Small Methods. 2023 Mar 12:e2201605. doi: 10.1002/smtd.202201605. Online ahead of print.

ABSTRACT

Viability CRISPR screens have proven indispensable in parsing genome function. However, their application in new, more physiologically relevant culturing systems like patient-derived organoids (PDOs) has been much slower. To probe epigenetic contribution to gastric cancer (GC), the third leading cause of cancer-related deaths worldwide, the first negative selection CRISPR screen in GC PDOs that faithfully preserve primary tumor characteristics is performed. Extensive quality control measurements showing feasibility of CRISPR screens in primary organoid culture are provided. The screen reveals the histone lysine demethylase-1A (KDM1A) to constitute a GC vulnerability. Both genetic and pharmacological inhibition of KDM1A cause organoid growth retardation. Further, it is shown that most of KDM1A cancer-supporting functions center on repression of N-myc downstream regulates gene-1 (NDRG1). De-repression of NDRG1 by KDM1A inhibitors (KDM1Ai) causes inhibition of Wnt signaling and a strong G1 cell cycle arrest. Finally, by profiling 20 GC PDOs, it is shown that NDRG1 upregulation predicts KDM1Ai response with 100% sensitivity and 82% specificity in the tested cohort. Thus, this work pioneers the use of negative selection CRISPR screens in patient-derived organoids, identifies a marker of KDM1Ai response, and accordingly a cohort of patients who may benefit from such therapy.

PMID:36908010 | DOI:10.1002/smtd.202201605

Trends Plant Sci. 2023 Mar 10:S1360-1385(23)00056-0. doi: 10.1016/j.tplants.2023.02.009. Online ahead of print.

ABSTRACT

Citizen science is an undervalued tool in a scientist's toolbox with the potential to go beyond primary data collection to strengthen fundamental and applied science. We call for the integration of these three disciplines to make agriculture sustainable and adaptive to climate change, with North-Western European soybean cultivation as showcase.

PMID:36907695 | DOI:10.1016/j.tplants.2023.02.009

J Hepatol. 2023 Mar 10:S0168-8278(23)00172-1. doi: 10.1016/j.jhep.2023.02.036. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Metastasis remains the major reason for high mortality of HCC patients. This study was designed to investigate the role of E-twenty-six-specific sequence variant 4 (ETV4) in promoting HCC metastasis and explored new combination therapy strategy for ETV4-mediated HCC metastasis.

METHODS: PLC/PRF/5, MHCC97H, Hepa1-6 and H22 cells were used to establishment of orthotopic HCC Models. Clodronate liposomes were used to clear macrophages in C57BL/6 mice. Gr-1 monoclonal antibody was used to clear myeloid derived suppressor cell (MDSCs) in C57BL/6 mice. Flow cytometry and immunofluorescence were used to detect the changes of key immune cells in tumor microenvironment.

RESULTS: ETV4 expression was positively related to higher TNM stage, poor tumor differentiation, microvascular invasion, and poor prognosis in human HCC. Overexpression of ETV4 in HCC cells transactivated programmed death ligand 1 (PD-L1) and chemokine (C-C motif) ligand 2 (CCL2) expression, which increased tumor-associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) infiltration and inhibited CD8+T cells accumulation. Knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAMs and MDSCs infiltration and HCC metastasis. Furthermore, fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) and hepatocyte growth factor (HGF)/c-MET jointly upregulated ETV4 expression through ERK1/2 pathway. Additionally, ETV4 upregulated FGFR4 expression and downregulation of FGFR4 decreased ETV4-enhanced HCC metastasis, which created a FGF19-ETV4-FGFR4 positive feedback loop. Finally, anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib prominently inhibited FGF19-ETV4 signaling induced HCC metastasis.

CONCLUSIONS: ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis.

IMPACT AND IMPLICATIONS: Here, we reported that ETV4 increased PD-L1 and chemokine CCL2 expression in HCC cells, which resulted in TAMs and MDSCs accumulation and CD8+T cell inhibition to facilitate HCC metastasis. More importantly, we found that anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib markedly inhibited FGF19-ETV4 signaling mediated HCC metastasis. This preclinical study will provide a theoretical basis for the development of new combination immunotherapy strategies for HCC patients.

