Morphological Alterations Research Articles

Chemoarchitectural signatures of subcortical shape alterations in generalized epilepsy

Genetic generalized epilepsies (GGE) exhibit widespread morphometric alterations in the subcortical structures. Subcortical structures are essential for understanding GGE pathophysiology, but their fine-grained morphological diversity has yet to be comprehensively investigated. Furthermore, the relationships between macroscale morphological disturbances and microscale molecular chemoarchitectures are unclear. High-resolution structural images were acquired from patients with GGE (n = 97) and sex- and age-matched healthy controls (HCs, n = 184). Individual measurements of surface shape features (thickness and surface area) of seven bilateral subcortical structures were quantified. The patients and HCs were then compared vertex-wise, and shape anomalies were co-located with brain neurotransmitter profiles. We found widespread morphological alterations in GGE and prominent disruptions in the thalamus, putamen, and hippocampus. Shape area dilations were observed in the bilateral ventral, medial, and right dorsal thalamus, as well as the bilateral lateral putamen. We found that the shape area deviation pattern was spatially correlated with the norepinephrine transporter and nicotinic acetylcholine (Ach) receptor (α4β2) profiles, but a distinct association was seen in the muscarinic Ach receptor (M1). The findings provided a comprehensive picture of subcortical morphological disruptions in GGE, and further characterized the associated molecular mechanisms. This information may increase our understanding of the pathophysiology of GGE.

Morphological changes in flatfoot: a 3D analysis using weight-bearing CT scans

BackgroundFlatfoot is a condition resulting from complex three-dimensional (3D) morphological changes. Most Previous studies have been constrained by using two-dimensional radiographs and non-weight-bearing conditions. The deformity in flatfoot is associated with the 3D morphology of the bone. These morphological changes affect the force line conduction of the hindfoot/midfoot/forefoot, leading to further morphological alterations. Given that a two-dimensional plane axis overlooks the 3D structural information, it is essential to measure the 3D model of the entire foot in conjunction with the definition under the standing position. This study aims to analyze the morphological changes in flatfoot using 3D measurements from weight-bearing CT (WBCT).MethodIn this retrospective comparative our CT database was searched between 4–2021 and 3–2022. Following inclusion criteria were used: Patients were required to exhibit clinical symptoms suggestive of flatfoot, including painful swelling of the medial plantar area or abnormal gait, corroborated by clinical examination and confirmatory radiological findings on CT or MRI. Healthy participants were required to be free of any foot diseases or conditions affecting lower limb movement. After applying the exclusion criteria (Flatfoot with other foot diseases), CT scans (mean age = 20.9375, SD = 16.1) confirmed eligible for further analysis. The distance, angle in sagittal/transverse/coronal planes, and volume of the two groups were compared on reconstructed 3D models using the t-test. Logistic regression was used to identify flatfoot risk factors, which were then analyzed using receiver operating characteristic curves and nomogram.ResultThe flatfoot group exhibited significantly lower values for calcaneofibular distance (p = 0.001), sagittal and transverse calcaneal inclination angle (p < 0.001), medial column height (p < 0.001), sagittal talonavicular coverage angle (p < 0.001), and sagittal (p < 0.001) and transverse (p = 0.015) Hibb angle. In contrast, the sagittal lateral talocalcaneal angle (p = 0.013), sagittal (p < 0.001) and transverse (p = 0.004) talocalcaneal angle, transverse talonavicular coverage angle (p < 0.001), coronal Hibb angle (p < 0.001), and sagittal (p < 0.001) and transverse (p = 0.001) Meary’s angle were significantly higher in the flatfoot group. The sagittal Hibb angle (B = − 0.379, OR = 0.684) and medial column height (B = − 0.990, OR = 0.372) were identified as significant risk factors for acquiring a flatfoot.ConclusionThe findings validate the 3D spatial position alterations in flatfoot. These include the abduction of the forefoot and prolapse of the first metatarsal proximal, the arch collapsed, subluxation of the talonavicular joint in the midfoot, adduction and valgus of the calcaneus, adduction and plantar ward movement of the talus in the hindfoot, along with the first metatarsal’s abduction and dorsiflexion in the forefoot.

