Disruption Of Architecture Research Articles

Analysis of Bone Phenotype Differences in MEN1-Related and Sporadic Primary Hyperparathyroidism Using 3D-DXA

Background: The rarity and variability of MEN1-related primary hyperparathyroidism (mPHPT) has led to contradictory data regarding the bone phenotype in this patient population. Methods: A single-center retrospective study was conducted among young age- and sex-matched patients with mPHPT and sporadic hyperparathyroidism (sPHPT). The main parameters of calcium–phosphorus metabolism, bone remodeling markers, and bone mineral density (BMD) measurements were obtained during the active phase of hyperparathyroidism before parathyroidectomy (PTE) and 1 year after. Trabecular Bone Score (TBS) and 3D-DXA analysis of the proximal femur were used to evaluate the differences in bone architecture disruption between groups. Results: Patients with mPHPT had significant lower preoperative BMD compared to sPHPT at lumbar spine—LS (p = 0.002); femur neck—FN (p = 0.001); and total hip—TH (p = 0.002). 3D-DXA analysis showed the prevalence of cortical rather than trabecular bone damage in mPHPT compared to sPHPT: cortical thickness (p < 0.001); cortical surface BMD (p = 0.001); cortical volumetric BMD (p = 0.007); and trabecular volumetric BMD (p = 0.029). One year after, PTE DXA and 3D-DXA parameters were similar between groups, while 3D-visualisation showed more extensive regeneration in cortical sBMD and cortical thickness in mPHPT. Conclusions: mPHPT is associated with lower preoperative BMD values with predominant architecture disruption in the cortical bone. The absence of differences in DXA and 3D-DXA parameters 1 year after PTE between mPHPT/sPHPT combined with significantly lower BMD in mPHPT at the initial stage may indicate faster bone recovery after surgery in mPHPT than in sPHPT.

The ameliorating effects of adipose-derived stromal vascular fraction cells on blue light-induced rat retinal injury via modulation of TLR4 signaling, apoptosis, and glial cell activity.

Blue light (BL)-induced retinal injury has become a very common problem due to over exposure to blue light-emitting sources. This study aimed to investigate the possible ameliorating impact of stromal vascular fraction cells (SVFCs) on BL-induced retinal injury. Forty male albino rats were randomly allocated into four groups. The control group rats were kept in 12-h light/12-h dark. Rats of SVFC-control as the control group, but rats were intravenously injected once by SVFCs. Rats of both the BL-group and BL-SVFC group were exposed to BL for 2 weeks; then rats of the BL-SVFC group were intravenously injected once by SVFCs. Following the BL exposure, rats were kept for 8 weeks. Physical and physiological studies were performed; then retinal tissues were collected for biochemical and histological studies. The BL-group showed physical and physiological changes indicating affection of the visual function. Biochemical marker assessment showed a significant increase in MDA, TLR4 and MYD88 tissue levels with a significant decrease in TAC levels. Histological and ultrastructural assessment showed disruption of the normal histological architecture with retinal pigment epithelium, photoreceptors, and ganglion cell deterioration. A significant increase in NF-κB, caspase-3, and GFAP immunoreactivity was also detected. BL-SVFC group showed a significant improvement in physical, physiological, and biochemical parameters. Retinal tissues revealed amelioration of retinal structural and ultrastructural deterioration and a significant decrease in NF-κB and caspase-3 immunoreactivity with a significant increase in GFAP immunoreaction. This study concluded that SVFCs could ameliorate the BL-induced retinal injury through TLR-4/MYD-88/NF-κB signaling inhibition, regenerative, anti-oxidative, and anti-apoptotic effects.

Exploring the link between comorbid insomnia and sleep apnea (COMISA) and erectile dysfunction: implications for male sexual health.

