Circulation. 2024 Mar 26;149(13):1056-1058. doi: 10.1161/CIRCULATIONAHA.123.067510. Epub 2024 Mar 25.

NO ABSTRACT

PMID:38527133 | DOI:10.1161/CIRCULATIONAHA.123.067510

Oncologist. 2024 Mar 25:oyae014. doi: 10.1093/oncolo/oyae014. Online ahead of print.

ABSTRACT

MEK signaling pathway targeting has emerged as a valuable addition to the options available for the treatment of advanced cancers including melanoma and non-small cell lung cancer. Ophthalmologic monitoring of patients taking part in clinical trials of MEK inhibitors has shown that while ocular effects are common, generally emerging during the first days to weeks of treatment, the majority are either asymptomatic or have minimal visual impact and are benign, resolving without intervention or the need to reduce or stop MEK inhibitor therapy. However rare cases of serious, potentially vision-threatening ocular toxicities have been reported during MEK inhibitor therapy. There is currently no recommendation for routine ophthalmologic screening or monitoring of patients with advanced cancer who are initiating MEK inhibitor therapy. However, baseline ophthalmologic examination may be useful for all patients initiating MEK inhibitor therapy to allow the differentiation of preexisting pathology versus the development of MEK inhibitor-associated retinopathy in the event of the emergence of symptomatic ocular events. Regular ophthalmologic examination may be appropriate for patients at increased risk for ocular events, such as patients with a history of ocular inflammation, infection, or underlying macular/retinal disease. All patients reporting visual disturbance should be referred for prompt ophthalmologic review to determine the potential seriousness of any underlying abnormalities and whether there is a need for treatment modification or specific intervention. Understanding the potential consequences of ocular toxicities is of particular importance in the context of decision-making for the continuation of potentially life-prolonging medications such as MEK inhibitors.

PMID:38527005 | DOI:10.1093/oncolo/oyae014

Elife. 2024 Mar 25;12:RP90259. doi: 10.7554/eLife.90259.

ABSTRACT

Circadian clocks are composed of transcription-translation negative feedback loops that pace rhythms of gene expression to the diurnal cycle. In the filamentous fungus Neurospora crassa, the proteins Frequency (FRQ), the FRQ-interacting RNA helicase (FRH), and Casein-Kinase I (CK1) form the FFC complex that represses expression of genes activated by the white-collar complex (WCC). FRQ orchestrates key molecular interactions of the clock despite containing little predicted tertiary structure. Spin labeling and pulse-dipolar electron spin resonance spectroscopy provide domain-specific structural insights into the 989-residue intrinsically disordered FRQ and the FFC. FRQ contains a compact core that associates and organizes FRH and CK1 to coordinate their roles in WCC repression. FRQ phosphorylation increases conformational flexibility and alters oligomeric state, but the changes in structure and dynamics are non-uniform. Full-length FRQ undergoes liquid-liquid phase separation (LLPS) to sequester FRH and CK1 and influence CK1 enzymatic activity. Although FRQ phosphorylation favors LLPS, LLPS feeds back to reduce FRQ phosphorylation by CK1 at higher temperatures. Live imaging of Neurospora hyphae reveals FRQ foci characteristic of condensates near the nuclear periphery. Analogous clock repressor proteins in higher organisms share little position-specific sequence identity with FRQ; yet, they contain amino acid compositions that promote LLPS. Hence, condensate formation may be a conserved feature of eukaryotic clocks.

PMID:38526948 | DOI:10.7554/eLife.90259

Rice (N Y). 2024 Mar 25;17(1):20. doi: 10.1186/s12284-024-00700-4.