Impaired vascular function among young users of anabolic–androgenic steroids

Supraphysiological doses of anabolic–androgenic steroids (AAS) is popular among recreational weightlifters and bodybuilders due to the performance-enhancing properties but is also associated with adverse cardiovascular effects. The knowledge about how AAS affect the vasculature is limited, although results from previous studies suggest alterations in vasoreactivity and morphology. In the present study we investigate the association between long-term use of AAS and vascular function. Hundred and twenty-three males were included in the study, 56 of them current AAS users and 67 weightlifting controls. Vascular function was evaluated by carotid artery reactivity and flow-mediated dilation. AAS users had significantly reduced carotid artery reactivity (p < 0.001) and flow-mediated dilation (p < 0.001) compared to weightlifting controls. Results from the present study indicate that long-term use of AAS affect the cardiovascular system negatively, measured as reduced carotid artery reactivity and flow-mediated dilation. These findings could partly explain sudden cardiovascular events among young long-term users of AAS.

Cyclase-associated protein (CAP) inhibits inverted formin 2 (INF2) to induce dendritic spine maturation

The morphology of dendritic spines, the postsynaptic compartment of most excitatory synapses, decisively modulates the function of neuronal circuits as also evident from human brain disorders associated with altered spine density or morphology. Actin filaments (F-actin) form the backbone of spines, and a number of actin-binding proteins (ABP) have been implicated in shaping the cytoskeleton in mature spines. Instead, only little is known about the mechanisms that control the reorganization from unbranched F-actin of immature spines to the complex, highly branched cytoskeleton of mature spines. Here, we demonstrate impaired spine maturation in hippocampal neurons upon genetic inactivation of cyclase-associated protein 1 (CAP1) and CAP2, but not of CAP1 or CAP2 alone. We found a similar spine maturation defect upon overactivation of inverted formin 2 (INF2), a nucleator of unbranched F-actin with hitherto unknown synaptic function. While INF2 overactivation failed in altering spine density or morphology in CAP-deficient neurons, INF2 inactivation largely rescued their spine defects. From our data we conclude that CAPs inhibit INF2 to induce spine maturation. Since we previously showed that CAPs promote cofilin1-mediated cytoskeletal remodeling in mature spines, we identified them as a molecular switch that control transition from filopodia-like to mature spines.

Monotropein mitigates methotrexate-induced liver injury by activating autophagy and inhibiting ferroptosis

Methotrexate (MTX) is effective for the therapy of cancer, lupus erythematosus, rheumatoid arthritis, psoriasis and other diseases. However, the hepatotoxicity of MTX often leads to withdrawal and discontinuation of drugs, and then limits its clinical application. Monotropein (MON), an iridoid glycosides distributing in many edible and medicinal plants, has been exhibited to prevent liver and kedney injury induced by chemicals and related diseases. The current study aimed to assess the potential beneficial effects of MON in mitigating MTX-induced liver injury together with delineating the implicated mechanisms. A MTX-induced liver injury model in mice and BRL 3A cells were developed to explore the hepatoprotection of MON. GEO and WGCNA analysis were conducted to predict the possible mechanism of MTX on liver injury. The results demonstrated that MON can decrease the serum levels of AST and ALT, increase the activities of antioxidant SOD and GSH, and improve the morphological alteration of liver tissue, and reduce the accumulation of lipids in hepatocytes and liver tissue of mice treated with MTX. Moreover, our results also exhibited that MON can activate autophagy as assessed by autophagosome formation, expression of protein related with autophagy, and inhibit ferroptosis as evaluated by mitochondrial integrity, Fe2+level and key protein expression changes, and CQ (inhibitor of autophagy) and RSL-3 (the activator of ferroptosis) reversed the effects of MON on autophagy and ferroptosis of hepatocytes injured by MTX. Therefore, MON attenuates liver injury of MTX by activating autophagy and inhibiting ferroptosis. These findings provide new insights into MON as a potential healthy ingredient in functional food.

