-
The Journal of Clinical Endocrinology... Jun 2024Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive,...
Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.
PubMed: 38941154
DOI: 10.1210/clinem/dgae412 -
Journal of Radiation Research Jun 2024The ionizing radiation with high linear energy transfer (LET), such as a heavy ion beam, induces more serious biological effects than low LET ones, such as gamma- and...
The ionizing radiation with high linear energy transfer (LET), such as a heavy ion beam, induces more serious biological effects than low LET ones, such as gamma- and X-rays. This indicates a difference in the DNA damage produced by low and high LET radiations and their biological effects. We have been studying the differences in DNA damage produced by gamma-rays and carbon ion beams. Therefore, we analyze mutations induced by both ionizing radiations to discuss the differences in their biological effects in this study. pUC19 plasmid DNA was irradiated by carbon ion beams in the solution containing 1M dimethyl sulfoxide to mimic a cellular condition. The irradiated DNA was cloned in competent cells of Escherichia coli. The clones harboring some mutations in the region of lacZα were selected, and the sequence alterations were analyzed. A one-deletion mutation is significant in the carbon-irradiated DNA, and the C:G↔T:A transition is minor. On the other hand, the gamma-irradiated DNA shows mainly G:C↔T:A transversion. These results suggest that carbon ion beams produce complex DNA damage, and gamma-rays are prone to single oxidative base damage, such as 8-oxoguanine. Carbon ion beams can also introduce oxidative base damage, and the damage species is 5-hydroxycytosine. This was consistent with our previous results of DNA damage caused by heavy ion beams. We confirmed the causal DNA damage by mass spectrometry for these mutations.
PubMed: 38940734
DOI: 10.1093/jrr/rrae050 -
MSystems Jun 2024Skin ulceration syndrome (SUS) is currently the main disease threatening aquaculture due to its higher mortality rate and infectivity, which is caused by . Our previous...
Skin ulceration syndrome (SUS) is currently the main disease threatening aquaculture due to its higher mortality rate and infectivity, which is caused by . Our previous studies have demonstrated that SUS is accompanied by intestinal microbiota (IM) dysbiosis, alteration of short-chain fatty acids (SCFAs) content and the damage to the intestinal barrier. However, the mediating effect of IM on intestine dysfunction is largely unknown. Herein, we conducted comprehensive intestinal microbiota transplantation (IMT) to explore the link between IM and SUS development. Furthermore, we isolated and identified a strain with an ability to produce acetic acid from both healthy individual and SUS individual with IM from healthy donors. We found that dysbiotic IM and intestinal barrier function in SUS recipients could be restored by IM from healthy donors. The strain could restore IM community and intestinal barrier function. Consistently, acetate supply also restores intestinal homeostasis of SUS-diseased and -infected . Mechanically, acetate was found to specifically bind to its receptor-free fatty acid receptor 2 (FFAR2) to mediate IM structure community and intestinal barrier function. Knockdown of FFAR2 by transfection of specific FFAR2 siRNA could hamper acetate-mediated intestinal homeostasis . Furthermore, we confirmed that acetate/FFAR2 could inhibit -activated NF-κB-MLCK-MLC signaling pathway to restore intestinal epithelium integrity and upregulated the expression of ZO-1 and Occludin. Our findings provide the first evidence that restores pathogen-induced intestinal barrier dysfunction via acetate/FFAR2-NF-κB-MLCK-MLC axis, which provides new insights into the control and prevention of SUS outbreak from an ecological perspective.IMPORTANCESkin ulceration syndrome (SUS) as a main disease in aquaculture has severely restricted the developmental aquaculture industry. Intestinal microbiota (IM) has been studied extensively due to its immunomodulatory properties. Short-chain fatty acids (SCFAs) as an essential signal molecule for microbial regulation of host health also have attracted wide attention. Therefore, it is beneficial to explore the link between IM and SUS for prevention and control of SUS. In the study, the contribution of IM to SUS development has been examined. Additionally, our research further validated the restoration of SCFAs on intestinal barrier dysfunction caused by SUS via isolating SCFAs-producing bacteria. Notably, this restoration might be achieved by inhibition of NF-κB-MLCK-MLC signal pathway, which could be activated by . These findings may have important implications for exploration of the role of IM in SUS occurrence and provide insight into the SUS treatment.
PubMed: 38940521
DOI: 10.1128/msystems.00602-24 -
The Journal of Clinical Endocrinology... Jun 2024Atypical parathyroid tumor (APT) represents a neoplasm characterized by histological features typical of parathyroid carcinoma (PC) but lacking local infiltration and/or...