PMID:36907560 | DOI:10.1016/j.jhep.2023.02.036

J Biol Chem. 2023 Mar 10:104599. doi: 10.1016/j.jbc.2023.104599. Online ahead of print.

ABSTRACT

Immune cells adopt a variety of metabolic states to support their many biological functions, which include fighting pathogens, removing tissue debris, and tissue remodeling. One of the key mediators of these metabolic changes is the transcription factor hypoxia-inducible factor 1α (HIF-1α). Single-cell dynamics have been shown to be an important determinant of cell behavior; however, despite the importance of HIF-1α, little is known about its single-cell dynamics or their effect on metabolism. To address this knowledge gap, here we optimized a HIF-1α fluorescent reporter and applied it to study single-cell dynamics. First, we showed that single cells are likely able to differentiate multiple levels of prolyl hydroxylase inhibition, a marker of metabolic change, via HIF-1α activity. We then applied a physiological stimulus known to trigger metabolic change, interferon-γ, and observed heterogeneous, oscillatory HIF-1α responses in single cells. Finally, we input these dynamics into a mathematical model of HIF-1α-regulated metabolism, and discovered a profound difference between cells exhibiting high versus low HIF-1α activation. Specifically, we found cells with high HIF-1α activation are able to meaningfully reduce flux through the tricarboxylic acid cycle and show a notable increase in the NAD+/NADH ratio compared to cells displaying low HIF-1α activation. Altogether, this work demonstrates an optimized reporter for studying HIF-1α in single cells and reveals previously unknown principles of HIF-1α activation.

PMID:36907438 | DOI:10.1016/j.jbc.2023.104599

Nat Commun. 2023 Mar 11;14(1):1341. doi: 10.1038/s41467-023-36017-x.

ABSTRACT

The frequent outbreak of global infectious diseases has prompted the development of rapid and effective diagnostic tools for the early screening of potential patients in point-of-care testing scenarios. With advances in mobile computing power and microfluidic technology, the smartphone-based mobile health platform has drawn significant attention from researchers developing point-of-care testing devices that integrate microfluidic optical detection with artificial intelligence analysis. In this article, we summarize recent progress in these mobile health platforms, including the aspects of microfluidic chips, imaging modalities, supporting components, and the development of software algorithms. We document the application of mobile health platforms in terms of the detection objects, including molecules, viruses, cells, and parasites. Finally, we discuss the prospects for future development of mobile health platforms.

PMID:36906581 | DOI:10.1038/s41467-023-36017-x

Gastroenterology. 2023 Mar 9:S0016-5085(23)00256-1. doi: 10.1053/j.gastro.2023.02.047. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Colon cancer patients with liver metastases may be cured by surgery, but the presence of additional lung metastases often precludes curative treatment. Little is known about the processes driving lung metastasis. This study aimed to elucidate the mechanisms governing lung versus liver metastasis formation.

METHODS: Patient-derived organoid (PDO) cultures were established from colon tumors with distinct patterns of metastasis. Mouse models recapitulating metastatic organotropism were created by implanting PDOs into the caecum wall. Optical barcoding was applied to trace the origin and clonal composition of liver- and lung-metastases. RNA-sequencing and immunohistochemistry were used to identify candidate-determinants of metastatic organotropism. Genetic, pharmacological, and in-vitro and in-vivo modeling strategies identified essential steps in lung metastasis formation. Validation was performed by analyzing patient-derived tissues.

RESULTS: Caecum transplantation of three distinct PDOs yielded models with distinct metastatic organotropism: liver-only, lung-only, and liver-and-lung. Liver-metastases were seeded by single cells derived from select clones. Lung-metastases were seeded by polyclonal clusters of tumor cells entering the lymphatic vasculature with very limited clonal selection. Lung-specific metastasis was associated with high expression of desmosome markers, including plakoglobin. Plakoglobin deletion abrogated tumor cell-cluster formation, lymphatic invasion, and lung metastasis formation. Pharmacological inhibition of lymphangiogenesis attenuated lung metastasis formation. Primary human colon, rectum, esophagus, and stomach tumors with lung-metastases had a higher N-stage and more plakoglobin-expressing intra-lymphatic tumor cell-clusters than those without lung-metastases.

CONCLUSION: Lung and liver metastasis formation are fundamentally distinct processes, with different evolutionary bottlenecks, seeding entities, and anatomical routing. Polyclonal lung-metastases originate from plakoglobin-dependent tumor cell-clusters entering the lymphatic vasculature at the primary tumor site.