ABSTRACT

The aus (Oryza sativa L.) varietal group comprises of aus, boro, ashina and rayada seasonal and/or field ecotypes, and exhibits unique stress tolerance traits, making it valuable for rice breeding. Despite its importance, the agro-morphological diversity and genetic control of yield traits in aus rice remain poorly understood. To address this knowledge gap, we investigated the genetic structure of 181 aus accessions using 399,115 SNP markers and evaluated them for 11 morpho-agronomic traits. Through genome-wide association studies (GWAS), we aimed to identify key loci controlling yield and plant architectural traits.Our population genetic analysis unveiled six subpopulations with strong geographical patterns. Subpopulation-specific differences were observed in most phenotypic traits. Principal component analysis (PCA) of agronomic traits showed that principal component 1 (PC1) was primarily associated with panicle traits, plant height, and heading date, while PC2 and PC3 were linked to primary grain yield traits. GWAS using PC1 identified OsSAC1 on Chromosome 7 as a significant gene influencing multiple agronomic traits. PC2-based GWAS highlighted the importance of OsGLT1 and OsPUP4/ Big Grain 3 in determining grain yield. Haplotype analysis of these genes in the 3,000 Rice Genome Panel revealed distinct genetic variations in aus rice.In summary, this study offers valuable insights into the genetic structure and phenotypic diversity of aus rice accessions. We have identified significant loci associated with essential agronomic traits, with GLT1, PUP4, and SAC1 genes emerging as key players in yield determination.

PMID:38526679 | DOI:10.1186/s12284-024-00700-4

Elife. 2024 Mar 25;13:e86493. doi: 10.7554/eLife.86493. Online ahead of print.

ABSTRACT

During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.

PMID:38526524 | DOI:10.7554/eLife.86493

J Clin Lab Anal. 2024 Mar 25:e25032. doi: 10.1002/jcla.25032. Online ahead of print.

ABSTRACT

BACKGROUND: Kidney disease is fairly unique due to the lack of symptoms associated with disease activity, and it is therefore dependent on biological monitoring. Dried biofluids, particularly dried capillary blood spots, are an accessible, easy-to-use technology that have seen increased utility in basic science research over the past decade. However, their use is yet to reach the kidney patient population clinically or in large-scale discovery science initiatives. The aim of this study was to systematically evaluate the existing literature surrounding the use of dried biofluids in kidney research.

METHODS: A systematic literature review was conducted using three search engines and a predefined search term strategy. Results were summarised according to the collection method, type of biofluid, application to kidney disease, cost, sample stability and patient acceptability.

RESULTS: In total, 404 studies were identified and 67 were eligible. In total, 34,739 patients were recruited to these studies with a skew towards male participants (> 73%). The majority of samples were blood, which was used either for monitoring anti-rejection immunosuppressive drug concentrations or for kidney function. Dried biofluids offered significant cost savings to the patient and healthcare service. The majority of patients preferred home microsampling when compared to conventional monitoring.

CONCLUSION: There is an unmet need in bringing dried microsampling technology to advance kidney disease despite its advantages. This technology provides an opportunity to upscale patient recruitment and longitudinal sampling, enhance vein preservation and overcome participation bias in research.

PMID:38525922 | DOI:10.1002/jcla.25032

J Cell Sci. 2024 Mar 25:jcs.261737. doi: 10.1242/jcs.261737. Online ahead of print.

ABSTRACT

In neurons, the microtubule (MT) cytoskeleton forms the basis for long-distance protein transport from the cell body into and out of dendrites and axons. To maintain neuronal polarity, the axon initial segment (AIS) serves as a physical barrier, separating the axon from the somatodendritic compartment and acting as a filter for axonal cargo. Selective trafficking is further instructed by axonal enrichment of MT post-translational modifications, which affect MT dynamics and the activity of motor proteins. Here, we compared two knockout mouse lines lacking the respective enzymes for MT tyrosination and detyrosination and found that both knockouts led to a shortening of the AIS. Neurons from both lines also showed an increased immobile fraction of endolysosomes present in the axon, whereas mobile organelles displayed shortened run distances in the retrograde direction. Overall, our results highlight the importance of maintaining the balance of tyrosinated/detyrosinated MT for proper AIS length and axonal transport processes.

PMID:38525600 | DOI:10.1242/jcs.261737

J Appl Stat. 2023 Jan 16;51(5):845-865. doi: 10.1080/02664763.2022.2163379. eCollection 2024.

ABSTRACT

Statistical learning of the structures of cellular networks, such as protein signaling pathways, is a topical research field in computational systems biology. To get the most information out of experimental data, it is often required to develop a tailored statistical approach rather than applying one of the off-the-shelf network reconstruction methods. The focus of this paper is on learning the structure of the mTOR protein signaling pathway from immunoblotting protein phosphorylation data. Under two experimental conditions eleven phosphorylation sites of eight key proteins of the mTOR pathway were measured at ten non-equidistant time points. For the statistical analysis we propose a new advanced hierarchically coupled non-homogeneous dynamic Bayesian network (NH-DBN) model, and we consider various data imputation methods for dealing with non-equidistant temporal observations. Because of the absence of a true gold standard network, we propose to use predictive probabilities in combination with a leave-one-out cross validation strategy to objectively cross-compare the accuracies of different NH-DBN models and data imputation methods. Finally, we employ the best combination of model and data imputation method for predicting the structure of the mTOR protein signaling pathway.

