iScience. 2023 May 19;26(7):106909. doi: 10.1016/j.isci.2023.106909. eCollection 2023 Jul 21.

ABSTRACT

Characterizing perturbation of molecular pathways in congenital Zika virus (ZIKV) infection is critical for improved therapeutic approaches. Leveraging integrative systems biology, proteomics, and RNA-seq, we analyzed embryonic brain tissues from an immunocompetent, wild-type congenital ZIKV infection mouse model. ZIKV induced a robust immune response accompanied by the downregulation of critical neurodevelopmental gene programs. We identified a negative correlation between ZIKV polyprotein abundance and host cell cycle-inducing proteins. We further captured the downregulation of genes/proteins, many of which are known to be causative for human microcephaly, including Eomesodermin/T-box Brain Protein 2 (EOMES/TBR2) and Neuronal Differentiation 2 (NEUROD2). Disturbances of distinct molecular pathways in neural progenitors and post-mitotic neurons may contribute to complex brain phenotype of congenital ZIKV infection. Overall, this report on protein- and transcript-level dynamics enhances understanding of the ZIKV immunopathological landscape through characterization of fetal immune response in the developing brain.

PMID:37332674 | PMC:PMC10275723 | DOI:10.1016/j.isci.2023.106909

iScience. 2023 May 29;26(7):107010. doi: 10.1016/j.isci.2023.107010. eCollection 2023 Jul 21.

ABSTRACT

Cold therapy has been used for centuries, from Julius Caesar to Mohandas Gandhi, as a potent therapeutic approach. However, it has been largely forgotten in modern medicine. This review explores the history of cold therapy and its potential application as a therapeutic strategy against various diseases, including cancer. We examine the different techniques of cold exposure and the use of other therapeutical approaches, such as cryoablation, cryotherapy, cryoimmunotherapy, cryothalectomy, and delivery of cryogen agents. While clinical trials using cold therapy for cancer treatment are still limited, recent research shows promising results in experimental animal cancer models. This area of research is becoming increasingly significant and warrants further investigation.

PMID:37332670 | PMC:PMC10275721 | DOI:10.1016/j.isci.2023.107010

ArXiv. 2023 May 24:arXiv:2305.15453v1. Preprint.

ABSTRACT

In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce Drugst.One, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, Drugst.One turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, Drugst.One has been successfully integrated with 21 computational systems medicine tools. Available at https://drugst.one, Drugst.One has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research.

PMID:37332567 | PMC:PMC10274948

FEMS Microbes. 2022 Jul 8;3:xtac021. doi: 10.1093/femsmc/xtac021. eCollection 2022.

ABSTRACT

Few strains of Dehalococcoides mccartyi harbour and express the vinyl chloride reductase (VcrA) that catalyzes the dechlorination of vinyl chloride (VC), a carcinogenic soil and groundwater contaminant. The vcrA operon is found on a Genomic Island (GI) and, therefore, believed to participate in horizontal gene transfer (HGT). To try to induce HGT of the vcrA-GI, we blended two enrichment cultures in medium without ammonium while providing VC. We hypothesized that these conditions would select for a mutant strain of D. mccartyi that could both fix nitrogen and respire VC. However, after more than 4 years of incubation, we found no evidence for HGT of the vcrA-GI. Rather, we observed VC-dechlorinating activity attributed to the trichloroethene reductase TceA. Sequencing and protein modelling revealed a mutation in the predicted active site of TceA, which may have influenced substrate specificity. We also identified two nitrogen-fixing D. mccartyi strains in the KB-1 culture. The presence of multiple strains of D. mccartyi with distinct phenotypes is a feature of natural environments and certain enrichment cultures (such as KB-1), and may enhance bioaugmentation success. The fact that multiple distinct strains persist in the culture for decades and that we could not induce HGT of the vcrA-GI suggests that it is not as mobile as predicted, or that mobility is restricted in ways yet to be discovered to specific subclades of Dehalococcoides.

PMID:37332513 | PMC:PMC10117805 | DOI:10.1093/femsmc/xtac021

Trends Plant Sci. 2023 Jun 16:S1360-1385(23)00164-4. doi: 10.1016/j.tplants.2023.05.012. Online ahead of print.

ABSTRACT

The discovery of the CRISPR/Cas genome-editing system has revolutionized our understanding of the plant genome. CRISPR/Cas has been used for over a decade to modify plant genomes for the study of specific genes and biosynthetic pathways as well as to speed up breeding in many plant species, including both model and non-model crops. Although the CRISPR/Cas system is very efficient for genome editing, many bottlenecks and challenges slow down further improvement and applications. In this review we discuss the challenges that can occur during tissue culture, transformation, regeneration, and mutant detection. We also review the opportunities provided by new CRISPR platforms and specific applications related to gene regulation, abiotic and biotic stress response improvement, and de novo domestication of plants.