Characteristics of inhibition of Aspergillus flavus growth and degradation of aflatoxin B1 by cell-free fermentation supernatant of Bacillus velezensis 906

Aflatoxin, a harmful secondary metabolite produced by Aspergillus flavus and Aspergillus parasiticus, poses a significant risk to human health and food safety. Therefore, the development of safe and environmentally friendly techniques for controlling A. flavus and its aflatoxin production is imperative. In this study, Bacillus velezensis 906 cell-free fermentation supernatant (CFS) inhibited the germination of A. flavus spores and mycelium growth. Scanning electron microscopy and fluorescence microscopy revealed that CFS altered cell morphology and damaged the cell membrane of A. flavus leading to cell death. Fourier transform infrared spectroscopy indicated changes in the functional groups of A. flavus filaments treated with CFS. The trend in ergosterol content demonstrated that CFS effectively inhibited the normal growth of A. flavus cell membranes. The CFS exhibited remarkable efficacy in degrading aflatoxin B1 (AFB1), achieving a degradation rate of up to 60% after 48 h of interaction. The addition of 0.2 mg/mL Cu2+ or Fe3+ metal ions to CFS significantly increased the degradation rate of AFB1 up to 90%. Furthermore, the analysis indicated that the active components responsible for AFB1 degradation might be heat-resistance and exhibit resistance to protease K. These findings underscore the potential of CFS as a green, safe, and economically viable strategy for controlling aflatoxin production by A. flavus, offering promising prospects for mitigating mold contamination in food and feed applications.

Modeling gastric intestinal metaplasia in 3D organoids using nitrosoguanidine.

Gastric intestinal metaplasia (GIM) represents a precancerous stage characterized by morphological and pathophysiological changes in the gastric mucosa, where gastric epithelial cells transform into a phenotype resembling that of intestinal cells. Previous studies have demonstrated that the intragastric administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces both gastric carcinoma and intestinal metaplasia in mice. Here, we show that MNNG induces GIM in three-dimensional (3D) mouse organoids. Our histological analyses reveal that MNNG-induced gastric organoids undergo classical morphological alterations, exhibiting a distinct up-regulation of CDX2 and MUC2, along with a down-regulation of ATP4B and MUC6. Importantly, metaplastic cells observed in MNNG-treated organoids originate from MIST1+ cells, indicating their gastric chief cell lineage. Functional analyses show that activation of the RAS signaling pathway drives MNNG-induced metaplasia in 3D organoids, mirroring the characteristics observed in human GIM. Consequently, modeling intestinal metaplasia using 3D organoids offers valuable insights into the molecular mechanisms and spatiotemporal dynamics of the gastric epithelial lineage during the development of intestinal metaplasia within the gastric mucosa. We conclude that the MNNG-induced metaplasia model utilizing 3D organoids provides a robust platform for developing preventive and therapeutic strategies to mitigate the risk of gastric cancer before precancerous lesions occur.

Laser ignition on single droplet characteristics of aviation kerosene at different pressures and initial diameters: ignition, combustion and micro-explosion

In this study, an experimental system for single-droplet ignition by laser under different pressures is established, and the laser ignition is used to examine how pressure and initial diameter influence ignition properties of RP-3 aviation kerosene single-droplet. The findings reveal that depending on the extent of the impact of bubble rupture on the droplet's shape, The droplet's morphological alterations can be classified into three types: micro-expansion, puffing, and micro-explosion. The ignition and combustion of droplets is segmented into four distinct phases: heating, ignition, intense combustion, boiling combustion. The flame width diminishes with rising pressure. Single droplet ignition delay time is strongly influenced by the pressure, which is reduced by 92.7 %, 94.1 % and 94.3 % for the three droplets from small to large diameters with the pressure increases from 1 bar to 4 bar. The change trends of droplet diameters are first increasing and then decreasing. The whole burning rate of RP-3 droplets goes up with the rise of pressure. A droplet laser ignition model is proposed, the minimum ignition energy of RP-3 droplets with an initial diameter of 1.42 mm at pressures of 1–4 bar are obtained to be 0.88 J, 0.80 J, 0.68 J, and 0.59 J, respectively.