This review explores the interplay between comorbid insomnia and sleep apnea (COMISA) and erectile dysfunction (ED), 2 conditions that significantly impact men's health. COMISA, a recently recognized condition characterized by the coexistence of insomnia and obstructive sleep apnea, has been shown to disrupt sleep architecture and cause intermittent hypoxia. These disturbances are increasingly linked to the exacerbation of ED, a prevalent issue among men. Understanding the connection between COMISA and ED is crucial for developing integrated treatment approaches that address both sleep and sexual health. We aim to explore the epidemiological, physiological, and potential therapeutic intersections of COMISA and ED. This review sets out to develop a better understanding of the relationship between these conditions and to emphasize the need for an integrated diagnostic and therapeutic approach that addresses both sleep and sexual health. Through a comprehensive analysis, including a detailed examination of extant studies, we address the hormonal imbalances and alterations in neural pathways that collectively contribute to the complex pathophysiology of ED and how these are particularly susceptible to the concurrent presence of COMISA. Our analysis indicates that disruptions in sleep architecture and intermittent hypoxia associated with COMISA can exacerbate ED. Hormonal imbalances, endothelial dysfunction, autonomic imbalance, and increased inflammation and oxidative stress are key mechanisms through which COMISA influences ED. These factors collectively impair vascular health, reduce testosterone levels, disrupt neural control of erections, and contribute to the severity of ED. This review underscores the necessity for an integrated approach to diagnosis and therapy that considers both sleep and sexual health to improve overall outcomes. These insights should foster a deeper understanding of the relationship between COMISA and ED, encourage further research in this area, and potentially lead to the development of innovative treatment strategies to manage these closely intertwined health concerns.

Role of the SaeRS Two-Component Regulatory System in Group B Streptococcus Biofilm Formation on Human Fibrinogen.

Streptococcus agalactiae, also known as Group B Streptococcus or GBS, is a commensal colonizer of human vaginal and gastrointestinal tracts that can also be a deadly pathogen for newborns, pregnant women, and the elderly. The SaeRS two-component regulatory system (TCS) positively regulates the expression of two GBS adhesins genes, but its role in the formation of biofilm, an important step in pathogenesis, has not been investigated. In the present study, we set up a novel model of GBS biofilm formation using surfaces coated with human fibrinogen (hFg). Biofilm mass and structure were analyzed by crystal violet staining and three-dimensional fluorescence microscopy, respectively. GBS growth on hFg resulted in the formation of a mature and abundant biofilm composed of bacterial cells and an extracellular matrix containing polysaccharides, proteins, and extracellular DNA (eDNA). Enzymatic and genetic analysis showed that GBS biofilm formation on hFg is dependent on proteins and eDNA in the extracellular matrix and on the presence of covalently linked cell wall proteins on the bacterial surface but not on the type-specific capsular polysaccharide. In the absence of the SaeR regulator of the SaeRS TCS, there was a significant reduction in biomass formation, with reduced numbers of bacterial cells, reduced eDNA content, and disruption of the biofilm architecture. Overall, our data suggest that GBS binding to hFg contributes to biofilm formation and that the SaeRS TCS plays an important role in this process.

The Lacunocanalicular Network is Denser in C57BL/6 Compared to BALB/c Mice.

The lacunocanalicular network (LCN) is an intricate arrangement of cavities (lacunae) and channels (canaliculi), which permeates the mineralized bone matrix. In its porosity, the LCN accommodates the cell network of osteocytes. These two nested networks are attributed a variety of essential functions including transport, signaling, and mechanosensitivity due to load-induced fluid flow through the LCN. For a more quantitative assessment of the networks' function, the three-dimensional architecture has to be known. For this reason, we aimed (i) to quantitatively characterize spatial heterogeneities of the LCN in whole mouse tibial cross-sections of BALB/c mice and (ii) to analyze differences in LCN architecture by comparison with another commonly used inbred mouse strain, the C57BL/6 mouse. Both tibiae of five BALB/c mice (female, 26-week-old) were stained using rhodamine 6G and whole tibiae cross-sections were imaged using confocal laser scanning microscopy. Using image analysis, the LCN was quantified in terms of density and connectivity and lacunar parameters, such as lacunar degree, volume, and shape. In the same tibial cross-sections, the calcium content was measured using quantitative backscattered electron imaging (qBEI). A structural analysis of the LCN properties showed that spatially denser parts of the LCN are mainly due to a higher density of branching points in the network. While a high intra-individual variability of network density was detected within the cortex, the inter-individual variability between different mice was low. In comparison to C57BL/6J mice, BALB/c mice showed a distinct lower canalicular density. This reduced network was already detectable on a local network level with fewer canaliculi emanating from lacunae. Spatial correlation with qBEI images demonstrated that bone modeling resulted in disruptions in the network architecture. The spatial heterogeneity and differences in density of the LCN likely affects the fluid flow within the network and therefore bone's mechanoresponse to loading.

