fluid Dynamics (CFD) simulations were carried out to investigate the effect of growth factor transporting efficiency on different drug release systems. To overcome the challenges posed by the current NGCs in treating long nerve gap injuries (>4 cm), a novel 'relay' NGC design is first proposed in this paper and has the potential to improve the nerve regeneration performance to next level. The intermediate cavities introduced along the length of the multi-channel NGCs act as a relay to further enhance the cell concentrations or growth factor delivery as well as the regeneration performance. Four different drug release systems, namely, a single-layer microsphere system, a double-layer microsphere system, bulk hydrogel, and hydrogel film, were chosen for the simulation. The results show that the double-layer microsphere system achieves the highest growth factor volume fraction among all the drug release systems. For the single-layer microsphere system, growth factor concentration can be significantly improved by increasing the microsphere quantities and decreasing the diameter and adjacent distance of microspheres. Bulk hydrogel systems hold the lowest growth factor release performance, and the growth factor concentration monotonically increased with the increase of film thickness in the hydrogel film system. Owing to the easy fabrication of hydrogel film and the even distribution of growth factors, the hydrogel film system can be regarded as a strong candidate in drug-eluting NGCs. The use of computational simulations can be regarded as a guideline for the design and application of drug release systems, as well as a promising tool for further nerve tissue engineering study.

The Time Machine framework: monitoring and prediction of biodiversity loss.

Transdisciplinary solutions are needed to achieve the sustainability of ecosystem services for future generations. We propose a framework to identify the causes of ecosystem function loss and to forecast the future of ecosystem services under different climate and pollution scenarios. The framework (i) applies an artificial intelligence (AI) time-series analysis to identify relationships among environmental change, biodiversity dynamics and ecosystem functions; (ii) validates relationships between loss of biodiversity and environmental change in fabricated ecosystems; and (iii) forecasts the likely future of ecosystem services and their socioeconomic impact under different pollution and climate scenarios. We illustrate the framework by applying it to watersheds, and provide system-level approaches that enable natural capital restoration by associating multidecadal biodiversity changes to chemical pollution.