PMID:36906044 | DOI:10.1053/j.gastro.2023.02.047

Sci Total Environ. 2023 Mar 9:162607. doi: 10.1016/j.scitotenv.2023.162607. Online ahead of print.

ABSTRACT

Although ceramic objects are an important part of the worldwide cultural heritage, few investigations on the effects of lithobiontic growth on their outdoor conservation are available in the literature. Many aspects of the interaction between lithobionts and stones are still unknown or strongly debated, as in the case of equilibria between biodeterioration and bioprotection. This paper describes research on the colonization by lithobionts on outdoor ceramic Roman dolia and contemporary sculptures of the International Museum of Ceramics, Faenza (Italy). Accordingly, the study i) characterized the mineralogical composition and petrographic structure of the artworks, ii) performed porosimetric measurements, iii) identified lichen and microbial diversity, iv) elucidated the interaction of the lithobionts with the substrates. Moreover, v) the measurements of variability in stone surface hardness and in water absorption of colonized and uncolonized areas were collected to assess damaging and/or protective effects by the lithobionts. The investigation showed how the biological colonization depends on physical properties of the substrates as well on climatic conditions of environments in which the ceramic artworks are located. The results indicated that lichens Protoparmeliopsis muralis and Lecanora campestris may have a bioprotective effect on ceramics with high total porosity and pores with very small diameters, as they poorly penetrate the substrate, do not negatively affect surface hardness and are able to reduce the amount of absorbed water limiting the water ingress. By contrast, Verrucaria nigrescens, here widely found in association with rock-dwelling fungi, deeply penetrate terracotta causing substrate disaggregation, with negative consequences on surface hardness and water absorption. Accordingly, a careful evaluation of the negative and positive effects of lichens must be carried out before deciding their removal. Regarding biofilms, their barrier efficacy is related to their thickness and composition. Even if thin, they can impact negatively on substrates enhancing the water absorption in comparison to uncolonized parts.

PMID:36906030 | DOI:10.1016/j.scitotenv.2023.162607

Sensors (Basel). 2023 Feb 27;23(5):2607. doi: 10.3390/s23052607.

ABSTRACT

Cannabis is commercially cultivated for both therapeutic and recreational purposes in a growing number of jurisdictions. The main cannabinoids of interest are cannabidiol (CBD) and delta-9 tetrahydrocannabidiol (THC), which have applications in different therapeutic treatments. The rapid, nondestructive determination of cannabinoid levels has been achieved using near-infrared (NIR) spectroscopy coupled to high-quality compound reference data provided by liquid chromatography. However, most of the literature describes prediction models for the decarboxylated cannabinoids, e.g., THC and CBD, rather than naturally occurring analogues, tetrahydrocannabidiolic acid (THCA) and cannabidiolic acid (CBDA). The accurate prediction of these acidic cannabinoids has important implications for quality control for cultivators, manufacturers and regulatory bodies. Using high-quality liquid chromatography-mass spectroscopy (LCMS) data and NIR spectra data, we developed statistical models including principal component analysis (PCA) for data quality control, partial least squares regression (PLS-R) models to predict cannabinoid concentrations for 14 different cannabinoids and partial least squares discriminant analysis (PLS-DA) models to characterise cannabis samples into high-CBDA, high-THCA and even-ratio classes. This analysis employed two spectrometers, a scientific grade benchtop instrument (Bruker MPA II-Multi-Purpose FT-NIR Analyzer) and a handheld instrument (VIAVI MicroNIR Onsite-W). While the models from the benchtop instrument were generally more robust (99.4-100% accuracy prediction), the handheld device also performed well (83.1-100% accuracy prediction) with the added benefits of portability and speed. In addition, two cannabis inflorescence preparation methods were evaluated: finely ground and coarsely ground. The models generated from coarsely ground cannabis provided comparable predictions to that of the finely ground but represent significant timesaving in terms of sample preparation. This study demonstrates that a portable NIR handheld device paired with LCMS quantitative data can provide accurate cannabinoid predictions and potentially be of use for the rapid, high-throughput, nondestructive screening of cannabis material.

PMID:36904818 | DOI:10.3390/s23052607

Nutrients. 2023 Mar 2;15(5):1260. doi: 10.3390/nu15051260.