PMID:38524794 | PMC:PMC10956916 | DOI:10.1080/02664763.2022.2163379

Biophys Rep. 2023 Dec 31;9(6):299-308. doi: 10.52601/bpr.2023.230042.

ABSTRACT

Efficient quantification of fatty-acid (FA) composition (fatty-acidome) in biological samples is crucial for understanding physiology and pathophysiology in large population cohorts. Here, we report a rapid GC-FID/MS method for simultaneous quantification of all FAs in numerous biological matrices. Within eight minutes, this method enabled simultaneous quantification of 50 FAs as fatty-acid methyl esters (FAMEs) in femtomole levels following the efficient transformation of FAs in all lipids including FFAs, cholesterol-esters, glycerides, phospholipids and sphingolipids. The method showed satisfactory inter-day and intra-day precision, stability and linearity (R2 > 0.994) within a concentration range of 2-3 orders of magnitude. FAs were then quantified in typical multiple biological matrices including human biofluids (urine, plasma) and cells, animal intestinal content and tissue samples. We also established a quantitative structure-retention relationship (QSRR) for analytes to accurately predict their retention time and aid their reliable identification. We further developed a novel no-additive retention index (NARI) with endogenous FAMEs reducing inter-batch variations to 15 seconds; such NARI performed better than the alkanes-based classical RI, making meta-analysis possible for data obtained from different batches and platforms. Collectively, this provides an inexpensive high-throughput analytical system for quantitative phenotyping of all FAs in 8-minutes multiple biological matrices in large cohort studies of pathophysiological effects.

PMID:38524698 | PMC:PMC10960574 | DOI:10.52601/bpr.2023.230042

iScience. 2024 Feb 26;27(3):109121. doi: 10.1016/j.isci.2024.109121. eCollection 2024 Mar 15.

ABSTRACT

Dysregulation of liver metabolism associated with obesity during feeding and fasting leads to the breakdown of metabolic homeostasis. However, the underlying mechanism remains unknown. Here, we measured multi-omics data in the liver of wild-type and leptin-deficient obese (ob/ob) mice at ad libitum feeding and constructed a differential regulatory trans-omic network of metabolic reactions. We compared the trans-omic network at feeding with that at 16 h fasting constructed in our previous study. Intermediate metabolites in glycolytic and nucleotide metabolism decreased in ob/ob mice at feeding but increased at fasting. Allosteric regulation reversely shifted between feeding and fasting, generally showing activation at feeding while inhibition at fasting in ob/ob mice. Transcriptional regulation was similar between feeding and fasting, generally showing inhibiting transcription factor regulations and activating enzyme protein regulations in ob/ob mice. The opposite metabolic dysregulation between feeding and fasting characterizes breakdown of metabolic homeostasis associated with obesity.

PMID:38524370 | PMC:PMC10960062 | DOI:10.1016/j.isci.2024.109121

Front Immunol. 2024 Mar 8;15:1368749. doi: 10.3389/fimmu.2024.1368749. eCollection 2024.