PMID:37331842 | DOI:10.1016/j.tplants.2023.05.012

Res Microbiol. 2023 Jun 16:104091. doi: 10.1016/j.resmic.2023.104091. Online ahead of print.

ABSTRACT

Staphylococcus aureus is typically treated with antibiotics, however, due to its widespread and unselective usage, resistant strains of S. aureus have increased to a great extent. Treatment failure and recurring staphylococcal infections are also brought on by biofilm development, which boosts an organism's ability to withstand antibiotics and is thought to be a virulence factor in patients. The present study investigates the antibiofilm activity of naturally available polyphenol Quercetin against drug-resistant S. aureus. Tube dilution and tube addition methods were performed to evaluate the antibiofilm activity of quercetin against S.aureus. Quercetin treatment resulted in remarkably reduction of biofilm in S. aureus cells. Further we performed a study to investigate binding efficacies of quercetin with genes icaB and icaC from ica locus involved in biofilm formation. 3D structure of icaB, icaC and quercetin were retrieved from Protein data bank and PubChem chemical compound database, respectively. All computational simulation were carried out using AutoDock Vina and AutoDockTools (ADT) v 1.5.4. In silico study demonstrated a strong complex formation, large binding constants (Kb) and low free binding energy (ΔG) between quercetin and icaB (Kb= 1.63 × 10-5, ΔG= -7.2 Kcal/Mol) and icaC (Kb=1.98 × 10-6, ΔG= -8.7 Kcal/Mol). This in silico analysis indicates that quercetin is capable of targeting icaB and icaC proteins which are essential for biofilm formation in S. aureus. Our study highlighted the antibiofilm activity of quercetin against drug resistant pathogen S.aureus.

PMID:37331493 | DOI:10.1016/j.resmic.2023.104091

STAR Protoc. 2023 Jun 16;4(3):102362. doi: 10.1016/j.xpro.2023.102362. Online ahead of print.

ABSTRACT

Here, we present a protocol to identify transcriptional regulators potentially mediating downstream biological effects of germline variants associated with complex traits of interest, which enables functional hypothesis generation independent of colocalizing expression quantitative trait loci (eQTLs). We describe steps for tissue-/cell-type-specific co-expression network modeling, expression regulator activity inference, and identification of representative phenotypic master regulators. Finally, we detail activity QTL and eQTL analyses. This protocol requires genotype, expression, and relevant covariables and phenotype data from existing eQTL datasets. For complete details on the use and execution of this protocol, please refer to Hoskins et al.1.

PMID:37330907 | DOI:10.1016/j.xpro.2023.102362

J Invest Dermatol. 2023 Jun 15:S0022-202X(23)01962-0. doi: 10.1016/j.jid.2023.01.042. Online ahead of print.

ABSTRACT

Neurofibromatosis 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.

PMID:37330719 | DOI:10.1016/j.jid.2023.01.042

Int Immunol. 2023 Jun 18:dxad021. doi: 10.1093/intimm/dxad021. Online ahead of print.

ABSTRACT

Vaccination stands as the cornerstone in the battle against infectious diseases, and its efficacy hinges upon multifaceted host-related factors encompassing genetics, age, and metabolic status. Remarkably, suboptimal immune responses triggered by metabolic dysregulation is frequently observed in susceptible populations - ranging from malnourished individuals to the obese and elderly - pose a formidable threat to vaccine efficacy. The emerging field of immunometabolism aims to unravel the intricate interplay between immune regulation and metabolic pathways, and recent research has revealed diverse metabolic signatures linked to various vaccine responses and outcomes. In this review, we summarise the major metabolic pathways utilised by B and T cells during vaccine responses, their complex and varied metabolic requirements, and the impact of micronutrients and metabolic hormones on vaccine outcomes. Furthermore, we examine how systemic metabolism influences vaccine responses and the evidence suggesting that metabolic dysregulation in vulnerable populations can lead to impaired vaccine responses. Lastly, we reflect on the challenge of proving causality with respect to the contribution of metabolic dysregulation to poor vaccine outcomes, and highlight the need for a systems biology approach that combines multimodal profiling and mathematical modelling to reveal the underlying mechanisms of such complex interactions.

PMID:37330692 | DOI:10.1093/intimm/dxad021

Microbiome. 2023 Jun 17;11(1):136. doi: 10.1186/s40168-023-01568-0.

