Nat Commun. 2023 Nov 16;14(1):7435. doi: 10.1038/s41467-023-43245-8.

ABSTRACT

SND1 and MTDH are known to promote cancer and therapy resistance, but their mechanisms and interactions with other oncogenes remain unclear. Here, we show that oncoprotein ERG interacts with SND1/MTDH complex through SND1's Tudor domain. ERG, an ETS-domain transcription factor, is overexpressed in many prostate cancers. Knocking down SND1 in human prostate epithelial cells, especially those overexpressing ERG, negatively impacts cell proliferation. Transcriptional analysis shows substantial overlap in genes regulated by ERG and SND1. Mechanistically, we show that ERG promotes nuclear localization of SND1/MTDH. Forced nuclear localization of SND1 prominently increases its growth promoting function irrespective of ERG expression. In mice, prostate-specific Snd1 deletion reduces cancer growth and tumor burden in a prostate cancer model (PB-Cre/Ptenflox/flox/ERG mice), Moreover, we find a significant overlap between prostate transcriptional signatures of ERG and SND1. These findings highlight SND1's crucial role in prostate tumorigenesis, suggesting SND1 as a potential therapeutic target in prostate cancer.

PMID:37973913 | DOI:10.1038/s41467-023-43245-8

Sci Rep. 2023 Nov 16;13(1):20057. doi: 10.1038/s41598-023-47267-6.

ABSTRACT

We aimed to find out which are the most frequent complications for patients who suffer a traumatic brain injury (TBI) and its relation with brain biomarker levels. We conducted a hospital cohort study with patients who attended the Hospital Emergency Department between 1 June 2018 and 31 December 2020. Different variables were collected such as biomarkers levels after 6 h and 12 h of TBI (S100, NSE, UCHL1 and GFAP), clinical and sociodemographic variables, complementary tests, and complications 48 h and 7 days after TBI. Qualitative variables were analysed with Pearson's chi-square test, and quantitative variables with the Mann-Whitney U test. A multivariate logistic regression model for the existence of complications one week after discharge was performed to assess the discriminatory capacity of the clinical variables. A total of 51 controls and 540 patients were included in this study. In the TBI group, the mean age was 83 years, and 53.9% of the patients were male. Complications at seven days were associated with the severity of TBI (p < 0.05) and the number of platelets (p = 0.016). All biomarkers except GFAP showed significant differences in their distribution of values according to gender, with significantly higher values of the three biomarkers for women with respect to men. Patients with complications presented significantly higher S100 values (p < 0.05). The patient's baseline status, the severity of the TBI and the S100 levels can be very important elements in determining whether a patient may develop complications in the few hours after TBI.

PMID:37973882 | DOI:10.1038/s41598-023-47267-6

Drug Metab Dispos. 2023 Nov 16:DMD-AR-2023-001463. doi: 10.1124/dmd.123.001463. Online ahead of print.

ABSTRACT

Lung cancer is the leading cause of cancer deaths worldwide. We found that the cytochrome P450 isoform CYP4F11 is significantly overexpressed in patients with lung squamous cell carcinoma. CYP4F11 is a fatty acid w-hydroxylase and catalyzes the production of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. 20-HETE promotes cell proliferation and migration in cancer. An inhibition of 20-HETE-generating cytochrome P450 enzymes has been implicated as novel cancer therapy for more than a decade. However, the exact role of CYP4F11 and its potential as drug target for lung cancer therapy has not been established yet. Thus, we performed a transient knockdown of CYP4F11 in the lung cancer cell line NCI-H460. Knockdown of CYP4F11 significantly inhibits the lung cancer cell proliferation and migration while the 20-HETE production is significantly reduced. For biochemical characterization of CYP4F11-inhibitor interactions, we generated recombinant human CYP4F11. Spectroscopic ligand binding assays were conducted to evaluate CYP4F11 binding to the unselective CYP4A/F inhibitor HET0016. HET0016 shows high affinity to recombinant CYP4F11 and inhibits CYP4F11-mediated 20-HETE production in vitro with a nanomolar IC 50 Cross evaluation of HET0016 in NCI-H460 cells shows that lung cancer cell proliferation is significantly reduced together with 20-HETE production. However, HET0016 also displays antiproliferative effects which are not 20-HETE mediated. Future studies aim to establish the role of CYP4F11 in lung cancer and the underlying mechanism and investigate the potential of CYP4F11 as a therapeutic target for lung cancer. Significance Statement Lung cancer is a deadly cancer with limited treatment options. The cytochrome P450 4F11 (CYP4F11) is significantly upregulated in lung squamous cell carcinoma. A knockdown of CYP4F11 in a lung cancer cell line significantly attenuates cell proliferation and migration with reduced production of the lipid mediator 20-HETE. Studies with the unselective inhibitor HET0016 shows a high inhibitory potency of CYP4F11-mediated 20-HETE production using recombinant enzyme. Overall, our studies show the potential of targeting CYP4F11 for new transformative lung cancer treatment.