ABSTRACT

Numerous studies have shown that immune checkpoint inhibitor (ICI) immunotherapy has great potential as a cancer treatment, leading to significant clinical improvements in numerous cases. However, it benefits a minority of patients, underscoring the importance of discovering reliable biomarkers that can be used to screen for potential beneficiaries and ultimately reduce the risk of overtreatment. Our comprehensive review focuses on the latest advancements in predictive biomarkers for ICI therapy, particularly emphasizing those that enhance the efficacy of programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors immunotherapies. We explore biomarkers derived from various sources, including tumor cells, the tumor immune microenvironment (TIME), body fluids, gut microbes, and metabolites. Among them, tumor cells-derived biomarkers include tumor mutational burden (TMB) biomarker, tumor neoantigen burden (TNB) biomarker, microsatellite instability (MSI) biomarker, PD-L1 expression biomarker, mutated gene biomarkers in pathways, and epigenetic biomarkers. TIME-derived biomarkers include immune landscape of TIME biomarkers, inhibitory checkpoints biomarkers, and immune repertoire biomarkers. We also discuss various techniques used to detect and assess these biomarkers, detailing their respective datasets, strengths, weaknesses, and evaluative metrics. Furthermore, we present a comprehensive review of computer models for predicting the response to ICI therapy. The computer models include knowledge-based mechanistic models and data-based machine learning (ML) models. Among the knowledge-based mechanistic models are pharmacokinetic/pharmacodynamic (PK/PD) models, partial differential equation (PDE) models, signal networks-based models, quantitative systems pharmacology (QSP) models, and agent-based models (ABMs). ML models include linear regression models, logistic regression models, support vector machine (SVM)/random forest/extra trees/k-nearest neighbors (KNN) models, artificial neural network (ANN) and deep learning models. Additionally, there are hybrid models of systems biology and ML. We summarized the details of these models, outlining the datasets they utilize, their evaluation methods/metrics, and their respective strengths and limitations. By summarizing the major advances in the research on predictive biomarkers and computer models for the therapeutic effect and clinical utility of tumor ICI, we aim to assist researchers in choosing appropriate biomarkers or computer models for research exploration and help clinicians conduct precision medicine by selecting the best biomarkers.

PMID:38524135 | PMC:PMC10957591 | DOI:10.3389/fimmu.2024.1368749

iScience. 2024 Mar 6;27(4):109441. doi: 10.1016/j.isci.2024.109441. eCollection 2024 Apr 19.

ABSTRACT

Insect physiology and reproduction depend on several terpenoid compounds, whose biosynthesis is mainly unknown. One enigmatic group of insect monoterpenoids are mealybug sex pheromones, presumably resulting from the irregular coupling activity of unidentified isoprenyl diphosphate synthases (IDSs). Here, we performed a comprehensive search for IDS coding sequences of the pest mealybug Planococcus citri. We queried the available genomic and newly generated short- and long-read P. citri transcriptomic data and identified 18 putative IDS genes, whose phylogenetic analysis indicates several gene family expansion events. In vitro testing confirmed regular short-chain coupling activity with five gene products. With the candidate with highest IDS activity, we also detected low amounts of irregular coupling products, and determined amino acid residues important for chain-length preference and irregular coupling activity. This work therefore provides an important foundation for deciphering terpenoid biosynthesis in mealybugs, including the sex pheromone biosynthesis in P. citri.

PMID:38523795 | PMC:PMC10960109 | DOI:10.1016/j.isci.2024.109441

iScience. 2024 Feb 28;27(4):109333. doi: 10.1016/j.isci.2024.109333. eCollection 2024 Apr 19.

ABSTRACT

Kinases as important enzymes can transfer phosphate groups from high-energy and phosphate-donating molecules to specific substrates and play essential roles in various cellular processes. Existing algorithms for kinase activity from phosphorylated proteomics data are often costly, requiring valuable samples. Moreover, methods to extract kinase activities from bulk RNA sequencing data remain undeveloped. In this study, we propose a computational framework KinPred-RNA to derive kinase activities from bulk RNA-sequencing data in cancer samples. KinPred-RNA framework, using the extreme gradient boosting (XGBoost) regression model, outperforms random forest regression, multiple linear regression, and support vector machine regression models in predicting kinase activities from cancer-related RNA sequencing data. Efficient gene signatures from the LINCS-L1000 dataset were used as inputs for KinPred-RNA. The results highlight its potential to be related to biological function. In conclusion, KinPred RNA constitutes a significant advance in cancer research by potentially facilitating the identification of cancer.

PMID:38523792 | PMC:PMC10959666 | DOI:10.1016/j.isci.2024.109333

iScience. 2024 Mar 1;27(4):109383. doi: 10.1016/j.isci.2024.109383. eCollection 2024 Apr 19.

