Multiple Changes Research Articles

Abstract 3605: Peroxiredoxin IV promotes prostate cancer malignancy through the activation of NF-kB signaling

Abstract Background: The peroxiredoxin (Prx) family of proteins functions as major cellular antioxidants to maintain redox homeostasis as well as mediate oxidative signaling in both physiological and pathological conditions. Our previous studies show that Prx4 is highly expressed in prostate cancer and promotes tumor growth in vitro and in vivo. But how Prx4 contributes to prostate cancer cell invasion and metastasis remains to be elucidated. The purpose of this study is to understand the oncogenic signaling pathways that are mediated by Prx4 in prostate cancer cells. Methods: Bioinformatic analysis of existing database were used to examine the expression of Prx4 in primary and metastatic prostate cancer samples. CRISPR/Cas9 technique was used to establish Prx4 knockout in cultured human prostate cancer cell lines. Matrigel invasion assays were performed to evaluate cell migration and invasion. RNAseq was performed to examine the differences of gene expression between control and Prx4KO cells. Gene Set Enrichment Analysis (GSEA) and Gene Oncology (GO) enrichment analysis were performed using RNAseq results. RT-PCR and immunoblotting were used to validate findings from RNAseq and enrichment analysis. Results: Compared with normal prostate, transcript levels of PRDX4 are found to be upregulated in specimens of patients with prostate cancer, and those with bone metastasis show even higher levels. Knockout of Prx4 in cultured human prostate cancer cells leads to significantly reduced ability of cell migration and invasion. Gene expression profiling reveals that loss of Prx4 leads to the upregulation of epithelial as well as downregulation of mesenchymal markers, and multiple signaling pathway changes including the inhibition of cellular response to inflammatory factors such as tumor necrosis factors and interleukins. These changes are also associated with variety of cellular activities such as wound healing, interferon signaling, and antigen processing & presentation. Among known target genes downstream of NF-κB signaling, E-cadherin, vimentin and matrix metalloproteinase 14 (MMP14) were found to be significantly affected by the loss of Prx4. Therefore, Prx4 plays a critical role in human prostate cancer cell malignancy through regulation of intracellular cell signaling pathways. Conclusions: A combination of bioinformatic, cellular and molecular methods reveals that Prx4 plays a critical role in promoting prostate cancer metastasis. Prx4 is a potential therapeutic target to reduce prostate cancer metastasis. Citation Format: Na Ding, Hong Jiang, Pratik Thapa, Yanning Hao, Aziza Alshahrani, Vivek Rangnekar, Xiaoqi Liu, Qiou Wei. Peroxiredoxin IV promotes prostate cancer malignancy through the activation of NF-kB signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3605.

Two-Scaled Identification of Landscape Character Types and Areas: A Case Study of the Yunnan–Vietnam Railway (Yunnan Section), China

In recent decades, the role of heritage railways has gradually shifted from transportation, economy, and trade to tourism, culture, and ecology. The heritage railway landscape is experiencing multiple changes along with a value ambiguity problem. There is a need to comprehensively recognize this landscape in order to promote the transformations and monitor the changes. Inspired by Landscape Character Assessment (LCA), this paper adopts a two-scaled identification framework of landscape character types and areas of the Yunnan–Vietnam Railway (Yunnan section) by integrating holistic and parametric methods. At the regional scale, the landscape character was divided by five natural variables: landform, vegetation, hydrology, soil, and geology. At the corridor scale, the landscape character was classified by five natural and cultural variables: altitude, slope, aspect, land use, and heritage density. At these two scales, k-prototype cluster analysis and multiresolution segmentation (MRS) tool were used to identify landscape character types and areas. The results showed that there were 11 different landscape character types and 80 landscape character areas at the regional scale, and 12 different landscape character types and 58 landscape character areas at the corridor scale. Furthermore, the composition, area, and distribution of these landscape character types and areas were described. The results of this study can form a database for planning, management, and evaluation of the railway.

Post-Disaster Recovery Challenges of Public Housing Residents: Lumberton, North Carolina After Hurricane Matthew

The floods caused by Hurricane Matthew in 2016 affected Lumberton, a socioeconomically diverse city in North Carolina with 729 public housing units. Public housing residents face unique challenges in accessing resources and post-disaster temporary accommodations, further delaying their recovery compared to other survivors. This paper investigates the obstacles to public housing recovery and the residents’ recovery challenges using descriptive statistics, mapping, and qualitative analysis in Lumberton. Findings show the dependency of public housing units’ recovery on assistance policies and decisions of various organizations, including local housing authorities. Multiple changes in recovery plans and limited, uncertain, delayed funding and bureaucratic obstacles to funding allocation slow the units’ recovery and prolong the residents’ displacement, adversely affecting their recovery. Hence, pre-disaster resilience initiatives should address these vulnerabilities and the recovery policy's limitations to support public housing units and residents’ recovery. Moreover, affordable housing recovery must become a priority in national housing recovery policies.