PMID:37973374 | DOI:10.1124/dmd.123.001463

Pharmacol Res. 2023 Nov 14:106994. doi: 10.1016/j.phrs.2023.106994. Online ahead of print.

ABSTRACT

The functional interdependencies between the molecular components of a biological process demands for a network medicine platform that integrates systems biology and network science, to explore the interactions among biological components in health and disease. Access to large-scale omics datasets (genomics, transcriptomics, proteomics, metabolomics, metagenomics, phenomics, etc.) has significantly advanced our opportunity along this direction. Studies utilizing these techniques have begun to provide us with a deeper understanding of how the interaction between the intestinal microbes and their host affects the cardiovascular system in health and disease. Within the framework of a multiomics network approach, we highlight here how tryptophan metabolism may orchestrate the host-microbes interaction in cardiovascular diseases and the implications for precision medicine and therapeutics, including nutritional interventions.

PMID:37972721 | DOI:10.1016/j.phrs.2023.106994

Cell. 2023 Nov 8:S0092-8674(23)01106-6. doi: 10.1016/j.cell.2023.10.007. Online ahead of print.

ABSTRACT

Cav1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Cav1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSDII. Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Nav channels, a series of structural changes occur, including upward movement of VSDII coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5III merges with S5III to become a single helix, resulting in a widened but still non-conductive intracellular gate.

PMID:37972591 | DOI:10.1016/j.cell.2023.10.007

Cell Rep Methods. 2023 Nov 7:100645. doi: 10.1016/j.crmeth.2023.100645. Online ahead of print.

ABSTRACT

In spatial transcriptomics (ST) data, biologically relevant features such as tissue compartments or cell-state transitions are reflected by gene expression gradients. Here, we present SpaceWalker, a visual analytics tool for exploring the local gradient structure of 2D and 3D ST data. The user can be guided by the local intrinsic dimensionality of the high-dimensional data to define seed locations, from which a flood-fill algorithm identifies transcriptomically similar cells on the fly, based on the high-dimensional data topology. In several use cases, we demonstrate that the spatial projection of these flooded cells highlights tissue architectural features and that interactive retrieval of gene expression gradients in the spatial and transcriptomic domains confirms known biology. We also show that SpaceWalker generalizes to several different ST protocols and scales well to large, multi-slice, 3D whole-brain ST data while maintaining real-time interaction performance.

PMID:37972590 | DOI:10.1016/j.crmeth.2023.100645

Environ Int. 2023 Nov 2;182:108285. doi: 10.1016/j.envint.2023.108285. Online ahead of print.

ABSTRACT

Water scarcity, one of the most pressing challenges we face today, has developed for many reasons, including the increasing number of waterborne pollutants that affect the safety of the water environment. Waterborne human, animal and plant viruses represent huge health, environmental, and financial burden and thus it is important to efficiently inactivate them. Therefore, the main objective of this study was to construct a unique device combining plasma with supercavitation and to evaluate its efficiency for water decontamination with the emphasis on inactivation of viruses. High inactivation (>5 log10 PFU/mL) of bacteriophage MS2, a human enteric virus surrogate, was achieved after treatment of 0.43 L of recirculating water for up to 4 min. The key factors in the inactivation were short-lived reactive plasma species that damaged viral RNA. Water treated with plasma for a short time required for successful virus inactivation did not cause cytotoxic effects in the in vitro HepG2 cell model system or adverse effects on potato plant physiology. Therefore, the combined plasma-supercavitation device represents an environmentally-friendly technology that could provide contamination-free and safe water.

PMID:37972530 | DOI:10.1016/j.envint.2023.108285

Cortex. 2023 Oct 27;169:279-289. doi: 10.1016/j.cortex.2023.09.015. Online ahead of print.