Investigating the role of allelochemicals in the interaction between Alexandrium monilatum and other phytoplankton species

Species of the dinoflagellate genus Alexandrium can release bioactive extracellular compounds with allelopathic effects (e.g., immobilization, inhibition of growth, photosynthesis or lysis) towards other phytoplanktonic organisms. In the lower Chesapeake Bay, Virginia, US, succession or co-occurrence of blooms of Akashiwo sanguinea, Margalefidinium polykrikoides and the goniodomin-producing A. monilatum tend to be common during summer months, however the allelopathic potential of A. monilatum, and how it may affect bloom dynamics, has not be studied. We used a rapid fluorescence-based bioassay as well as flow cytometry and an assessment of immobilization to determine the potential effects of A. monilatum culture supernatants on M. polykrikoides, A. sanguinea and the diatom Chaetoceros muelleri (included as a reference strain). In addition, we also investigated the effects of standards of known A. monilatum toxins goniodomin A (GDA) and GDA seco-acid (GDA-sa). Exposure of C. muelleri to culture supernatants from two different strains of A. monilatum resulted in an inhibition of the maximum quantum yield of the photosystem II (Fv/Fm) and cell lysis of the diatom, with strain-specific variation observed, highlighted by a 30-fold difference in the effective concentration resulting in 10 % inhibition (EC10) and 2-fold difference in the lethal concentration resulting in 50 % mortality (LC50) between the two A. monilatum strains tested. Exposure of M. polykrikoides to A. monilatum culture supernatants resulted in a decrease in motility (at ≥ 500 eq. cells mL-1) along with a decrease in Fv/Fm (at ≥ 1,500 cells mL-1) and altered cellular morphology (at ≥ 3,500 eq. cells mL-1). No effect was observed when A. sanguinea was exposed to A. monilatum culture supernatants (at the concentrations tested in these studies). When M. polykrikoides was exposed to the GDA standard, its Fv/Fm (at ≥ 1,951 nM) and motility (at ≥ 390 nM) decreased, and its morphology (at ≥ 975 nM) was modified. The study of supernatant time- and temperature-stability, and the absence of a relationship between observed effects and goniodomin concentrations suggested the presence of additional unknown allelochemicals distinct from goniodomins, as has been observed for other Alexandrium species. Immobilization of M. polykrikoides by A. monilatum culture supernatants and GDA standard in laboratory-based exposure experiments may indicate that A. monilatum has a competitive advantage when both species co-occur in the Chesapeake Bay and this warrants further testing.

Hebbian instruction of axonal connectivity by endogenous correlated spontaneous activity.

Spontaneous activity refines neural connectivity prior to the onset of sensory experience, but it remains unclear how such activity instructs axonal connectivity with subcellular precision. We simultaneously measured spontaneous retinal waves and the activity of individual retinocollicular axons and tracked morphological changes in axonal arbors across hours in vivo in neonatal mice. We demonstrate that the correlation of an axon branch's activity with neighboring axons or postsynaptic neurons predicts whether the branch will be added, stabilized, or eliminated. Desynchronizing individual axons from their local networks, changing the pattern of correlated activity, or blocking N-methyl-d-aspartate receptors all significantly altered single-axon morphology. These observations provide the first direct evidence in vivo that endogenous patterns of correlated neuronal activity instruct fine-scale refinement of axonal processes.