ABSTRACT

The co-culture of two adult human colorectal cancer cell lines, Caco-2 and HT29, on Transwell is commonly used as an in vitro gut mimic, yet the translatability of insights from such a system to adult human physiological contexts is not fully characterized. Here, we used single-cell RNA sequencing on the co-culture to obtain a detailed survey of cell type heterogeneity in the system and conducted a holistic comparison with human physiology. We identified the intestinal stem cell-, transit amplifying-, enterocyte-, goblet cell-, and enteroendocrine-like cells in the system. In general, the co-culture was fetal intestine-like, with less variety of gene expression compared to the adult human gut. Transporters for major types of nutrients were found in the majority of the enterocytes-like cells in the system. TLR 4 was not expressed in the sample, indicating that the co-culture model is incapable of mimicking the innate immune aspect of the human epithelium.

PMID:38523788 | PMC:PMC10959667 | DOI:10.1016/j.isci.2024.109383

iScience. 2024 Mar 5;27(4):109421. doi: 10.1016/j.isci.2024.109421. eCollection 2024 Apr 19.

ABSTRACT

Defective interfering particles (DIPs) are regarded as potent broad-spectrum antivirals. We developed a mathematical model that describes intracellular co-infection dynamics of influenza standard virus (STV) and "OP7", a new type of influenza DIP discovered recently. Based on experimental data from in vitro studies to calibrate the model and confirm its predictions, we deduce OP7's mechanisms of interference, which were yet unknown. Simulations suggest that the "superpromoter" on OP7 genomic viral RNA enhances its replication and results in a depletion of viral proteins. This reduces STV genomic RNA replication, which appears to constitute an antiviral effect. Further, a defective viral protein (M1-OP7) likely causes the deficiency of OP7's replication. It appears unable to bind to genomic viral RNAs to facilitate their nuclear export, a critical step in the viral life cycle. An improved understanding of OP7's antiviral mechanism is crucial toward application in humans as a prospective antiviral treatment strategy.

PMID:38523782 | PMC:PMC10959662 | DOI:10.1016/j.isci.2024.109421

Mol Ecol Resour. 2024 Mar 25:e13953. doi: 10.1111/1755-0998.13953. Online ahead of print.

ABSTRACT

Recent declines in insect abundances, especially populations of wild pollinators, pose a threat to many natural and agricultural ecosystems. Traditional species monitoring relies on morphological character identification and is inadequate for efficient and standardized surveys. DNA barcoding has become a standard approach for molecular identification of organisms, aiming to overcome the shortcomings of traditional biodiversity monitoring. However, its efficacy depends on the completeness of reference databases. Large DNA barcoding efforts are (almost entirely) lacking in many European countries and such patchy data limit Europe-wide analyses of precisely how to apply DNA barcoding in wild bee identification. Here, we advance towards an effective molecular identification of European wild bees. We conducted a high-effort survey of wild bees at the junction of central and southern Europe and DNA barcoded all collected morphospecies. For global analyses, we complemented our DNA barcode dataset with all relevant European species and conducted global analyses of species delimitation, general and genus-specific barcoding gaps and examined the error rate in DNA data repositories. We found that (i) a sixth of all specimens from Slovenia could not be reliably identified, (ii) species delimitation methods show numerous systematic discrepancies, (iii) there is no general barcoding gap across all bees and (iv) the barcoding gap is genus specific, but only after curating for errors in DNA data repositories. Intense sampling and barcoding efforts in underrepresented regions and strict curation of DNA barcode repositories are needed to enhance the use of DNA barcoding for the identification of wild bees.

PMID:38523561 | DOI:10.1111/1755-0998.13953

J Fish Dis. 2024 Mar 24:e13940. doi: 10.1111/jfd.13940. Online ahead of print.

ABSTRACT

Vibrio alginolyticus is the causative agent of vibriosis, a common bacterial infection in grouper aquaculture that is associated with the development of haemorrhagic and non-haemorrhagic ulcerations on the fish. In the present study, comparative proteome analysis was performed on serum samples from Vibrio-resistant and Vibrio-susceptible grouper. Samples were analysed using high-throughput LC-MS/MS and identified 2770 unique peptides that corresponded to 344 proteins. Subsequent analysis identified 21 proteins that were significantly up-regulated in the resistant group compared to the control and the susceptible groups. Those proteins are associated with immunostimulatory effects, signalling and binding cascade, metabolism, and maintaining tissue integrity and physiological condition. Besides, potential protein biomarkers related to the immune system were identified, which could be associated with the disease-resistant phenotype. These data provide insights into the underlying immune mechanism of hybrid groupers upon Vibrio sp. infection.