ABSTRACT

Social networks are an important factor in developing and maintaining social relationships. The social brain network comprises brain regions that differ in terms of their location, structure, and functioning, and these differences tend to vary among individuals with different social network sizes. However, it remains unknown how social cognitive abilities such as empathy can affect social network size. The goal of our study was to examine the relationship between brain regions in the social brain network, empathy, and individual social network size by using the Social Network Index, which measures social network diversity, size, and complexity by assessing 12 different types of relationships. We performed voxel-based morphometry and mediation analyses using data from questionnaires and structural magnetic resonance imaging data in a sample of 204 young adults. Our findings showed that the gray matter volume of the dorsomedial prefrontal cortex (dmPFC) was inversely associated with social network size and cognitive empathy mediated this association, suggesting that decreased gray matter volume in the dmPFC is associated with greater utilization of cognitive empathy, which, in turn, seems to increase social network size. A potential mechanism explaining this inverse relationship could be cognitive pruning, a phenomenon that occurs in the brain between early adolescence and adulthood, but future longitudinal studies are needed. In conclusion, our findings provide information about the neurocognitive mechanisms involved in the formation and maintenance of social networks.

PMID:37972460 | DOI:10.1016/j.cortex.2023.09.015

Plant Physiol. 2023 Nov 16:kiad615. doi: 10.1093/plphys/kiad615. Online ahead of print.

ABSTRACT

Photosynthetic organisms harvest light using pigment-protein complexes. In cyanobacteria, these are water-soluble antennae known as phycobilisomes (PBSs). The light absorbed by PBS is transferred to the photosystems in the thylakoid membrane to drive photosynthesis. The energy transfer between these complexes implies that protein-protein interactions allow the association of PBS with the photosystems. However, the specific proteins involved in the interaction of PBS with the photosystems are not fully characterized. Here, we show in the cyanobacteria Synechocystis sp. PCC 6803 that the recently discovered PBS linker protein ApcG (sll1873) interacts specifically with photosystem II through its N-terminal region. Growth of cyanobacteria is impaired in apcG deletion strains under light-limiting conditions. Furthermore, complementation of these strains using a phospho-mimicking version of ApcG causes reduced growth under normal growth conditions. Interestingly, the interaction of ApcG with photosystem II is affected when a phospho-mimicking version of ApcG is used, targeting the positively charged residues interacting with the thylakoid membrane, suggesting a regulatory role mediated by phosphorylation of ApcG. Low-temperature fluorescence measurements showed decreased photosystem I fluorescence in apcG deletion and complementation strains. The photosystem I fluorescence was the lowest in the phospho-mimicking complementation strain while the pull-down experiment showed no interaction of ApcG with PSI under any tested condition. Our results highlight the importance of ApcG for selectively directing energy harvested by the PBS and imply that the phosphorylation status of ApcG plays a role in regulating energy transfer from PSII to PSI.

PMID:37972281 | DOI:10.1093/plphys/kiad615

Proc Natl Acad Sci U S A. 2023 Nov 21;120(47):e2305215120. doi: 10.1073/pnas.2305215120. Epub 2023 Nov 16.

ABSTRACT

Transmembrane Cav2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Cav2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pain but is encumbered by side effects and abuse liability. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Cav2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Cav2.2-CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the A1R2 dipeptide in CBD3 as the anchoring Cav2.2 motif and designed pharmacophore models to screen 27 million compounds on the open-access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion neurons. Nine small molecules were tested electrophysiologically, while one (CBD3063) was also evaluated biochemically and behaviorally. CBD3063 uncoupled Cav2.2 from CRMP2, reduced membrane Cav2.2 expression and Ca2+ currents, decreased neurotransmission, reduced fiber photometry-based calcium responses in response to mechanical stimulation, and reversed neuropathic and inflammatory pain across sexes in two different species without changes in sensory, sedative, depressive, and cognitive behaviors. CBD3063 is a selective, first-in-class, CRMP2-based peptidomimetic small molecule, which allosterically regulates Cav2.2 to achieve analgesia and pain relief without negative side effect profiles. In summary, CBD3063 could potentially be a more effective alternative to GBP for pain relief.

PMID:37972067 | DOI:10.1073/pnas.2305215120

PLoS One. 2023 Nov 16;18(11):e0294313. doi: 10.1371/journal.pone.0294313. eCollection 2023.