CONTEXT
Atypical parathyroid tumor (APT) represents a neoplasm characterized by histological features typical of parathyroid carcinoma (PC) but lacking local infiltration and/or distant metastasis, leading to uncertainty regarding its malignant potential.
OBJECTIVE
To characterize the molecular landscape and deregulated pathways in APT.
METHODS
Whole exome sequencing (WES) was conducted on 16 APTs. DNA from tumors and matched peripheral blood underwent WES using Illumina HiSeq3000.
RESULTS
A total of 192 nonsynonymous variants were identified. The median number of protein-altering mutations was 9. The most frequently mutated genes included BCOR, CLMN, EZH1, JAM2, KRTAP13-3, MUC16, MUC19, and OR1S1. Seventeen mutated genes belong to the Cancer Gene Census list. The most consistent hub genes identified through STRING network analysis were ATM, COL4A5, EZH2, MED12, MEN1, MTOR, PI3, PIK3CA, PIK3CB, and UBR5. Deregulated pathways included the PI3 K/AKT/mTOR pathway, Wnt signaling, and extracellular matrix organization. Variants in genes such as MEN1, CDC73, EZH2, PIK3CA, and MTOR, previously reported as established or putative/candidate driver genes in benign adenoma (PA) and/or PC, were also identified in APT.
CONCLUSIONS
APT does not appear to have a specific molecular signature but shares genomic alterations with both PA and PC. The incidence of CDC73 mutations is low, and it remains unclear whether these mutations are associated with a higher risk of recurrence. Our study confirms that PI3 K/AKT/mTOR and Wnt signaling represents the pivotal pathways in parathyroid tumorigenesis and also revealed mutations in key epigenetic modifier genes (BCOR, KDM2A, MBD4, and EZH2) involved in chromatin remodeling, DNA, and histone methylation.
PubMed: 38940486
DOI: 10.1210/clinem/dgae441 -
Bioinformatics (Oxford, England) Jun 2024Phenotype-based drug screening emerges as a powerful approach for identifying compounds that actively interact with cells. Transcriptional and proteomic profiling of...
SUMMARY
Phenotype-based drug screening emerges as a powerful approach for identifying compounds that actively interact with cells. Transcriptional and proteomic profiling of cell lines and individual cells provide insights into the cellular state alterations that occur at the molecular level in response to external perturbations, such as drugs or genetic manipulations. In this paper, we propose cycleCDR, a novel deep learning framework to predict cellular response to external perturbations. We leverage the autoencoder to map the unperturbed cellular states to a latent space, in which we postulate the effects of drug perturbations on cellular states follow a linear additive model. Next, we introduce the cycle consistency constraints to ensure that unperturbed cellular state subjected to drug perturbation in the latent space would produces the perturbed cellular state through the decoder. Conversely, removal of perturbations from the perturbed cellular states can restore the unperturbed cellular state. The cycle consistency constraints and linear modeling in the latent space enable to learn transferable representations of external perturbations, so that our model can generalize well to unseen drugs during training stage. We validate our model on four different types of datasets, including bulk transcriptional responses, bulk proteomic responses, and single-cell transcriptional responses to drug/gene perturbations. The experimental results demonstrate that our model consistently outperforms existing state-of-the-art methods, indicating our method is highly versatile and applicable to a wide range of scenarios.
AVAILABILITY AND IMPLEMENTATION
The source code is available at: https://github.com/hliulab/cycleCDR.
Topics: Single-Cell Analysis; Humans; Deep Learning; Computational Biology; Proteomics
PubMed: 38940153
DOI: 10.1093/bioinformatics/btae248 -
Brain : a Journal of Neurology Jun 2024SCN2A gene-related early-infantile developmental and epileptic encephalopathy (EI-DEE) is a rare and severe disorder that manifests in early infancy. SCN2A mutations...