ABSTRACT

BACKGROUND: Non-nutritive sweeteners (NNS) are part of personalized nutrition strategies supporting healthy glycemic control. In contrast, the consumption of non-nutritive sweeteners has been related to person-specific and microbiome-dependent glycemic impairments. Reports on the effects of NNS on our highly individual cellular immune system are sparse. The recent identification of taste receptor expression in a variety of immune cells, however, suggested their immune-modulatory relevance.

METHODS: We studied the influence of a beverage-typical NNS system on the transcriptional profiling of sweetener-cognate taste receptors, selected cytokines and their receptors, and on Ca2+ signaling in isolated blood neutrophils. We determined plasma concentrations of saccharin, acesulfame-K, and cyclamate by HPLC-MS/MS, upon ingestion of a soft drink-typical sweetener surrogate. In an open-labeled, randomized intervention study, we determined pre- versus post-intervention transcript levels by RT-qPCR of sweetener-cognate taste receptors and immune factors.

RESULTS: Here we show that the consumption of a food-typical sweetener system modulated the gene expression of cognate taste receptors and induced the transcriptional regulation signatures of early homeostasis- and late receptor/signaling- and inflammation-related genes in blood neutrophils, shifting their transcriptional profile from homeostasis to priming. Notably, sweeteners at postprandial plasma concentrations facilitated fMLF (N-formyl-Met-Leu-Phe)-induced Ca2+ signaling.

CONCLUSIONS: Our results support the notion of sweeteners priming neutrophils to higher alertness towards their adequate stimuli.

PMID:36904259 | DOI:10.3390/nu15051260

Nutrients. 2023 Feb 27;15(5):1202. doi: 10.3390/nu15051202.

ABSTRACT

The question of whether variable risk factors and various nutrients are causally related to inflammatory bowel diseases (IBDs) has remained unanswered so far. Thus, this study investigated whether genetically predicted risk factors and nutrients play a function in the occurrence of inflammatory bowel diseases, including ulcerative colitis (UC), non-infective colitis (NIC), and Crohn's disease (CD), using Mendelian randomization (MR) analysis. Utilizing the data of genome-wide association studies (GWASs) with 37 exposure factors, we ran Mendelian randomization analyses based on up to 458,109 participants. Univariable and multivariable MR analyses were conducted to determine causal risk factors for IBD diseases. Genetic predisposition to smoking and appendectomy as well as vegetable and fruit intake, breastfeeding, n-3 PUFAs, n-6 PUFAs, vitamin D, total cholesterol, whole-body fat mass, and physical activity were related to the risk of UC (p < 0.05). The effect of lifestyle behaviors on UC was attenuated after correcting for appendectomy. Genetically driven smoking, alcohol consumption, appendectomy, tonsillectomy, blood calcium, tea intake, autoimmune diseases, type 2 diabetes, cesarean delivery, vitamin D deficiency, and antibiotic exposure increased the risk of CD (p < 0.05), while vegetable and fruit intake, breastfeeding, physical activity, blood zinc, and n-3 PUFAs decreased the risk of CD (p < 0.05). Appendectomy, antibiotics, physical activity, blood zinc, n-3 PUFAs, and vegetable fruit intake remained significant predictors in multivariable MR (p < 0.05). Besides smoking, breastfeeding, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs were associated with NIC (p < 0.05). Smoking, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs remained significant predictors in multivariable MR (p < 0.05). Our results provide new and comprehensive evidence demonstrating that there are approving causal effects of various risk factors on IBDs. These findings also supply some suggestions for the treatment and prevention of these diseases.

PMID:36904201 | DOI:10.3390/nu15051202

Nutrients. 2023 Feb 26;15(5):1170. doi: 10.3390/nu15051170.

ABSTRACT

The important role of nutrition on both health and sports performance, and particularly its joint association with physical exercise, is becoming increasingly clear in recent years [...].

PMID:36904169 | DOI:10.3390/nu15051170

Nutrients. 2023 Feb 24;15(5):1143. doi: 10.3390/nu15051143.