PMID:38523352 | DOI:10.1111/jfd.13940

Anal Bioanal Chem. 2024 Mar 25. doi: 10.1007/s00216-024-05215-x. Online ahead of print.

ABSTRACT

Drug screening tests are mandatory in the search for drugs in forensic biological samples, and immunological methods and mass spectrometry (e.g., gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry) are commonly used for that purpose. However, these methods have some drawbacks, and developing new screening methods is required. In this study, we develop a rapid-fire drug screening method by probe electrospray ionization tandem mass spectrometry (PESI-MS/MS), which is an ambient ionization mass spectrometry method, for human urine, named RaDPi-U. RaDPi-U is carried out in three steps: (1) mixing urine with internal standard (IS) solution and ethanol, followed by vortexing; (2) pipetting the mixture onto a sample plate for PESI; and (3) rapid-fire analysis by PESI-MS/MS. RaDPi-U targets 40 forensically important drugs, which include illegal drugs, hypnotics, and psychoactive substances. The analytical results were obtained within 3 min because of the above-mentioned simple workflow of RaDPi-U. The calibration curves of each analyte were constructed using the IS method, and they were quantitatively valid, resulting in good linearity (0.972-0.999) with a satisfactory lower limit of detection and lower limit of quantitation (0.01-7.1 ng/mL and 0.02-21 ng/mL, respectively). Further, both trueness and precisions were 28% or less, demonstrating the high reliability and repeatability of the method. Finally, we applied RaDPi-U to three postmortem urine specimens and successfully detected different drugs in each urine sample. The practicality of the method is proven, and RaDPi-U will be a strong tool as a rapid-fire drug screening method not only in forensic toxicology but also in clinical toxicology.

PMID:38523158 | DOI:10.1007/s00216-024-05215-x

J Biol Chem. 2024 Mar 22:107220. doi: 10.1016/j.jbc.2024.107220. Online ahead of print.

ABSTRACT

Circadian rhythms are generated by complex interactions among genes and proteins. Self-sustained ∼24 hour oscillations require negative feedback loops and sufficiently strong nonlinearities that are the product of molecular and network switches. Here we review common mechanisms to obtain switch-like behavior, including cooperativity, antagonistic enzymes, multisite phosphorylation, positive feedback, and sequestration. We discuss how network switches play a crucial role as essential components in cellular circadian clocks, serving as integral parts of transcription-translation feedback loops (TTFLs) that form the basis of circadian rhythm generation. The design principles of network switches and circadian clocks are illustrated by representative mathematical models that include bistable systems and negative feedback loops combined with Hill functions. This work underscores the importance of negative feedback loops and network switches as essential design principles for biological oscillations, emphasizing how an understanding of theoretical concepts can provide insights into the mechanism generating biological rhythms.

PMID:38522517 | DOI:10.1016/j.jbc.2024.107220

Comput Biol Med. 2024 Mar 11;173:108259. doi: 10.1016/j.compbiomed.2024.108259. Online ahead of print.

ABSTRACT

Despite efforts to elucidate Zika virus (ZIKV) teratogenesis, still several issues remain unresolved, particularly on the molecular mechanisms behind the pathogenesis of Congenital Zika Syndrome (CZS). To answer this question, we used bioinformatics tools, animal experiments and human gene expression analysis to investigate genes related to brain development potentially involved in CZS. Searches in databases for genes related to brain development and CZS were performed, and a protein interaction network was created. The expression of these genes was analyzed in a CZS animal model and secondary gene expression analysis (DGE) was performed in human cells exposed to ZIKV. A total of 2610 genes were identified in the databases, of which 1013 were connected. By applying centrality statistics of the global network, 36 candidate genes were identified, which, after selection resulted in nine genes. Gene expression analysis revealed distinctive expression patterns for PRKDC, PCNA, ATM, SMC3 as well as for FGF8 and SHH in the CZS model. Furthermore, DGE analysis altered expression of ATM, PRKDC, PCNA. In conclusion, systems biology are helpful tools to identify candidate genes to be validated in vitro and in vivo. PRKDC, PCNA, ATM, SMC3, FGF8 and SHH have altered expression in ZIKV-induced brain malformations.

PMID:38522248 | DOI:10.1016/j.compbiomed.2024.108259