SCN2A gene-related early-infantile developmental and epileptic encephalopathy (EI-DEE) is a rare and severe disorder that manifests in early infancy. SCN2A mutations affecting the fast inactivation gating mechanism can result in altered voltage dependence and incomplete inactivation of the encoded neuronal Nav1.2 channel and lead to abnormal neuronal excitability. In this study, we evaluated clinical data of seven missense Nav1.2 variants associated with DEE and performed molecular dynamics simulations, patch-clamp electrophysiology, and dynamic clamp real-time neuronal modelling to elucidate the molecular and neuron-scale phenotypic consequences of the mutations. The N1662D mutation almost completely prevented fast inactivation without affecting activation. The comparison of wild-type and N1662D channel structures suggested that the ambifunctional hydrogen bond formation between residues N1662 and Q1494 is essential for fast inactivation. Fast inactivation could also be prevented with engineered Q1494A or Q1494L Nav1.2 channel variants, whereas Q1494E or Q1494 K variants resulted in incomplete inactivation and persistent current. Molecular dynamics simulations revealed a reduced affinity of the hydrophobic IFM-motif to its receptor site with N1662D and Q1494L variants relative to wild-type. These results demonstrate that the interactions between N1662 and Q1494 underpin the stability and the orientation of the inactivation gate and are essential for the development of fast inactivation. Six DEE-associated Nav1.2 variants, with mutations mapped to channel segments known to be implicated in fast inactivation were also evaluated. Remarkably, the L1657P variant also prevented fast inactivation and produced biophysical characteristics that were similar to those of N1662D, whereas the M1501 V, M1501T, F1651C, P1658S, and A1659 V variants resulted in biophysical properties that were consistent with gain-of-function and enhanced action potential firing of hybrid neurons in dynamic action potential clamp experiments. Paradoxically, low densities of N1662D or L1657P currents potentiated action potential firing, whereas increased densities resulted in sustained depolarization. Our results provide novel structural insights into the molecular mechanism of Nav1.2 channel fast inactivation and inform treatment strategies for SCN2A-related EI-DEE. The contribution of non-inactivating Nav1.2 channels to neuronal excitability may constitute a distinct cellular mechanism in the pathogenesis of SCN2A-related DEE.
PubMed: 38939966
DOI: 10.1093/brain/awae213 -
Frontiers in Plant Science 2024Precise semantic segmentation of microbial alterations is paramount for their evaluation and treatment. This study focuses on harnessing the SegFormer segmentation model...
INTRODUCTION
Precise semantic segmentation of microbial alterations is paramount for their evaluation and treatment. This study focuses on harnessing the SegFormer segmentation model for precise semantic segmentation of strawberry diseases, aiming to improve disease detection accuracy under natural acquisition conditions.
METHODS
Three distinct Mix Transformer encoders - MiT-B0, MiT-B3, and MiT-B5 - were thoroughly analyzed to enhance disease detection, targeting diseases such as Angular leaf spot, Anthracnose rot, Blossom blight, Gray mold, Leaf spot, Powdery mildew on fruit, and Powdery mildew on leaves. The dataset consisted of 2,450 raw images, expanded to 4,574 augmented images. The Segment Anything Model integrated into the Roboflow annotation tool facilitated efficient annotation and dataset preparation.
RESULTS
The results reveal that MiT-B0 demonstrates balanced but slightly overfitting behavior, MiT-B3 adapts rapidly with consistent training and validation performance, and MiT-B5 offers efficient learning with occasional fluctuations, providing robust performance. MiT-B3 and MiT-B5 consistently outperformed MiT-B0 across disease types, with MiT-B5 achieving the most precise segmentation in general.
DISCUSSION
The findings provide key insights for researchers to select the most suitable encoder for disease detection applications, propelling the field forward for further investigation. The success in strawberry disease analysis suggests potential for extending this approach to other crops and diseases, paving the way for future research and interdisciplinary collaboration.
PubMed: 38938642
DOI: 10.3389/fpls.2024.1352935 -
The New Phytologist Jun 2024Pollination presents a risky journey for pollen grains. Pollen loss is sometimes thought to favour greater pollen investment to compensate for the inefficiency of...
Pollination presents a risky journey for pollen grains. Pollen loss is sometimes thought to favour greater pollen investment to compensate for the inefficiency of transport. Sex allocation theory, to the contrary, has consistently concluded that postdispersal loss should have no selective effect on investment in either sex function. But the intuitively appealing compensation idea continues to be raised despite the lack of theoretical endorsement. We address the theoretical issue with a model that directly represents pollen loss (and ovule loss through floral demise or loss of receptivity) as rate-dependent dynamical processes. These loss rates can be varied to examine the effect of pollination efficiency on optimal sex allocation. Pollen-ovule ratios follow from the sex allocation based on the resource costs of pollen and ovule production. This model confirms conventional findings that pollen loss should have essentially no effect on sexual resource allocation in large, panmictic populations. Pollen limitation of seed set does not alter this conclusion. These results force us to rethink the empirical association of pollination efficiency with low pollen-ovule ratios. This pattern could arise if efficient pollen transport commonly results in stigmatic deposition of cohorts of related pollen. Empirical evidence of correlated paternity supports this explanation.