ABSTRACT

Protein-energy malnutrition still impacts children's growth and development. We investigated the prolonged effects of egg supplementation on growth and microbiota in primary school children. For this study, 8-14-year-old students (51.5% F) in six rural schools in Thailand were randomly assigned into three groups: (1) whole egg (WE), consuming 10 additional eggs/week (n = 238) (n = 238); (2) protein substitute (PS), consuming yolk-free egg substitutes equivalent to 10 eggs/week (n = 200); and (3) control group (C, (n = 197)). The outcomes were measured at week 0, 14, and 35. At the baseline, 17% of the students were underweight, 18% were stunted, and 13% were wasted. At week 35, compared to the C group the weight and height difference increased significantly in the WE group (3.6 ± 23.5 kg, p < 0.001; 5.1 ± 23.2 cm, p < 0.001). No significant differences in weight or height were observed between the PS and C groups. Significant decreases in atherogenic lipoproteins were observed in the WE, but not in PS group. HDL-cholesterol tended to increase in the WE group (0.02 ± 0.59 mmol/L, ns). The bacterial diversity was similar among the groups. The relative abundance of Bifidobacterium increased by 1.28-fold in the WE group compared to the baseline and differential abundance analysis which indicated that Lachnospira increased and Varibaculum decreased significantly. In conclusion, prolonged whole egg supplementation is an effective intervention to improve growth, nutritional biomarkers, and gut microbiota with unaltered adverse effects on blood lipoproteins.

PMID:36904143 | DOI:10.3390/nu15051143

Plants (Basel). 2023 Mar 2;12(5):1126. doi: 10.3390/plants12051126.

ABSTRACT

Changes in soil fungal communities caused by land use have not been sufficiently studied in South American Andosols, which are considered key food production areas. Since fungal communities play an important role in soil functionality, this study analysed 26 soil samples of Andosols collected from locations devoted to conservation, agriculture and mining activities in Antioquia, Colombia, to establish differences between fungal communities as indicators of soil biodiversity loss using Illumina MiSeq metabarcoding on nuclear ribosomal ITS2 region. A non-metric multidimensional scaling allowed to explore driver factors of changes in fungal communities, while the significance of these variations was assessed by PERMANOVA. Furthermore, the effect size of land use over relevant taxa was quantified. Our results suggest a good coverage of fungal diversity with a detection of 353,312 high-quality ITS2 sequences. We found strong correlations of Shannon and Fisher indexes with dissimilarities on fungal communities (r = 0.94). These correlations allow grouping soil samples according to land use. Variations in temperature, air humidity and organic matter content lead to changes in abundances of relevant orders (Wallemiales and Trichosporonales). The study highlights specific sensitivities of fungal biodiversity features in tropical Andosols, which may serve as a basis for robust assessments of soil quality in the region.

PMID:36903986 | DOI:10.3390/plants12051126

Plants (Basel). 2023 Mar 1;12(5):1111. doi: 10.3390/plants12051111.

ABSTRACT

In maize (Zea mays), fungal-elicited immune responses include the accumulation of terpene synthase (TPS) and cytochrome P450 monooxygenases (CYP) enzymes resulting in complex antibiotic arrays of sesquiterpenoids and diterpenoids, including α/β-selinene derivatives, zealexins, kauralexins and dolabralexins. To uncover additional antibiotic families, we conducted metabolic profiling of elicited stem tissues in mapping populations, which included B73 × M162W recombinant inbred lines and the Goodman diversity panel. Five candidate sesquiterpenoids associated with a chromosome 1 locus spanning the location of ZmTPS27 and ZmTPS8. Heterologous enzyme co-expression studies of ZmTPS27 in Nicotiana benthamiana resulted in geraniol production while ZmTPS8 yielded α-copaene, δ-cadinene and sesquiterpene alcohols consistent with epi-cubebol, cubebol, copan-3-ol and copaborneol matching the association mapping efforts. ZmTPS8 is an established multiproduct α-copaene synthase; however, ZmTPS8-derived sesquiterpene alcohols are rarely encountered in maize tissues. A genome wide association study further linked an unknown sesquiterpene acid to ZmTPS8 and combined ZmTPS8-ZmCYP71Z19 heterologous enzyme co-expression studies yielded the same product. To consider defensive roles for ZmTPS8, in vitro bioassays with cubebol demonstrated significant antifungal activity against both Fusarium graminearum and Aspergillus parasiticus. As a genetically variable biochemical trait, ZmTPS8 contributes to the cocktail of terpenoid antibiotics present following complex interactions between wounding and fungal elicitation.