Copper overload exacerbates testicular aging mediated by lncRNA:CR43306 deficiency through ferroptosis in Drosophila

Testicular aging manifests as impaired spermatogenesis and morphological alterations in Drosophila. Nonetheless, the comprehensive molecular regulatory framework remains largely undisclosed. This investigation illustrates the impact of copper overload on testicular aging and underscores the interplay between copper overload and lncRNA. Copper overload triggers Cuproptosis through the mitochondrial TCA cycle, facilitating intracellular interactions with Ferroptosis, thereby governing testicular aging. Dysfunction of lncRNA:CR43306 also contributes to testicular aging in Drosophila, emphasizing the significance of lncRNA:CR43306 as a novel aging-associated lncRNA. Moreover, copper overload exacerbates spermatid differentiation defects mediated by lncRNA:CR43306 deficiency through oxidative stress, copper, and iron transport. Therapeutically, Ferrostatin-1 and Resveratrol emerge as potential remedies for addressing testicular aging. This study offers perspectives on the regulatory mechanisms involving copper overload and lncRNA:CR43306 deficiency in the context of testicular aging.

Meldonium, as a potential neuroprotective agent, promotes neuronal survival by protecting mitochondria in cerebral ischemia–reperfusion injury

BackgroundStroke is a globally dangerous disease capable of causing irreversible neuronal damage with limited therapeutic options. Meldonium, an inhibitor of carnitine-dependent metabolism, is considered an anti-ischemic drug. However, the mechanisms through which meldonium improves ischemic injury and its potential to protect neurons remain largely unknown.MethodsA rat model with middle cerebral artery occlusion (MCAO) was used to investigate meldonium’s neuroprotective efficacy in vivo. Infarct volume, neurological deficit score, histopathology, neuronal apoptosis, motor function, morphological alteration and antioxidant capacity were explored via 2,3,5-Triphenyltetrazolium chloride staining, Longa scoring method, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, rotarod test, transmission electron microscopy and Oxidative stress index related kit. A primary rat hippocampal neuron model subjected to oxygen–glucose deprivation reperfusion was used to study meldonium’s protective ability in vitro. Neuronal viability, mitochondrial membrane potential, mitochondrial morphology, respiratory function, ATP production, and its potential mechanism were assayed by MTT cell proliferation and cytotoxicity assay kit, cell-permeant MitoTracker® probes, mitochondrial stress, real-time ATP rate and western blotting.ResultsMeldonium markedly reduced the infarct size, improved neurological function and motor ability, and inhibited neuronal apoptosis in vivo. Meldonium enhanced the morphology, antioxidant capacity, and ATP production of mitochondria and inhibited the opening of the mitochondrial permeability transition pore in the cerebral cortex and hippocampus during cerebral ischemia–reperfusion injury (CIRI) in rats. Additionally, meldonium improved the damaged fusion process and respiratory function of neuronal mitochondria in vitro. Further investigation revealed that meldonium activated the Akt/GSK-3β signaling pathway to inhibit mitochondria-dependent neuronal apoptosis.ConclusionOur study demonstrated that meldonium shows a neuroprotective function during CIRI by preserving the mitochondrial function, thus prevented neurons from apoptosis.

Effects on anorectal function of endoscopic submucosal dissection for rectal tumors involving the dentate line.

Endoscopic submucosal dissection (ESD) is a specific procedure that uses an electrosurgical knife for en-bloc resectioning large tumors. However, no study has examined the effect of ESD on the defecation function of patients with rectal tumors. We aimed to investigate the potential effects caused by ESD by analyzing changes in the morphology and movement of the anorectum pre- and post-ESD. This prospective observational study included 11 patients with anorectal tumors who underwent ESD between April 2020 and February 2022. Pre-ESD assessments included anorectal manometry and defecography. Post-ESD assessments were conducted 2 months later, including anorectal manometry, defecography, and proctoscopy for ulcer and stenosis evaluation. The median patient age was 73 years, including seven males and four females. Eight patients (73%) had a tumor in the lower rectum, and the extent of resection was less than 50% of the rectal lumen. Resection reached the dentate line in six cases (55%). In the patients with post-ESD mucosal defects involving the dentate line, the median of functional anal canal length significantly decreased from (3.4 cm pre-ESD to 2.8 cm post-ESD, p = 0.04). Defecography revealed one case with incomplete evacuation (<50%) and incontinence post-ESD. Interestingly, patients with pre-existing rectoceles noted resolution of lesions post-ESD. None of the patients reported daily constipation or fecal incontinence. While rectal ESD is unlikely to cause significant real-world defecation difficulties, alterations in rectal and anal canal morphology and function may occur if the dentate line is involved in the resection range.