Histomorphological scoring of murine colitis models: A practical guide for the evaluation of colitis and colitis-associated cancer

Background and aimsHistomorphology is a powerful and cost-efficient tool for evaluating inflammatory and neoplastic conditions. Inflammatory bowel disease (IBD) is a widespread condition with globally rising incidences, and a lot of research is done to better understand the pathogenesis of IBD and to identify potential therapeutic approaches. However, standardized and reproducible scores for the histomorphological evaluation of murine IBD models are lacking. Therefore, we aimed to develop an easy-to-use and reproducible score for standardized assessment of colitis and associated cancer models. MethodsIn this study, samples from three different colitis models with and without associated cancer formation were analyzed to develop a universal, robust, and reproducible score for the grading of murine colitis models using the following three parameters: 1. Extent of leucocyte infiltration, 2. Tissue damage, 3. Architectural disruption of the mucosa. ResultsA scoring system was established for different kinds of colitis models (genetically induced enterocolitis, genetically induced metabolic injury, and chemically induced colitis-associated cancer) and all stages of the disease, from mild inflammatory changes to severe inflammation with neoplastic changes as the extreme extent of IBD. The scoring scheme is easy to use, can easily be learned, and proves to have a high interrater reliability. ConclusionsWe propose a robust histological scoring system for the assessment of murine colitis and colitis-associated cancer models, giving more researchers access to conclusive and reliable histological assessment.

Inflammation of the temporalis muscle and adjacent nerve tissue in giant cell arteritis: expanding the spectrum of inflammatory lesions.

To investigate the histopathological features of the temporalis muscle (TM) and adjacent nerve tissue in active cranial giant cell arteritis (C-GCA). Temporal artery biopsy (TAB) specimens containing fragments of the TM from patients with active C-GCA fulfilling the 2022 ACR/EULAR classification criteria (n = 11) were assessed by conventional histology and immunohistochemistry in comparison with non-GCA controls (n = 3). Clinical, laboratory and imaging features based on patient charts at time of biopsy were retrospectively recorded. The majority of the studied TAB specimens showed inflammation of the TM (10/11) and adjacent nerve fascicles (7/11) that was characterized by prominent endomysial lymphomonocytic infiltrates, whereas controls showed no inflammatory lesions and no disruption of the local architecture. Association of active C-GCA with sarcolemmal MHC class I (8/8) and MHC class II (6/11) upregulation suggests primary inflammation of the TM in a subset of patients. αB-Crystallin positivity (10/11) highlights areas of pre-necrotic myofibres within the TM. The presence of endomysial fibrosis, signs of atrophy and variations of muscle fibre size suggest a rather longstanding and potentially subclinical process of myoinflammation. Our results expand the spectrum of inflammatory lesions known to be associated with active C-GCA. Specifically, inflammatory infiltration of the TM and adjacent nerve structures could contribute to localized symptoms of the temporomandibular region and may be included in future concepts of pathophysiology.

LINE1 and PRC2 control nucleolar organization and repression of the 8C state in human ESCs.

The mechanisms that ensure developmental progression in the early human embryo remain largely unknown. Here, we show that the family of long interspersed nuclear element 1 (LINE1) transposons prevents the reversion of naive human embryonic stem cells (hESCs) to 8-cell-like cells (8CLCs). LINE1 RNA contributes to maintenance of H3K27me3 levels, particularly at chromosome 19 (Chr19). Chr19 is enriched for key 8C regulators, H3K27me3, and genes derepressed upon LINE1 knockdown or PRC2 inhibition. Moreover, Chr19 is strongly associated with the nucleolus in hESCs but less in 8CLCs. Direct inhibition of PRC2 activity induces the 8C program and leads to a relocalization of Chr19 away from the nucleolus. LINE1 KD or PRC2 inhibition induces nucleolar stress, and disruption of nucleolar architecture is sufficient to de-repress the 8C program. These results indicate that LINE1 RNA and PRC2 maintain H3K27me3-mediated gene repression and 3D nuclear organization to prevent developmental reversion of hESCs.

Schwann cell-secreted frizzled-related protein 1 dictates neuroinflammation and peripheral nerve degeneration after neurotrauma.