A frameshift in Yersinia pestis rcsD alters canonical Rcs signalling to preserve flea-mammal plague transmission cycles.

Multiple genetic changes in the enteric pathogen Yersinia pseudotuberculosis have driven the emergence of Yesinia pestis, the arthropod-borne, etiological agent of plague. These include developing the capacity for biofilm-dependent blockage of the flea foregut to enable transmission by flea bite. Previously, we showed that pseudogenization of rcsA, encoding a component of the Rcs signalling pathway, is an important evolutionary step facilitating Y. pestis flea-borne transmission. Additionally, rcsD, another important gene in the Rcs system, harbours a frameshift mutation. Here, we demonstrated that this rcsD mutation resulted in production of a small protein composing the C-terminal RcsD histidine-phosphotransferase domain (designated RcsD-Hpt) and full-length RcsD. Genetic analysis revealed that the rcsD frameshift mutation followed the emergence of rcsA pseudogenization. It further altered the canonical Rcs phosphorylation signal cascade, fine-tuning biofilm production to be conducive with retention of the pgm locus in modern lineages of Y. pestis. Taken together, our findings suggest that a frameshift mutation in rcsD is an important evolutionary step that fine-tuned biofilm production to ensure perpetuation of flea-mammal plague transmission cycles.

Thermal, exergy and economic analysis of a cascaded packed-bed tank with multiple phase change materials for district cooling system

In Singapore's industry, the required temperature of a district cooling system's outlet and return water are 5 °C and 12 °C, respectively. Thus far, few researches have been reported on the cascaded phase change material (PCM) tank focusing on this temperature duration. In this study, a cascaded packed-bed tank for a district cooling system is proposed to improve heat transfer efficiency and decrease tank cost with the same cold energy capacity. The cascaded PCM system, employing PCM-1 and PCM-2 (volume ratio 50%–50% and 30%–70% tetradecane-hexadecane mixtures), is designed, modeled, and validated through experimental data. Key results revealed that the PCM-1 tank performs poorly during its charging phase, while the PCM-2 tank performs poorly in discharging phase. However, the proposed cascaded packed-bed tank that simultaneously PCM-1 and PCM-2 can achieve high average exergy efficiencies during the charging and discharging phases. Additionally, the cascaded system incorporating 0.42 of PCM-1 and 0.18 of PCM-2 demonstrates higher exergy efficiency and tank volume but incurs higher construction costs than other tank designs. Comparatively, the same cold energy capacity tank with 0.18 of PCM-1 and 0.42 of PCM-2 reduces construction cost by 6.8%, with a depreciation of exergy efficiency by 14.1% during the discharging phase.

Anti-Cancer Effect of Dorema Ammoniacum Gum by Targeting Metabolic Reprogramming by Regulating APC, P53, KRAS Gene Expression in HT-29 Human Colon Cancer Cells.

Colorectal cancer is a heterogeneous disease that leads to metabolic disorders due to multiple upstream genetic and molecular changes and interactions. The development of new therapies, especially herbal medicines, has received much global attention. Dorema ammoniacum is a medicinal plant. Its gum is used in healing known ailments. Studying metabolome profiles based on nuclear magnetic resonance 1HNMR as a non-invasive and reproducible tool can identify metabolic changes as a reflection of intracellular fluxes, especially in drug responses. This study aimed to investigate the anti-cancer effects of different gum extracts on metabolic changes and their impact on gene expression in HT-29 cell. Extraction of Dorema ammoniacum gum with hexane, chloroform, and dichloromethane organic solvents was performed. Cell inhibition growth percentage and IC50 were assessed. Following treating the cells with dichloromethane extract, p53, APC, and KRAS gene expression were determined. 1HNMR spectroscopy was conducted. Eventually, systems biology software tools interpreted combined metabolites and genes simultaneously. The lowest determined IC50 concentration was related to dichloromethane solvent, and the highest was hexane and chloroform. The expression of the KRAS oncogene gene decreased significantly after treatment with dichloromethane extract compared to the control group, and the expression of tumor suppressor gene p53 and APC increased significantly. Most gene-altered convergent metabolic phenotypes. This study's results indicate that the dichloromethane solvent of Dorema ammoniacum gum exhibits its antitumor properties by altering the expression of genes involved in HT-29 cells and the consequent change in downstream metabolic reprogramming.