Dexamethasone induces trabecular meshwork cell myofibroblast transdifferentiation through ARHGEF26.

Glucocorticoid use may cause elevated intraocular pressure, leading to the development of glucocorticoid-induced glaucoma (GIG). However, the mechanism of GIG development remains incompletely understood. In this study, we subjected primary human trabecular meshwork cells (TMCs) and mice to dexamethasone treatment to mimic glucocorticoid exposure. The myofibroblast transdifferentiation of TMCs was observed in cellular and mouse models, as well as in human trabecular mesh specimens. This was demonstrated by the cytoskeletal reorganization, alterations in cell morphology, heightened transdifferentiation markers, increased extracellular matrix deposition, and cellular dysfunction. Knockdown of Rho guanine nucleotide exchange factor 26 (ARHGEF26) expression ameliorated dexamethasone-induced changes in cell morphology and upregulation of myofibroblast markers, reversed dysfunction and extracellular matrix deposition in TMCs, and prevented the development of dexamethasone-induced intraocular hypertension. And, this process may be related to the TGF-β pathway. In conclusion, glucocorticoids induced the myofibroblast transdifferentiation in TMCs, which played a crucial role in the pathogenesis of GIG. Inhibition of ARHGEF26 expression protected TMCs by reversing myofibroblast transdifferentiation. This study demonstrated the potential of reversing the myofibroblast transdifferentiation of TMCs as a new target for treating GIG.

Impact of Nanoplastic Particles on Macrophage Inflammation and Intestinal Health in a Mouse Model of Inflammatory Bowel Disease.

The increasing presence of plastics in the human diet is raising public concern about the potential risks posed by nanoplastic (NP) particles, which can emerge from the degradation of plastic debris. NP ingestion poses particular risks to individuals with inflammatory bowel disease (IBD), as compromised epithelial barriers may facilitate NP translocation. In vitro, bone-marrow-derived macrophages (BMDMs) were exposed to 25 nm polymethacrylate (PMMA) or 50 nm polystyrene (PS) particles to assess morphological changes and alterations in pro- and anti-inflammatory gene expression. In vivo, mice received PMMA NP particles for 6 months before acute dextran sodium sulfate (DSS) colitis was induced to investigate NP impacts on intestinal health and inflammation. PMMA and PS NP exposure in BMDMs induced morphological changes indicative of a proinflammatory phenotype characterized by enlarged amoeboid cell shapes. It also triggered an inflammatory response, indicated by increased expression of proinflammatory cytokines such as Tnfa and Il6. Unexpectedly, long-term PMMA NP administration did not affect the intestinal epithelial barrier or exacerbate acute DSS-induced colitis in mice. Colonoscopy and histological analysis revealed no NP-related changes, suggesting adverse effects on intestinal health or inflammation. Our findings from animal models offer some reassurance to IBD patients regarding the effects of NP ingestion. However, variations in lifestyle and dietary habits may lead to significantly higher plastic intake in certain individuals, raising concerns about potential long-term gastrointestinal effects of lifelong plastic consumption.

Influence of collagen peptide supplementation on visible signs of skin and nail health and -aging in an East Asian population: A double blind, randomized, placebo-controlled trial.