Neurotrauma in limbs can induce sustained neuroinflammation, resulting in persistent disruption of nerve tissue architecture and retardation of axon regrowth. Despite macrophage-mediated inflammation promoting the removal of necrotic neural components and stimulating neo-vessel ingrowth, detrimental shifts in macrophage phenotype exacerbate nerve degeneration. Herein, we find that peripheral nerve injuries (PNIs) result in abundant secreted frizzled-related protein 1 (sFRP1) expression, particularly by Schwann cells (SCs). Heat shock protein 90 (HSP90) in macrophages recognizes sFRP1 and triggers a dysregulated secretion of inflammatory mediators. Single-cell atlas of human injured peripheral nerves reveals the appearance of sFRP1-expressing SCs with mesenchymal traits and macrophages with a proinflammatory genetic profile. Deletion of either SC-specific sFRP1 or macrophage-specific HSP90 alleviates neuroinflammation and prevents the progression of nerve degeneration. Together, our findings implicate the response of macrophages to SC-derived sFRP1 in exacerbating nerve damage following PNIs.

A Comprehensive Review of the Antitumor Properties and Mechanistic Insights of Duocarmycin Analogs.

The duocarmycin family is a group of potent cytotoxic agents originally isolated from the bacterium Streptomyces. This discovery has spurred significant interest due to duocarmycins' unique chemical structures and powerful mechanism of action. This review comprehensively details the history of the duocarmycin family, the current understanding of their therapeutic potential, and the major clinical trials that have been conducted. Chemically, the duocarmycin family is characterized by a DNA-binding unit that confers specificity, a subunit-linking amide that positions the molecule within the DNA helix, and an alkylating unit that interacts with the DNA. This configuration allows them to bind selectively to the minor groove of DNA and alkylate adenine bases, a notable deviation from the more common guanine targeting performed by other alkylating agents. Duocarmycin's mechanism of action involves the formation of covalent adducts with DNA, leading to the disruption of the DNA architecture and subsequent inhibition of replication and transcription. Recent advancements in drug delivery systems, such as antibody-drug conjugates (ADCs), have further elevated the therapeutic prospects of duocarmycin analogs by providing a promising mechanism for enhancing intracellular concentrations and selective tumor delivery. Preclinical studies have highlighted the efficacy of duocarmycin derivatives in various in vitro models, providing a strong foundation for translational research. However, further biological research is required to fully understand the toxicology of duocarmycin family members before it can be clinically relevant. The major focus of this review is to cache the major biologically relevant findings of different duocarmycin analogs as well as their biological shortcomings to propose next steps in the field of cancer therapy with these potent therapeutics.

LiverMap pipeline for 3D imaging of human liver reveals volumetric spatial dysregulation of cirrhotic vasculobiliary architecture.

The liver contains an intricate microstructure that is critical for liver function. Architectural disruption of this spatial structure is pathologic. Unfortunately, 2D histopathology - the gold standard for pathological understanding of many liver diseases - can misrepresent or leave gaps in our understanding of complex 3D structural features. Here, we utilized immunostaining, tissue clearing, microscopy, and computational software to create 3D multilobular reconstructions of both non-fibrotic and cirrhotic human liver tissue. We found that spatial architecture in human cirrhotic liver samples with varying etiologies had sinusoid zonation dysregulation, reduction in glutamine synthetase-expressing pericentral hepatocytes, regression of central vein networks, disruption of hepatic arterial networks, and fragmentation of biliary networks, which together suggest a pro-portalization/decentralization phenotype in cirrhotic tissue. Further implementation of 3D pathological analyses may provide a deeper understanding of cirrhotic pathobiology and inspire novel treatments for liver disease.

Exploring Sleep Architecture in Polish Patients with Multiple Sclerosis: A Polysomnography Study.