Hydrological modeling of spatial and temporal variations in streamflow due to multiple climate change scenarios in northwestern Morocco

Climate change is one of the most important factors impacting hydrological regimes. In this paper, climate change impact on streamflow of Loukkos basin (northwestern Morocco) is evaluated using SWAT model for three future periods: near (2021–2040), mid (2041–2070), and far (2071–2100), compared to baseline 1981–2020. A set of bias-corrected climate models was used: five regional climate models (EURO-CORDEX), four global climate models (CMIP6) and their ensemble mean, under two representative concentration pathways respectively (RCP 4.5; RCP 8.5) and (SSP2-4.5; SSP5-8.5). Furthermore, SUFI-2 algorithm in SWAT-CUP was performed to calibrate (1981–1997), validate (1998–2015), and analyze uncertainty for each dataset at ten hydrological stations. In most stations, statistical performance indicated a good simulation, with a Nash–Sutcliffe efficiency (NSE) greater than 0.77 and percent bias (PBIAS) within ±10% on a monthly basis. Overall, 82% of models indicated that future climate could decline streamflow. The largest decrease would be for 2071–2100 and under RCP 8.5/SSP5-8.5. Our findings could help planners and policymakers in developing reasonable water management policies and climate change adaptation measures.

Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors.

Vaccines and drugs have helped reduce disease severity and blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease [Mpro; 3C-like protease (3CLpro)] of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different resistance mutation profile. Importantly, phylogenetic analyses indicate that several of these resistant variants have pre-existed the introduction of these drugs into the human population and are capable of spreading. These results encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy.

Developing a Warning Model of Potentially Inappropriate Medications in Older Chinese Outpatients in Tertiary Hospitals: A Machine-Learning Study.

Due to multiple comorbid illnesses, polypharmacy, and age-related changes in pharmacokinetics and pharmacodynamics in older adults, the prevalence of potentially inappropriate medications (PIMs) is high, which affects the quality of life of older adults. Building an effective warning model is necessary for the early identification of PIMs to prevent harm caused by medication in geriatric patients. The purpose of this study was to develop a machine learning-based model for the warning of PIMs in older Chinese outpatients. This retrospective study was conducted among geriatric outpatients in nine tertiary hospitals in Chengdu from January 2018 to December 2018. The Beers criteria 2019 were used to assess PIMs in geriatric outpatients. Three problem transformation methods were used to tackle the multilabel classification problem in prescriptions. After the division of patient prescriptions into the training and test sets (8:2), we adopted six widely used classification algorithms to conduct the classification task and assessed the discriminative performance by the accuracy, precision, recall, F1 scores, subset accuracy (ss Acc), and Hamming loss (hm) of each model. The results showed that among 11,741 older patient prescriptions, 5816 PIMs were identified in 4038 (34.39%) patient prescriptions. A total of 41 types of PIMs were identified in these prescriptions. The three-problem transformation methods included label power set (LP), classifier chains (CC), and binary relevance (BR). Six classification algorithms were used to establish the warning models, including Random Forest (RF), Light Gradient Boosting Machine (LightGBM), eXtreme Gradient Boosting (XGBoost), CatBoost, Deep Forest (DF), and TabNet. The CC + CatBoost model had the highest accuracy value (97.83%), recall value (89.34%), F1 value (90.69%), and ss Acc value (97.79%) with a good precision value (92.18%) and the lowest hm value (0.0006). Therefore, the CC + CatBoost model was selected to predict the occurrence of PIM in geriatric Chinese patients. This study's novelty establishes a warning model for PIMs in geriatric patients by using machine learning. With the popularity of electronic patient record systems, sophisticated computer algorithms can be implemented at the bedside to improve medication use safety in geriatric patients in the future.

Profiles of lipid, protein and microRNA expression in exosomes derived from intestinal epithelial cells after ischemia-reperfusion injury in a cellular hypoxia model.