ABSTRACT

BACKGROUND: Disruption of the microbial community in the respiratory tract due to infections, like influenza, could impact transmission of bacterial pathogens. Using samples from a household study, we determined whether metagenomic-type analyses of the microbiome provide the resolution necessary to track transmission of airway bacteria. Microbiome studies have shown that the microbial community across various body sites tends to be more similar between individuals who cohabit in the same household than between individuals from different households. We tested whether there was increased sharing of bacteria from the airways within households with influenza infections as compared to control households with no influenza.

RESULTS: We obtained 221 respiratory samples that were collected from 54 individuals at 4 to 5 time points across 10 households, with and without influenza infection, in Managua, Nicaragua. From these samples, we generated metagenomic (whole genome shotgun sequencing) datasets to profile microbial taxonomy. Overall, specific bacteria and phages were differentially abundant between influenza positive households and control (no influenza infection) households, with bacteria like Rothia, and phages like Staphylococcus P68virus that were significantly enriched in the influenza-positive households. We identified CRISPR spacers detected in the metagenomic sequence reads and used these to track bacteria transmission within and across households. We observed a clear sharing of bacterial commensals and pathobionts, such as Rothia, Neisseria, and Prevotella, within and between households. However, due to the relatively small number of households in our study, we could not determine if there was a correlation between increased bacterial transmission and influenza infection.

CONCLUSION: We observed that airway microbial composition differences across households were associated with what appeared to be different susceptibility to influenza infection. We also demonstrate that CRISPR spacers from the whole microbial community can be used as markers to study bacterial transmission between individuals. Although additional evidence is needed to study transmission of specific bacterial strains, we observed sharing of respiratory commensals and pathobionts within and across households. Video Abstract.

PMID:37330554 | DOI:10.1186/s40168-023-01568-0

Parasit Vectors. 2023 Jun 17;16(1):204. doi: 10.1186/s13071-023-05800-6.

ABSTRACT

BACKGROUND: Quantifying infection intensity is a common goal in parasitological studies. We have previously shown that the amount of parasite DNA in faecal samples can be a biologically meaningful measure of infection intensity, even if it does not agree well with complementary counts of transmission stages (oocysts in the case of Coccidia). Parasite DNA can be quantified at relatively high throughput using quantitative polymerase chain reaction (qPCR), but amplification needs a high specificity and does not simultaneously distinguish between parasite species. Counting of amplified sequence variants (ASVs) from high-throughput marker gene sequencing using a relatively universal primer pair has the potential to distinguish between closely related co-infecting taxa and to uncover the community diversity, thus being both more specific and more open-ended.

METHODS: We here compare qPCR to the sequencing-based amplification using standard PCR and a microfluidics-based PCR to quantify the unicellular parasite Eimeria in experimentally infected mice. We use multiple amplicons to differentially quantify Eimeria spp. in a natural house mouse population.

RESULTS: We show that sequencing-based quantification has high accuracy. Using a combination of phylogenetic analysis and the co-occurrence network, we distinguish three Eimeria species in naturally infected mice based on multiple marker regions and genes. We investigate geographical and host-related effects on Eimeria spp. community composition and find, as expected, prevalence to be largely explained by sampling locality (farm). Controlling for this effect, the novel approach allowed us to find body condition of mice to be negatively associated with Eimeria spp. abundance.

CONCLUSIONS: We conclude that amplicon sequencing provides the underused potential for species distinction and simultaneous quantification of parasites in faecal material. The method allowed us to detect a negative effect of Eimeria infection on the body condition of mice in the natural environment.

PMID:37330545 | DOI:10.1186/s13071-023-05800-6

Trends Mol Med. 2023 Jun 7:S1471-4914(23)00115-6. doi: 10.1016/j.molmed.2023.06.001. Online ahead of print.

ABSTRACT

A recent publication by Barreto and colleagues showed that SARS-CoV-2 directly triggers hyperglycemia by infecting hepatocytes and inducing phosphoenolpyruvate carboxykinase (PEPCK)-dependent gluconeogenesis. Here, we discuss the biological importance of these findings, including the hepatic tropism of SARS-CoV-2. We also comment on the clinical implications of the bidirectional connection between COVID-19 and noncommunicable diseases.

PMID:37330366 | DOI:10.1016/j.molmed.2023.06.001

Immunity. 2023 Jun 12:S1074-7613(23)00234-0. doi: 10.1016/j.immuni.2023.05.017. Online ahead of print.