PMID:36903970 | DOI:10.3390/plants12051111

Plants (Basel). 2023 Feb 23;12(5):1014. doi: 10.3390/plants12051014.

ABSTRACT

Invasive species employ competitive strategies such as releasing allelopathic chemicals into the environment that negatively impact native species. Decomposing Amur honeysuckle (Lonicera maackii) leaves leach various allelopathic phenolics into the soil, decreasing the vigor of several native species. Notable differences in the net negative impacts of L. maackii metabolites on target species were argued to depend on soil properties, the microbiome, the proximity to the allelochemical source, the allelochemical concentration, or environmental conditions. This study is the first to address the role of target species' metabolic properties in determining their net sensitivity to allelopathic inhibition by L. maackii. Gibberellic acid (GA3) is a critical regulator of seed germination and early development. We hypothesized that GA3 levels might affect the target sensitivity to allelopathic inhibitors and evaluated differences in the response of a standard (control, Rbr), a GA3-overproducing (ein), and a GA3-deficient (ros) Brassica rapa variety to L. maackii allelochemicals. Our results demonstrate that high GA3 concentrations substantially alleviate the inhibitory effects of L. maackii allelochemicals. A better understanding of the importance of target species' metabolic properties in their responses to allelochemicals will contribute to developing novel invasive species control and biodiversity conservation protocols and may contribute to applications in agriculture.

PMID:36903875 | DOI:10.3390/plants12051014

Plants (Basel). 2023 Feb 23;12(5):1013. doi: 10.3390/plants12051013.

ABSTRACT

Systemic acquired resistance (SAR) occurs when primary infected leaves produce several SAR-inducing chemical or mobile signals that are transported to uninfected distal parts via apoplastic or symplastic compartments and activate systemic immunity. The transport route of many chemicals associated with SAR is unknown. Recently, it was demonstrated that pathogen-infected cells preferentially transport salicylic acid (SA) through the apoplasts to uninfected areas. The pH gradient and deprotonation of SA may lead to apoplastic accumulation of SA before it accumulates in the cytosol following pathogen infection. Additionally, SA mobility over a long distance is essential for SAR, and transpiration controls the partitioning of SA into apoplasts and cuticles. On the other hand, glycerol-3-phosphate (G3P) and azelaic acid (AzA) travel via the plasmodesmata (PD) channel in the symplastic route. In this review, we discuss the role of SA as a mobile signal and the regulation of SA transport in SAR.

PMID:36903874 | DOI:10.3390/plants12051013

Nanomaterials (Basel). 2023 Mar 6;13(5):949. doi: 10.3390/nano13050949.

ABSTRACT

Magnetometers based on nitrogen-vacancy (NV) centers in diamonds have promising applications in fields of living systems biology, condensed matter physics, and industry. This paper proposes a portable and flexible all-fiber NV center vector magnetometer by using fibers to substitute all conventional spatial optical elements, realizing laser excitation and fluorescence collection of micro-diamond with multi-mode fibers simultaneously and efficiently. An optical model is established to investigate multi-mode fiber interrogation of micro-diamond to estimate the optical performance of NV center system. A new analysis method is proposed to extract the magnitude and direction of the magnetic field, combining the morphology of the micro-diamond, thus realizing μm-scale vector magnetic field detection at the tip of the fiber probe. Experimental testing shows our fabricated magnetometer has a sensitivity of 0.73 nT/Hz1/2, demonstrating its feasibility and performance in comparison with conventional confocal NV center magnetometers. This research presents a robust and compact magnetic endoscopy and remote-magnetic measurement approach, which will substantially promote the practical application of magnetometers based on NV centers.

PMID:36903827 | DOI:10.3390/nano13050949

Molecules. 2023 Mar 5;28(5):2384. doi: 10.3390/molecules28052384.