Intestinal ischemia-reperfusion injury leads to proinflammatory responses via gut-derived mediators, and accumulating evidence suggests that exosomes secreted by intestinal epithelial cells are involved in the development of systemic inflammation. Studies have reported changes in protein, lipid, and microRNA (miRNA) expression; however, considering the different experimental conditions, information on the relationships among these biomolecules remains insufficient. The aim of this study was to elucidate the multiple changes that simultaneously occur in exosomes after ischemic stimulation. Here, differentiated human intestinal Caco-2 cells were exposed to 95% air (normoxia group) or 5% O2 (hypoxia group) for 6 h. Cells in each group were subsequently incubated for 24 h in an atmosphere of 5% CO2 plus 95% air. The conditioned medium of each group was collected for isolating intestinal epithelial cell-derived exosomes. Together with proteome analyses, lipid analyses, and miRNA quantification, biological functional assays were performed using monocytic NF-κB reporter cells. Lipid metabolism-related protein expression was upregulated, miRNA levels were slightly altered, and unsaturated fatty acid-containing lysophosphatidylcholine concentration increased after hypoxia and reoxygenation injury; this suggested that the changes in exosomal components associated with ischemia-reperfusion injury activates inflammation, including the NF-κB pathway. This study elucidated the multiple changes that co-occur in exosomes after ischemic stimulation and partially clarified the mechanism underlying exosome-mediated inflammation after intestinal ischemic recanalization.

Integrating territorial pattern and socioeconomic development into ecosystem service value assessment

To clarify the intrinsic linkages and mechanisms between territorial pattern changes and ecosystem service value (ESV) changes in coastal areas, this study tried to integrate territorial pattern and socio-economic development into ESV assessment. Taking the Beibu Gulf area as a case study, we estimated and analyzed the ESV changes using the equivalent factor method. And we combined relative importance analysis and pathway analysis to elucidate the contributions of different drivers to ESV changes, establishing the link between territorial pattern changes and ESV changes. The results indicated that increased ESV during 2000–2020 were mainly located in the areas where environmental policies were implemented, while the largest ESV decreases were concentrated in the areas with urban expansion. ESV changes are closely related to territorial pattern changes. Population factors are the most important drivers of ESV changes, likely as a result of the rapidly growing population placing more pressure on land use, and causing multiple land changes that affect ESV. Moreover, the population dynamic factor, agriculture production factor, tourism output factor and tourism equipment factor all contributed to increasing the ESV of regional ecosystems, while the population size factor, population structure factor and economic production factor reduced the ESV to some extent. In conclusion, economic development, population growth and ecological engineering implementation were the key factors influencing ESV changes by changing the territorial pattern. Therefore, appropriate land use policies could balance ecological protection and economic development to maximize human benefits acquired from ecosystems. Moreover, we proposed ecosystem management and landscape planning for typical land use types (i.e., forestland, farmland, orchards and water bodies) in the Beibu Gulf to improve the ESV and provide a reference for coastal areas.

Modelling quantitative fungicide resistance and breakdown of resistant cultivars: Designing integrated disease management strategies for Septoria of winter wheat.

Plant pathogens respond to selection pressures exerted by disease management strategies. This can lead to fungicide resistance and/or the breakdown of disease-resistant cultivars, each of which significantly threaten food security. Both fungicide resistance and cultivar breakdown can be characterised as qualitative or quantitative. Qualitative (monogenic) resistance/breakdown involves a step change in the characteristics of the pathogen population with respect to disease control, often caused by a single genetic change. Quantitative (polygenic) resistance/breakdown instead involves multiple genetic changes, each causing a smaller shift in pathogen characteristics, leading to a gradual alteration in the effectiveness of disease control over time. Although resistance/breakdown to many fungicides/cultivars currently in use is quantitative, the overwhelming majority of modelling studies focus on the much simpler case of qualitative resistance. Further, those very few models of quantitative resistance/breakdown which do exist are not fitted to field data. Here we present a model of quantitative resistance/breakdown applied to Zymoseptoria tritici, which causes Septoria leaf blotch, the most prevalent disease of wheat worldwide. Our model is fitted to data from field trials in the UK and Denmark. For fungicide resistance, we show that the optimal disease management strategy depends on the timescale of interest. Greater numbers of fungicide applications per year lead to greater selection for resistant strains, although over short timescales this can be oset by the increased control oered by more sprays. However, over longer timescales higher yields are attained using fewer fungicide applications per year. Deployment of disease-resistant cultivars is not only a valuable disease management strategy, but also oers the secondary benefit of protecting fungicide effectiveness by delaying the development of fungicide resistance. However, disease-resistant cultivars themselves erode over time. We show how an integrated disease management strategy with frequent replacement of disease-resistant cultivars can give a large improvement in fungicide durability and yields.