ABSTRACT

Finding the best knockout strategy for coupling biomass growth and production of a target metabolite using a mathematic model of metabolism is a challenge in biotechnology. In this research, a three-step method named OptEnvelope is presented based on finding minimal set of active reactions for a target point in the feasible solution space (envelope) using a mixed-integer linear programming formula. The method initially finds the reduced desirable solution space envelope in the product versus biomass plot by removing all inactive reactions. Then, with reinsertion of the deleted reactions, OptEnvelope attempts to reduce the number of knockouts so that the desirable production envelope is preserved. Additionally, OptEnvelope searches for envelopes with higher minimum production rates or fewer knockouts by evaluating different target points within the desired solution space. It is possible to limit the maximal number of knockouts. The method was implemented on metabolic models of E. coli and S. cerevisiae to test the method benchmarking the capability of these industrial microbes for overproduction of acetate and glycerol under aerobic conditions and succinate and ethanol under anaerobic conditions. The results illustrate that OptEnvelope is capable to find multiple strong coupled envelopes located in the desired solution space because of its novel target point oriented strategy of envelope search. The results indicate that E. coli is more appropriate to produce acetate and succinate while S. cerevisiae is a better host for glycerol production. Gene deletions for some of the proposed reaction knockouts have been previously reported to increase the production of these metabolites in experiments. Both organisms are suitable for ethanol production, however, more knockouts for the adaptation of E. coli are required. OptEnvelope is available at https://github.com/lv-csbg/optEnvelope.

PMID:37972019 | DOI:10.1371/journal.pone.0294313

J Agric Food Chem. 2023 Nov 16. doi: 10.1021/acs.jafc.3c04015. Online ahead of print.

ABSTRACT

The aroma of red wine is suggested to be influenced by interactions with nonvolatile polymers. To investigate this aroma binding effect in red wine, the key aroma compounds of a Primitivo red wine were quantified using GC-MS and an aroma recombinant with 27 odorants was prepared. In sensory experiments, an overall strong effect on the odor perception of the aroma recombinant was observed when high-molecular-weight (HMW) polymers of Primitivo red wine were added. An 1H NMR-based approach was developed to get an insight into the molecular mechanisms of this aroma binding effect in red wine. Evaluation of qualitative changes in the NMR spectra and quantitative time-dependent measurements revealed a clear distinction between different molecular interaction types: (i) no interactions for esters, alcohols, furanones, ketones, and C13-norisoprenoids, (ii, iii) noncovalent interactions for acids, aldehydes, and lactones, and (iv) π-π interactions for pyrazines and phenols. Additionally, the influence of the molecular weight of polymers was evaluated, where the HMW fraction 30-50 kDa showed the highest interaction activity, for example for π-π interactions. Based on these results, the new approach allowed the direct analysis of noncovalent interactions between odorants and HMW polymers and therefore allowed for the first time the description of the aroma binding effect on a molecular basis.

PMID:37970809 | DOI:10.1021/acs.jafc.3c04015

RMD Open. 2023 Nov;9(4):e003499. doi: 10.1136/rmdopen-2023-003499.

ABSTRACT

OBJECTIVES: Gout, as the most prevalent form of inflammatory arthritis, necessitates the use of animal models to investigate the molecular mechanisms involved in its development. Therefore, our objective was to develop a novel chronic mouse model of gout that more closely mimics the progression of gout in humans.

METHODS: A novel chronic mouse model of gout was established by a simple method, which does not require high technical proficiency, predominantly involves daily intraperitoneal injections of potassium oxonate for approximately 4 months, combined with a high fat-diet and injections of acetic acid into the hind paws to facilitate the formation of monosodium urate (MSU). Arthritis scores and paw oedema were assessed, behavioural tests were conducted, and histopathological and imaging evaluations of the arthritic paw joints were performed.

RESULTS: After 4 months of induction, mice in the model group exhibited noticeable increases in arthritis severity, joint and cartilage damage, as well as bone erosion. Gomori's methenamine silver stain revealed the presence of MSU crystal deposition or tophi in the paw joints or ankle joints of up to 37.9% of the model mice (11 out of 29 mice). Moreover, treatment with benzbromarone effectively prevented the further development of gout or tophi formation in model mice.

CONCLUSIONS: Our model more accurately replicates the pathological features of gouty arthritis compared with gout induced by MSU crystal injections. Therefore, it is particularly suitable for further investigations into the pathogenesis of gout and also serves as a valuable platform for screening potential antigout agents.