ABSTRACT

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

PMID:37329888 | DOI:10.1016/j.immuni.2023.05.017

Cell Host Microbe. 2023 Jun 12:S1931-3128(23)00220-2. doi: 10.1016/j.chom.2023.05.027. Online ahead of print.

ABSTRACT

Longitudinal microbiome data provide valuable insight into disease states and clinical responses, but they are challenging to mine and view collectively. To address these limitations, we present TaxUMAP, a taxonomically informed visualization for displaying microbiome states in large clinical microbiome datasets. We used TaxUMAP to chart a microbiome atlas of 1,870 patients with cancer during therapy-induced perturbations. Bacterial density and diversity were positively associated, but the trend was reversed in liquid stool. Low-diversity states (dominations) remained stable after antibiotic treatment, and diverse communities had a broader range of antimicrobial resistance genes than dominations. When examining microbiome states associated with risk for bacteremia, TaxUMAP revealed that certain Klebsiella species were associated with lower risk for bacteremia localize in a region of the atlas that is depleted in high-risk enterobacteria. This indicated a competitive interaction that was validated experimentally. Thus, TaxUMAP can chart comprehensive longitudinal microbiome datasets, enabling insights into microbiome effects on human health.

PMID:37329880 | DOI:10.1016/j.chom.2023.05.027

Pathol Res Pract. 2023 Jun 13;248:154614. doi: 10.1016/j.prp.2023.154614. Online ahead of print.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a cancer that is usually diagnosed at late stages. This highly aggressive tumor is resistant to most therapeutic approaches, necessitating identification of differentially expressed genes to design new therapies. Herein, we have analyzed single cell RNA-seq data with a systems biology approach to identify important differentially expressed genes in PDAC samples compared to adjacent non-cancerous samples. Our approach revealed 1462 DEmRNAs, including 1389 downregulated DEmRNAs (like PRSS1 and CLPS) and 73 upregulated DEmRNAs (like HSPA1A and SOCS3), 27 DElncRNAs, including 26 downregulated DElncRNAs (like LINC00472 and SNHG7) and 1 upregulated DElncRNA (SNHG5). We also listed a number of dysregulated signaling pathways, abnormally expressed genes and aberrant cellular functions in PDAC which can be used as possible biomarkers and therapeutic targets in this type of cancer.

PMID:37329816 | DOI:10.1016/j.prp.2023.154614

J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Apr 14;1226:123676. doi: 10.1016/j.jchromb.2023.123676. Online ahead of print.

ABSTRACT

Functional dyspepsia (FD) is one of the more common functional disorders, with a prevalence of 20-25 %. It seriously affects the quality life of patients. Xiaopi Hewei Capsule (XPHC) is a classic formula originated from the Chinese Miao minority. Clinical studies have demonstrated that XPHC can effectively alleviate the symptoms of FD, but the molecular mechanism has not been elucidated. The purpose of this work is to investigate the mechanism of XPHC on FD by integrating metabolomics and network pharmacology. The mice models of FD were established, and gastric emptying rate, small intestine propulsion rate, serum level of motilin and gastrin were evaluate to study the interventional effect of XPHC on FD. Next, a metabolomics strategy has been developed to screen differential metabolites and related metabolic pathways induced by XPHC. Then, prediction of active compounds, targets and pathways of XPHC in treating FD were carried out by commonly used network pharmacological method. Finally, two parts of the results were integrated to investigate therapeutic mechanism of XPHC on FD, which were preliminary validated based on molecular docking. Thus, twenty representative different metabolites and thirteen related pathways of XPHC in treating FD were identified. Most of these metabolites were restored using modulation after XPHC treatment. The results of the network pharmacology analysis showed ten crucial compounds and nine hub genes related to the treatment of FD with XPHC. The further integrated analysis focused on four key targets, such as albumin (ALB), epidermal growth factor receptor (EGFR), tumor necrosis factor (TNF) and roto-oncogene tyrosine-protein kinase Src (SRC), and three representative biomarkers such as citric acid, L-leucine and eicosapentaenoic acid. Furthermore, molecular docking results showed that ten bioactive compounds from XPHC have good binding interactions with the four key genes. The functional enrichment analysis indicated that the potential mechanism of XPHC in treating FD was mainly associated with energy metabolism, amino acid metabolism, lipid metabolism, inflammatory reactions and mucosal repair. Our work confirms that network pharmacology-integrated metabolomics strategyis a powerful means to reveal the therapeutic mechanisms of XPHC improves FD, which contribute its further scientific research.

PMID:37329776 | DOI:10.1016/j.jchromb.2023.123676

Comp Immunol Microbiol Infect Dis. 2023 Jun 1;98:102002. doi: 10.1016/j.cimid.2023.102002. Online ahead of print.