A healthy skin provides protection against intrinsic and extrinsic factors. Skin aging is characterized by structural and morphological alterations affecting skin health, integrity, and functionality, resulting in visible aging signs. The primary objective of this study was to assess the effect of a collagen peptide dietary supplement on skin aging in the East Asian population. Eighty-five healthy women, aged from 43 to 65 years old, were randomly assigned to the collagen supplement (CP, 5 g) or placebo (maltodextrin, 5 g) group. To standardize daily skin care, the volunteers in both groups used a specific face cream for 28 days prior to and throughout the supplementation period, creating an equal baseline for the assessment of the efficacy of CP on several skin parameters. At baseline, day 28 and day 84, the following hallmarks of skin and nail aging were assessed: dermis density, skin moisture and elasticity, wrinkle visibility, beauty perception, and nail color. After 84 days, a significant improvement of dermis density and skin moisture was observed in the collagen peptides group compared to the placebo group. Positive effects on skin elasticity, wrinkle visibility, nail color, and overall beauty perception were already observed within 28 days of supplementation in the CP group, while the same effects in the placebo group were only observed after 84 days. Taken together, these results show that, in addition to a standardized skin care, daily supplementation with 5 g of collagen peptides positively affects visible signs of skin and nail aging in the East Asian population.

Delving into the Complexity of Valproate-Induced Autism Spectrum Disorder: The Use of Zebrafish Models.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition with several identified risk factors, both genetic and non-genetic. Among these, prenatal exposure to valproic acid (VPA) has been extensively associated with the development of the disorder. The zebrafish, a cost- and time-effective model, is useful for studying ASD features. Using validated VPA-induced ASD zebrafish models, we aimed to provide new insights into VPA exposure effects during embryonic development and to identify new potential biomarkers associated with ASD-like features. Dose-response analyses were performed in vivo to study larval phenotypes and mechanisms underlying neuroinflammation, mitochondrial dysfunction, oxidative stress, microglial cell status, and motor behaviour. Wild-type and transgenic Tg(mpeg1:EGFP) zebrafish were water-exposed to VPA doses (5 to 500 µM) from 6 to 120 h post-fertilisation (hpf). Embryos and larvae were monitored daily to assess survival and hatching rates, and numerous analyses and tests were conducted from 24 to 120 hpf. VPA doses higher than 50 µM worsened survival and hatching rates, while doses of 25 µM or more altered morphology, microglial status, and larval behaviours. VPA 50 µM also affected mRNA expression of inflammatory cytokines and neurogenesis-related genes, mitochondrial respiration, and reactive oxygen species accumulation. The study confirmed that VPA alters brain homeostasis, synaptic interconnections, and neurogenesis-related signalling pathways, contributing to ASD aetiopathogenesis. Further studies are essential to identify novel ASD biomarkers for developing new drug targets and tailored therapeutic interventions for ASD.

Deep Neural Network Integrated into Network-Based Stratification (D3NS): A Method to Uncover Cancer Subtypes from Somatic Mutations.

(1) Background: The identification of tumor subtypes is fundamental in precision medicine for accurate diagnoses and personalized therapies. Cancer development is often driven by the accumulation of somatic mutations that can cause alterations in tissue functions and morphologies. In this work, a method based on a deep neural network integrated into a network-based stratification framework (D3NS) is proposed to stratify tumors according to somatic mutations. (2) Methods: This approach leverages the power of deep neural networks to detect hidden information in the data by combining the knowledge contained in a network of gene interactions, as typical of network-based stratification methods. D3NS was applied using real-world data from The Cancer Genome Atlas for bladder, ovarian, and kidney cancers. (3) Results: This technique allows for the identification of tumor subtypes characterized by different survival rates and significant associations with several clinical outcomes (tumor stage, grade or response to therapy). (4) Conclusion: D3NS can provide a base model in cancer research and could be considered as a useful tool for tumor stratification, offering potential support in clinical settings.