Social Vulnerability and Psychosocial Resilience in Adolescents and Young Adults From a Community Art Network.

Adolescence is a stage of transition with multiple changes and transformations. It is a critical phase to potentiate or disrupt the life course of human beings. In Latin America, adolescents and young adults from countries like Colombia have unequal access to socioeconomic resources, education, and the job market. This may generate social disadvantages and vulnerability. We aimed to identify conditions of social vulnerability and psychosocial resilience in the life course of adolescents and young adults from a community art network in Bogota, Colombia. We conducted a qualitative study with a multivocal design supported by the ethnic-social life history construction. The data were collected using narrative interviews. The interviews were transcribed, coded, categorized, and triangulated according to the principles of grounded theory as an analytical method. We adhered to the consolidated criteria for reporting qualitative research (COREQ) checklist. Eight adolescents and young adults between the ages of 12 and 24 years participated in the study. Five categories emerged: social vulnerability, social environment, artistic processes, psychosocial resilience, and life course. Social vulnerability and psychosocial resilience coexist during the life course of adolescents and young adults. Social support networks and community art processes have the potential to promote psychosocial resilience in adolescents and young adults.

A novel attempt to enhance the heat transfer rate of thermal energy storage using multitemperature phase change materials through experimental and numerical modelling

This work aims to develop the numerical model for the three-stage phase transition of multi-level phase change materials (PCMs) and present the comparative performance analysis between single PCM and multi-temperature PCM thermal energy storage (TES) systems. The performance of the thermal energy storage system was conducted by the implementation of multiple phase change materials (PCMs) which are arranged following the temperature profile of the heat transfer fluid. The proposed TES system has two models; the first is fully packed with single PCM – Erythritol TES, and the second is packed with multi-temperature PCMs, namely acetanilide in the first half of the tank and 1-Naphthol in the second half of the tank. The experiments are conducted to validate the numerical model values and observed that the results are in close agreement with each other and the percentage variation is within 3–5%. The results show that using multi-temperature PCMs provides better performance than single-PCM systems. Based on the results, the performance of the TES system can be enhanced with multi-level PCMs rather than choosing high-conductivity materials in the system, which lead to considerable potential in saving energy loss and an economical way of designing the efficient TES system.

Change-detection-assisted multiple testing for spatiotemporal data

This paper considers a large-scale multiple testing problem for spatiotemporal data with multiple change points. A data-driven procedure that aims to fully utilize the clustering information is proposed. Specifically, we first develop a new change-point detection algorithm that integrates the kernel-based aggregation of spatial observations with a global loss function at the temporal level to group data into several sets, and then derive an FDR control scheme for set-wise multiple testing. Under some mild conditions on the spatiotemporal dependence structure, FDR is shown to be strongly controlled. Theoretical analysis and numerical studies demonstrate the advantages of the algorithm over competing methods.

Soils worldwide suffer from the combined effects of multiple global change factors

Soils worldwide suffer from the combined effects of multiple global change factors

Recall bias of students' affective experiences in adolescence: The role of personality and internalizing behavior.

Adolescence is characterized by multiple biopsychosocial changes, associated with a high intraindividual variability of emotional experiences. Previous findings suggest that this intraindividual variability is reflected in a recall bias of adolescents' emotion reports. However, corresponding findings are scarce and inconclusive. Studies on predictors of recall bias in adulthood indicate that personality traits, especially neuroticism and extraversion, as well as specific internalizing disorders might affect recall bias of emotion reports. The sample consists of 118 Swiss adolescent students in grade 8 and 9 (Mage = 15.15, SDage = 0.89). The students' momentary affective experience was recorded using smartphones over seven consecutive days in situ at 42 randomly generated occasions (six per day), with a total of 1059 protocols on current events. At the end of the experience-sampling phase, students filled out an online questionnaire, providing information about their personality and typical behavior as well as their retrospective affective experience. In addition, the students' behavior was evaluated by their teachers. We applied two-level structural equation modeling with latent difference variables. Adolescents high in extraversion showed retrospective overestimation of positive affective experiences and underestimation of negative affective experiences. Adolescents with high neuroticism tended to overestimate negative affect retrospectively, showing no significant effects for positive affect. However, internalizing behavior did not predict a negative recall bias in adolescents' affective experience. Retrospective self-reports about adolescents' affective experience are biased by relatively stable individual factors, whereas less stable individual factors did not seem to have any influence.