PubMed: 38937955
DOI: 10.1111/nph.19929 -
Journal of Ovarian Research Jun 2024Ovarian cancer (OC) is characterized by a high recurrence rate, and homologous recombination deficiency (HRD) is an important biomarker in the clinical management of OC....
PURPOSE
Ovarian cancer (OC) is characterized by a high recurrence rate, and homologous recombination deficiency (HRD) is an important biomarker in the clinical management of OC. We investigated the differences in clinical genomic profiles between the primary and platinum-sensitive recurrent OC (PSROC), focusing on HRD status.
MATERIALS AND METHODS
A total of 40 formalin-fixed paraffin-embedded (FFPE) tissues of primary tumors and their first platinum-sensitive recurrence from 20 OC patients were collected, and comprehensive genomic profiling (CGP) analysis of FoundationOneCDx (F1CDx) was applied to explore the genetic (dis)similarities of the primary and recurrent tumors.
RESULTS
By comparing between paired samples, we found that genomic loss of heterozygosity (gLOH) score had a high intra-patient correlation (r = 0.79) and that short variants (including TP53, BRCA1/2 and NOTCH1 mutations), tumor mutational burden (TMB) and microsatellite stability status remained stable. The frequency of (likely) pathological BRCA1/2 mutations was 30% (12/40) in all samples positively correlated with gLOH scores, but the proportion of gLOH-high status (score > 16%) was 50% (10/20) and 55% (11/20) in the primary and recurrent samples, respectively. An additional 20% (4/20) of patients needed attention, a quarter of which carried the pathological BRCA1 mutation but had a gLOH-low status (gLOH < 16%), and three-quarters had different gLOH status in primary-recurrent pairs. Furthermore, we observed the PSROC samples had higher gLOH scores (16.1 ± 9.24 vs. 19.4 ± 11.1, p = 0.007), more CNVs (36.1% vs. 15.1% of discordant genomic alternations), and significant enrichment of altered genes in TGF-beta signaling and Hippo signaling pathways (p < 0.05 for all) than their paired primaries. Lastly, mutational signature and oncodrive gene analyses showed that the computed mutational signature similarity in the primary and recurrent tumors were best matched the COSMI 3 signature (Aetiology of HRD) and had consistent candidate cancer driver genes of MSH2, NOTCH1 and MSH6.
CONCLUSION
The high genetic concordance of the short variants remains stable along OC recurrence. However, the results reveal significantly higher gLOH scores in the recurrent setting than in paired primaries, supporting further clinically instantaneity HRD assay strategy.
Topics: Humans; Female; Ovarian Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Genomics; Aged; Mutation; Loss of Heterozygosity; Adult; Biomarkers, Tumor; Gene Expression Profiling
PubMed: 38937827
DOI: 10.1186/s13048-024-01455-8 -
Toxicology Mechanisms and Methods Jun 2024Cyclosporine A (CsA) has shown efficacy against immunity-related diseases despite its toxicity in various organs, including the liver, emphasizing the need to elucidate...
Cyclosporine A (CsA) has shown efficacy against immunity-related diseases despite its toxicity in various organs, including the liver, emphasizing the need to elucidate its underlying hepatotoxicity mechanism. This study aimed to capture the alterations in genome-wide expression over time and the subsequent perturbations of corresponding pathways across species. Six data from humans, mice, and rats, including animal liver tissue, human liver microtissues, and two liver cell lines exposed to CsA toxic dose, were used. The microtissue exposed to CsA for 10 d was analyzed to obtain dynamically differentially expressed genes (DEGs). Single-time points data at 1, 3, 5, 7, and 28 d of different species were used to provide additional evidence. Using liver microtissue-based longitudinal design, DEGs that were consistently up- or down-regulated over time were captured, and the well-known mechanism involved in CsA toxicity was elucidated. Thirty DEGs that consistently changed in longitudinal data were also altered in 28-d rat in-house data with concordant expression. Some genes (e.g. , , ) showed good concordance with identified DEGs in 1-d and 7-d mouse data. Pathway analysis revealed up-regulations of protein processing, asparagine N-linked glycosylation, and cargo concentration in the endoplasmic reticulum. Furthermore, the down-regulations of pathways related to biological oxidations and metabolite and lipid metabolism were elucidated. These pathways were also enriched in single-time-point data and conserved across species, implying their biological significance and generalizability. Overall, the human organoids-based longitudinal design coupled with cross-species validation provides temporal molecular change tracking, aiding mechanistic elucidation and biologically relevant biomarker discovery.
PubMed: 38937256
DOI: 10.1080/15376516.2024.2371894