PMID:37973536 | DOI:10.1136/rmdopen-2023-003499

Trends Microbiol. 2023 Nov 14:S0966-842X(23)00298-6. doi: 10.1016/j.tim.2023.10.009. Online ahead of print.

ABSTRACT

Nitrification is a key microbial process in the nitrogen (N) cycle that converts ammonia to nitrate. Excessive nitrification, typically occurring in agroecosystems, has negative environmental impacts, including eutrophication and greenhouse gas emissions. Nitrification inhibitors (NIs) are widely used to manage N in agricultural systems by reducing nitrification rates and improving N use efficiency. However, the effectiveness of NIs can vary depending on the soil conditions, which, in turn, affect the microbial community and the balance between different functional groups of nitrifying microorganisms. Understanding the mechanisms underlying the effectiveness of NIs, and how this is affected by the soil microbial communities or abiotic factors, is crucial for promoting sustainable fertilizer practices. Therefore, this review examines the different types of NIs and how abiotic parameters can influence the nitrifying community, and, therefore, the efficacy of NIs. By discussing the latest research in this field, we provide insights that could facilitate the development of more targeted, efficient, or complementary NIs that improve the application of NIs for sustainable management practices in agroecosystems.

PMID:37973432 | DOI:10.1016/j.tim.2023.10.009

J Cell Sci. 2023 Nov 16:jcs.261138. doi: 10.1242/jcs.261138. Online ahead of print.

ABSTRACT

Embryos repair wounds rapidly, with no inflammation or scarring. Embryonic wound healing is driven by the collective movement of the cells around the lesion. The cells adjacent to the wound polarize the cytoskeletal protein actin and the molecular motor non-muscle myosin II, which accumulate at the wound edge forming a supracellular cable around the wound. Adherens junction proteins including E-cadherin are internalized from the wound edge and localize to former tricellular junctions at the wound margin, in a process necessary for cytoskeletal polarity. We found that the cells adjacent to wounds in the Drosophila embryonic epidermis also polarized Talin, a core component of cell-extracellular matrix (ECM) adhesions. Integrin knock-down and inhibition of integrin binding delayed wound closure and reduced actin polarization and dynamics around the wound. Additionally, disrupting integrins caused a defect in E-cadherin reinforcement at tricellular junctions along the wound edge, suggesting crosstalk between integrin-based and cadherin-based adhesions. Our results show that cell-ECM adhesion contributes to embryonic wound repair and reveal an interplay between cell-cell and cell-ECM adhesion in the collective cell movements that drive rapid wound healing.

PMID:37970744 | DOI:10.1242/jcs.261138

ACS Omega. 2023 Oct 26;8(44):41680-41688. doi: 10.1021/acsomega.3c05931. eCollection 2023 Nov 7.

ABSTRACT

The success of machine learning is, in part, due to a large volume of data available to train models. However, the amount of training data for structure-based molecular property prediction remains limited. The previously described CrossDocked2020 data set expanded the available training data for binding pose classification in a molecular docking setting but did not address expanding the amount of receptor-ligand binding affinity data. We present experiments demonstrating that imputing binding affinity labels for complexes without experimentally determined binding affinities is a viable approach to expanding training data for structure-based models of receptor-ligand binding affinity. In particular, we demonstrate that utilizing imputed labels from a convolutional neural network trained only on the affinity data present in CrossDocked2020 results in a small improvement in the binding affinity regression performance, despite the additional sources of noise that such imputed labels add to the training data. The code, data splits, and imputation labels utilized in this paper are freely available at https://github.com/francoep/ImputationPaper.

PMID:37970017 | PMC:PMC10634251 | DOI:10.1021/acsomega.3c05931

J Biomol Tech. 2023 Aug 7;34(3):3fc1f5fe.a058bad4. doi: 10.7171/3fc1f5fe.a058bad4. eCollection 2023 Sep 30.