Effects of Multiple Global Change Factors on Symbiotic and Asymbiotic N2 Fixation: Results Based on a Pot Experiment

Biological N2 fixation, a major pathway for new nitrogen (N) input to terrestrial ecosystems, largely determines the dynamics of ecosystem structure and functions under global change. Nevertheless, the responses of N2 fixation to multiple global change factors remain poorly understood. Here, saplings of two N2-fixing plant species, Alnus cremastogyne and Cajanus cajan, were grown at rural and urban sites, respectively, with the latter representing an environment with changes in multiple factors occurring simultaneously. Symbiotic N2 fixation per unit of nodule was significantly higher at the urban site than the rural site for A. cremastogyne, but the rates were comparable between the two sites for C. cajan. The nodule investments were significantly lower at the urban site relative to the rural site for both species. Symbiotic N2 fixation per plant increased by 31.2 times for A. cremastogyne, while that decreased by 88.2% for C. cajan at the urban site compared to the rural site. Asymbiotic N2 fixation rate in soil decreased by 46.2% at the urban site relative to the rural site. The decrease in symbiotic N2 fixation per plant for C. cajan and asymbiotic N2 fixation in soil was probably attributed to higher N deposition under the urban conditions, while the increase in symbiotic N2 fixation per plant for A. cremastogyne was probably related to the higher levels of temperature, atmospheric CO2, and phosphorus deposition at the urban site. The responses of N2 fixation to multiple global change factors and the underlying mechanisms may be divergent either between symbiotic and asymbiotic forms or among N2-fixing plant species. While causative evidence is urgently needed, we argue that these differences should be considered in Earth system models to improve the prediction of N2 fixation under global change.

Aggregation-prone TDP-43 sequesters and drives pathological transitions of free nuclear TDP-43

Aggregation of the RNA-binding protein, TDP-43, is the unifying hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43-related neurodegeneration involves multiple changes to normal physiological TDP-43, which undergoes nuclear depletion, cytoplasmic mislocalisation, post-translational modification, and aberrant liquid–liquid phase separation, preceding inclusion formation. Along with toxic cytoplasmic aggregation, concurrent depletion and dysfunction of normal nuclear TDP-43 in cells with TDP-43 pathology is likely a key potentiator of neurodegeneration, but is not well understood. To define processes driving TDP-43 dysfunction, we used CRISPR/Cas9-mediated fluorescent tagging to investigate how disease-associated stressors and pathological TDP-43 alter abundance, localisation, self-assembly, aggregation, solubility, and mobility dynamics of normal nuclear TDP-43 over time in live cells. Oxidative stress stimulated liquid–liquid phase separation of endogenous TDP-43 into droplet-like puncta, or spherical shell-like anisosomes. Further, nuclear RNA-binding-ablated or acetylation-mimicking TDP-43 readily sequestered and depleted free normal nuclear TDP-43 into dynamic anisosomes, in which recruited endogenous TDP-43 proteins remained soluble and highly mobile. Large, phosphorylated inclusions formed by nuclear or cytoplasmic aggregation-prone TDP-43 mutants also caused sequestration, but rendered endogenous TDP-43 immobile and insoluble, indicating pathological transition. These findings suggest that RNA-binding deficiency and post-translational modifications including acetylation exacerbate TDP-43 aggregation and dysfunction by driving sequestration, mislocalisation, and depletion of normal nuclear TDP-43 in neurodegenerative diseases.

Retrofit-induced changes in the radiated noise and monopole source levels of container ships.

The container shipping line Maersk undertook a Radical Retrofit to improve the energy efficiency of twelve sister container ships. Noise reduction, identified as a potential added benefit of the retrofitting effort, was investigated in this study. A passive acoustic recording dataset from the Santa Barbara Channel off Southern California was used to compile over 100 opportunistic vessel transits of the twelve G-Class container ships, pre- and post-retrofit. Post-retrofit, the G-Class vessels' capacity was increased from ~9,000 twenty-foot equivalent units (TEUs) to ~11,000 TEUs, which required a draft increase of the vessel by 1.5 m on average. The increased vessel draft resulted in higher radiated noise levels (<2 dB) in the mid- and high-frequency bands. Accounting for the Lloyd's mirror (dipole source) effect, the monopole source levels of the post-retrofit ships were found to be significantly lower (>5 dB) than the pre-retrofit ships in the low-frequency band and the reduction was greatest at low speed. Although multiple design changes occurred during retrofitting, the reduction in the low-frequency band most likely results from a reduction in cavitation due to changes in propeller and bow design.