ABSTRACT

This study is an attempt to extract and analyse the microsatellites or simple sequence repeats (SSRs) from the genomes of eight species of the genus Orthopoxvirus. The average size of genomes included in the study was 205 kb while the GC% was 33% for all but one. A total of 10,584 SSRs and 854 cSSRs were observed. POX2 with the largest genome of 224.499 kb had maximum of 1493 SSRs and 121 cSSRs (compound SSR) while POX7 with the smallest genome of 185.578 kb had minimum incident SSRs and cSSRs at 1181 and 96, respectively. There was significant correlation between genome size and SSR incidence. Di-nucleotide repeats were the most prevalent (57.47%) followed by mono- at 33% and tri- at 8.6%. Mono-nucleotide SSRs were predominantly T (51%) and A (48.4%). A majority of 80.32% SSRs were in the coding region. The three most similar genomes as per heat map POX1, POX7 and POX5 (93% similarity) are adjacent to one another in the phylogenetic tree. Ankyrin/Ankyrin like protein and Kelch protein which are associated with host determination and divergence have the highest SSR density in almost all studied viruses. Thus, SSRs are involved in genome evolution and host determination of viruses.

PMID:37329681 | DOI:10.1016/j.cimid.2023.102002

Nat Commun. 2023 Jun 16;14(1):3576. doi: 10.1038/s41467-023-39252-4.

ABSTRACT

Resource competition can be the cause of unintended coupling between co-expressed genetic constructs. Here we report the quantification of the resource load imposed by different mammalian genetic components and identify construct designs with increased performance and reduced resource footprint. We use these to generate improved synthetic circuits and optimise the co-expression of transfected cassettes, shedding light on how this can be useful for bioproduction and biotherapeutic applications. This work provides the scientific community with a framework to consider resource demand when designing mammalian constructs to achieve robust and optimised gene expression.

PMID:37328476 | DOI:10.1038/s41467-023-39252-4

Nat Commun. 2023 Jun 16;14(1):3481. doi: 10.1038/s41467-023-38958-9.

ABSTRACT

Loss of a kidney results in compensatory growth of the remaining kidney, a phenomenon of considerable clinical importance. However, the mechanisms involved are largely unknown. Here, we use a multi-omic approach in a unilateral nephrectomy model in male mice to identify signaling processes associated with renal compensatory hypertrophy, demonstrating that the lipid-activated transcription factor peroxisome proliferator-activated receptor alpha (PPARα) is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.

PMID:37328470 | DOI:10.1038/s41467-023-38958-9

Sci Total Environ. 2023 Jun 14:164834. doi: 10.1016/j.scitotenv.2023.164834. Online ahead of print.

ABSTRACT

Climate change threatens freshwater fish species due to predicted changes in thermal, sedimentary and hydrological properties of stream ecosystems. Gravel-spawning fish are particularly sensitive to such alterations as warming, higher inputs of fine sediment and low-flow all have potentially negative effects on the functionality of their reproductive habitat, the hyporheic zone. Multiple stressors can interact in synergistic and antagonistic manners, causing surprise-effects that cannot be predicted from the additive consideration of individual stressors. For obtaining reliable, yet realistic data on the climate change stressor effects warming (+3-4 °C), fine sediment (increase in <0.85 mm by 22 %) and low-flow (eightfold discharge-reduction), we constructed a unique large-scale outdoor-mesocosm facility consisting of 24 flumes to study individual and combined stressor responses in a fully-crossed, 3-way-replicated design. To acquire representative results reflecting individual susceptibilities of gravel-spawning fish species due to taxonomic affiliation or spawning seasonality, we studied hatching success and embryonic development in the three fish species brown trout (Salmo trutta L.), common nase (Chondrostoma nasus L.) and Danube salmon (Hucho hucho L.). Fine sediment had the most significant single negative effect on both hatching rates and embryonic development (-80 % in brown trout, -50 % in nase, -60 % in Danube salmon). When fine sediment was combined with one or both of the other stressors, we observed strongly synergistic stressor responses, being distinctly stronger in the two salmonid species than in the cyprinid nase. Danube salmon was most susceptible to synergistic effects due to warmer spring water temperatures exacerbating the fine sediment-induced hypoxia, hence leading to complete mortality of fish eggs. This study highlights that individual and multiple-stressor effects depend strongly on life-history traits of respective species and that climate change stressors have to be assessed in combination to obtain representative results due to the high level of synergisms and antagonisms detected in this study.

PMID:37327887 | DOI:10.1016/j.scitotenv.2023.164834