ABSTRACT

Tubulin isotypes are known to regulate microtubule stability and dynamics, as well as to play a role in the development of resistance to microtubule-targeted cancer drugs. Griseofulvin is known to disrupt cell microtubule dynamics and cause cell death in cancer cells through binding to tubulin protein at the taxol site. However, the detailed binding mode involved molecular interactions, and binding affinities with different human β-tubulin isotypes are not well understood. Here, the binding affinities of human β-tubulin isotypes with griseofulvin and its derivatives were investigated using molecular docking, molecular dynamics simulation, and binding energy calculations. Multiple sequence analysis shows that the amino acid sequences are different in the griseofulvin binding pocket of βI isotypes. However, no differences were observed at the griseofulvin binding pocket of other β-tubulin isotypes. Our molecular docking results show the favorable interaction and significant affinity of griseofulvin and its derivatives toward human β-tubulin isotypes. Further, molecular dynamics simulation results show the structural stability of most β-tubulin isotypes upon binding to the G1 derivative. Taxol is an effective drug in breast cancer, but resistance to it is known. Modern anticancer treatments use a combination of multiple drugs to alleviate the problem of cancer cells resistance to chemotherapy. Our study provides a significant understanding of the involved molecular interactions of griseofulvin and its derivatives with β-tubulin isotypes, which may help to design potent griseofulvin analogues for specific tubulin isotypes in multidrug-resistance cancer cells in future.

PMID:36903629 | DOI:10.3390/molecules28052384

Int J Mol Sci. 2023 Mar 3;24(5):4947. doi: 10.3390/ijms24054947.

ABSTRACT

The heterogeneity of lung tumor nodules is reflected in their phenotypic characteristics in radiological images. The radiogenomics field employs quantitative image features combined with transcriptome expression levels to understand tumor heterogeneity molecularly. Due to the different data acquisition techniques for imaging traits and genomic data, establishing meaningful connections poses a challenge. We analyzed 86 image features describing tumor characteristics (such as shape and texture) with the underlying transcriptome and post-transcriptome profiles of 22 lung cancer patients (median age 67.5 years, from 42 to 80 years) to unravel the molecular mechanisms behind tumor phenotypes. As a result, we were able to construct a radiogenomic association map (RAM) linking tumor morphology, shape, texture, and size with gene and miRNA signatures, as well as biological correlates of GO terms and pathways. These indicated possible dependencies between gene and miRNA expression and the evaluated image phenotypes. In particular, the gene ontology processes "regulation of signaling" and "cellular response to organic substance" were shown to be reflected in CT image phenotypes, exhibiting a distinct radiomic signature. Moreover, the gene regulatory networks involving the TFs TAL1, EZH2, and TGFBR2 could reflect how the texture of lung tumors is potentially formed. The combined visualization of transcriptomic and image features suggests that radiogenomic approaches could identify potential image biomarkers for underlying genetic variation, allowing a broader view of the heterogeneity of the tumors. Finally, the proposed methodology could also be adapted to other cancer types to expand our knowledge of the mechanistic interpretability of tumor phenotypes.

PMID:36902378 | DOI:10.3390/ijms24054947

Int J Mol Sci. 2023 Mar 2;24(5):4806. doi: 10.3390/ijms24054806.

ABSTRACT

Earlier studies aimed at investigating the metabolism of endogenous nucleoside triphosphates in synchronous cultures of E. coli cells revealed an auto-oscillatory mode of functioning of the pyrimidine and purine nucleotide biosynthesis system, which the authors associated with the dynamics of cell division. Theoretically, this system has an intrinsic oscillatory potential, since the dynamics of its functioning are controlled through feedback mechanisms. The question of whether the nucleotide biosynthesis system has its own oscillatory circuit is still open. To address this issue, an integral mathematical model of pyrimidine biosynthesis was developed, taking into account all experimentally verified negative feedback in the regulation of enzymatic reactions, the data of which were obtained under in vitro conditions. Analysis of the dynamic modes of the model functioning has shown that in the pyrimidine biosynthesis system, both the steady-state and oscillatory functioning modes can be realized under certain sets of kinetic parameters that fit in the physiological boundaries of the investigated metabolic system. It has been demonstrated that the occurrence of the oscillatory nature of metabolite synthesis depended on the ratio of two parameters: the Hill coefficient, hUMP1-the nonlinearity of the UMP effect on the activity of carbamoyl-phosphate synthetase, and the parameter r characterizing the contribution of the noncompetitive mechanism of UTP inhibition to the regulation of the enzymatic reaction of UMP phosphorylation. Thus, it has been theoretically shown that the E. coli pyrimidine biosynthesis system possesses its own oscillatory circuit whose oscillatory potential depends to a significant degree on the mechanism of regulation of UMP kinase activity.

PMID:36902235 | DOI:10.3390/ijms24054806