ABSTRACT

Metaproteomics research using mass spectrometry data has emerged as a powerful strategy to understand the mechanisms underlying microbiome dynamics and the interaction of microbiomes with their immediate environment. Recent advances in sample preparation, data acquisition, and bioinformatics workflows have greatly contributed to progress in this field. In 2020, the Association of Biomolecular Research Facilities Proteome Informatics Research Group launched a collaborative study to assess the bioinformatics options available for metaproteomics research. The study was conducted in 2 phases. In the first phase, participants were provided with mass spectrometry data files and were asked to identify the taxonomic composition and relative taxa abundances in the samples without supplying any protein sequence databases. The most challenging question asked of the participants was to postulate the nature of any biological phenomena that may have taken place in the samples, such as interactions among taxonomic species. In the second phase, participants were provided a protein sequence database composed of the species present in the sample and were asked to answer the same set of questions as for phase 1. In this report, we summarize the data processing methods and tools used by participants, including database searching and software tools used for taxonomic and functional analysis. This study provides insights into the status of metaproteomics bioinformatics in participating laboratories and core facilities.

PMID:37969874 | PMC:PMC10644979 | DOI:10.7171/3fc1f5fe.a058bad4

Bioinformation. 2023 Oct 31;19(10):995-998. doi: 10.6026/97320630019995. eCollection 2023.

ABSTRACT

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy, pose a growing global health challenge due to an aging population. These conditions share common processes, including protein accumulation, oxidative stress, and neuro-inflammation, making their treatment complex and costly. Network pharmacology, an innovative approach integrating systems biology and computational biology, offers insights into multi-target formulations and the repurposing of existing medications for neurodegenerative diseases. We shortlisted 730 bioactive compounds from 25 traditional Himalayan plants, assessed their drug-like properties using ADME criteria, and predicted their potential target proteins through reverse docking and pharmacophore mapping. Our study identified 287 compounds with high gastrointestinal absorption and good blood-brain barrier permeability. These compounds were subjected to target prediction, yielding a list of 171 potential target proteins. Functional annotation and pathway enrichment analysis highlighted their involvement in steroid hormone-related pathways, MAPK signaling, FOXO signaling, TNF signaling, VEGF signaling, and neurotrophin signaling. Importantly, one plant, Valeriana jatamansi, exhibited an association with beta-amyloid binding activity, a potential therapeutic approach for AD. From our study we could understand how these plants modulate our body to manage these diseases. However, further in vitro and in vivo validation is needed before commercial and public use of this data.

PMID:37969663 | PMC:PMC10640792 | DOI:10.6026/97320630019995

Sci Rep. 2023 Nov 15;13(1):19973. doi: 10.1038/s41598-023-47095-8.

ABSTRACT

Cassava storage roots (SR) are an important source of food energy and raw material for a wide range of applications. Understanding SR initiation and the associated regulation is critical to boosting tuber yield in cassava. Decades of transcriptome studies have identified key regulators relevant to SR formation, transcriptional regulation and sugar metabolism. However, there remain uncertainties over the roles of the regulators in modulating the onset of SR development owing to the limitation of the widely applied differential gene expression analysis. Here, we aimed to investigate the regulation underlying the transition from fibrous (FR) to SR based on Dynamic Network Biomarker (DNB) analysis. Gene expression analysis during cassava root initiation showed the transition period to SR happened in FR during 8 weeks after planting (FR8). Ninety-nine DNB genes associated with SR initiation and development were identified. Interestingly, the role of trehalose metabolism, especially trehalase1 (TRE1), in modulating metabolites abundance and coordinating regulatory signaling and carbon substrate availability via the connection of transcriptional regulation and sugar metabolism was highlighted. The results agree with the associated DNB characters of TRE1 reported in other transcriptome studies of cassava SR initiation and Attre1 loss of function in literature. The findings help fill the knowledge gap regarding the regulation underlying cassava SR initiation.

PMID:37968317 | DOI:10.1038/s41598-023-47095-8

Drug Discov Today. 2023 Nov 13:103825. doi: 10.1016/j.drudis.2023.103825. Online ahead of print.

ABSTRACT

With increasing human life expectancy, the global medical burden of chronic diseases is growing. Hence, chronic diseases are a pressing health concern and will continue to be in decades to come. Chronic diseases often involve multiple malfunctioning organs in the body. An imminent question is how interorgan crosstalk contributes to the etiology of chronic diseases. We conceived the locked-state model (LoSM), which illustrates how interorgan communication can give rise to body-wide memory-like properties that 'lock' healthy or pathological conditions. Next, we propose cutting-edge systems biology and artificial intelligence strategies to decipher chronic multiorgan locked states. Finally, we discuss the clinical implications of the LoSM and assess the power of systems-based therapies to dismantle pathological multiorgan locked states while improving treatments for chronic diseases.

PMID:37967790 | DOI:10.1016/j.drudis.2023.103825