Exposure to Gynura japonica (Thunb.) Juel plants induces hepatoxicity in rats and Buffalo rat liver cells

Ethnopharmacological relevanceGynura japonica (Thunb.) Juel is often confused with the non-pyrrolizidine alkaloid-producing herbs, Tu-San-Qi (Sedum aizoon L.) and San-Qi (Panax notoginseng L.), due to similarities in name, appearance, and medicinal use. It contains pyrrolizidine alkaloids, which cause over 50% of cases of hepatic sinus obstruction syndrome. However, the mechanisms underlying G. japonica-induced hepatotoxicity remain poorly understood. Aim of the studyIn this study, we aimed to investigate the toxic effects of a G. japonica decoction on liver and Buffalo rat liver (BRL) cells and elucidate the associated mechanisms. Materials and methodsThis study employed G. japonica decoction and examined its effects on liver function and tissue damage in Sprague–Dawley rats. Bioinformatics analysis was employed to identify gene expression and enriched pathways related to hepatotoxicity. Laser scanning confocal microscopy and flow cytometric annexin V/PI labeling assays were utilized to observe apoptosis in BRL cells induced by G. japonica. Transmission electron microscopy and JC-1 staining were used to determine the effects of G. japonica on mitochondrial ultrastructure and membrane potential in BRL cells. The bicinchoninic acid method and enzyme-linked immunosorbent assays were used to detect the expression of apoptosis-related proteins and caspase-3 activity, respectively. ResultsComparisons of body weight, liver histopathology, and serum liver function-related indices in rats, t showed that exposure to G. japonica may cause liver damage. Bioinformatics analysis indicated that hepatotoxicity might be related to apoptotic signaling pathways, the positive regulation of programmed cell death, and responses to toxic substances. BRL cells exposed to the G. japonica decoction exhibited mid-to late-stage apoptosis and necrosis, along with alterations in mitochondrial morphology and membrane potential. Furthermore, expression of cytochrome C (Cyt C) and pro-apoptotic proteins was increased, anti-apoptotic proteins decreased, and caspase-3 activity elevated. ConclusionsThese findings indicate that G. japonica-induced hepatotoxicity involves the activation of mitochondria-mediated apoptosis. Our research enhances the scientific and theoretical foundation for clinical therapy and improves public awareness of the potential toxicity of herbal remedies.

Impaired Glucose Metabolism, Primary Cilium Defects, and Kidney Cystogenesis in Glycogen Storage Disease Type Ia.

Glycogen Storage Disease type Ia (GSDIa) is a rare metabolic disorder caused by mutations in the catalytic subunit of glucose-6 phosphatase (G6PC1). This leads to severe hypoglycemia and most young GSDIa patients develop CKD. The kidney pathology is characterized by the development of cysts, which typically occur at an advanced stage of CKD. To elucidate the molecular mechanisms responsible for cyst formation, we characterized renal metabolism, molecular pathways involved in cell proliferation and integrity primary cilium integrity, using mice in which G6pc1 was specifically deleted in the kidney from in utero stage. GSDIa mice exhibited renal fibrosis, high-inflammation, and cyst formation, leading to kidney dysfunction. In addition, the loss of G6PC1 led to the ectopic accumulation of glycogen and lipids in the kidneys, and a metabolic shift towards a Warburg-like metabolism. This metabolic adaptation was due to an excess of glucose-6 phosphate, which supports cell proliferation, driven by the MEK/ERK and AKT/mTOR pathways. Treatment of GSDIa mice with rapamycin, a target of the mTOR pathway, reduced cell proliferation and kidney damage. Our results also identified lipocalin 2 as a contributor to renal inflammation and an early biomarker of CKD progression in GSDIa mice. Its inactivation partially prevented kidney lesions in GSDIa. Importantly, primary cilium defects were observed in the kidneys of GSDIa mice. Metabolic adaptations due to glucose-6 phosphate accumulation in GSDIa renal tubules, towards a Warburg-like metabolism, appeared to promote cell proliferation and cyst formation in a similar manner to that observed in various cystic kidney diseases. This was associated with down-regulation of primary cilium gene expression and consequently, altered cilium morphology.