Sleep disturbances are a prevalent phenomenon in patients with multiple sclerosis (PwMS). The present study employs polysomnography (PSG) to quantify sleep efficiency and architecture in PwMS, aiming to elucidate the relationships between PSG parameters and factors including gender, disability level, brain lesion location, and subjective measures of insomnia, excessive daytime sleepiness (EDS), fatigue, pain, and mood disorders. The study cohort comprised 51 adult PwMS, of whom 31 underwent overnight PSG. The demographic and clinical characteristics, including age, gender, and Expanded Disability Status Scale (EDSS), were collated. The Athens Insomnia Scale, the Epworth Sleepiness Scale, the Fatigue Severity Scale, the Modified Fatigue Impact Scale (MFIS), the Numerical Pain Rating Scale, and the Hospital Anxiety and Depression Scale were employed for the assessment of insomnia, EDS, fatigue, pain, and mood disorders. The brain and spinal cord magnetic resonance imaging (MRI) were evaluated. A reduced sleep efficiency was observed among 30 PwMS (aged 38.9 ± 12.9), with a mean of 80 ± 12%, especially in those with brainstem demyelinating lesions. In those PwMS aberrant sleep onset latency (SOL) and wake after sleep onset were also noted (p < 0.05). The prevalence of sleep fragmentation, as measured by the total arousal index, was greater in male PwMS than in female (p < 0.05). Higher disability according to the EDSS correlated with longer SOL (ρ = 0.48, p < 0.05), and reduced N2 sleep stage correlated with cognitive fatigue according to MFIS (ρ = -0.46, p < 0.05). Age, disease duration, insomnia, EDS, physical fatigue, and mood disorders did not impact PSG parameters. The study demonstrated the disruption of sleep architecture in PwMS, and highlighted the importance of a comprehensive PSG assessment of sleep disturbances in this population.

Abstract A070: Time-Dependent Oxidation and Aggregation of Vimentin upon Binding by β-lap Induced Immunogenic Cell Death

Abstract β-lapachone (β-lap) has been demonstrated as an NAD(P)H:quinone oxidoreductase1 (NQO1) bioactivatable compound. It initiated a futile redox cycle catalyzed by NQO1, resulting in reactive oxygen species (ROS) generation, with consumption of the reductive NAD(P)H. After a 4-h pulse of sufficiently lethal dose of β-lap, high levels of ROS diffused into nuclei to induce tumor-selective DNA damage and programmed necrosis in cancers overexpressing NQO1. Recently, our experiments showed that prolonged low dose β-lap administration exerted significant and NQO1 independent antitumor efficacy in mouse models with no overt signs of toxicity. Thus, we synthesized a photoactive β-lap probe to identify the molecular target of β-lap. Vimentin, a major constituent of the intermediate filament family of proteins, was identified as the direct binding target of β-lap. Vimentin was highly upregulated in multiple cancers including PDAC, and was a binding partner of β-lap with a dissociation constant at micromolar levels. Ligand binding assays in Panc1 cells employing β-lap as a specific competitor showed that vimentin was bound by β-lap-probe in a β-lap-competitive manner, and further confirmed that the in vivobinding target of β-lap was vimentin. Moreover, it was manifested that endogenous vimentin mRNA levels directly correlated with sensitivity to prolonged exposure of β-lap in a panel of pancreatic cancer cell lines, and knockout of vimentin in Panc1 cells markedly decreased lethality after prolonged exposure of β-lap. Mechanistically, we revealed that β-lap bound to vimentin and induced disulfide bonds that participated in disulfide cross-linking between a pair of vimentin dimers in a concentration and time dependent manner, forming vimentin oligomers of approximately 150 kDa. Prolonged exposure of β-lap promoted the disruption of filament architecture and vimentin degradation, ultimately resulting in cell death. In addition, the cell death by targeting vimentin exhibited a more inflammatory condition and enhanced DC activation. Together, our findings unveiled an unknown molecular target for β-lap and provided valuable insights into its mechanism of action. Targeting vimentin also presented a new strategy that inhibited the tumor growth and synergized with immunotherapy to disrupt immune evasion and reduce immune suppression against pancreatic cancers. Citation Format: Feng Qian, Lei Dou, Kaixin Wang, Yi Xia, Zhidong Chen, Yumeng Zu, Shuang Xi. Time-Dependent Oxidation and Aggregation of Vimentin upon Binding by β-lap Induced Immunogenic Cell Death [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A070.

Three-dimensional chromatin mapping of sensory neurons reveals that promoter–enhancer looping is required for axonal regeneration

The in vivo three-dimensional genomic architecture of adult mature neurons at homeostasis and after medically relevant perturbations such as axonal injury remains elusive. Here, we address this knowledge gap by mapping the three-dimensional chromatin architecture and gene expression program at homeostasis and after sciatic nerve injury in wild-type and cohesin-deficient mouse sensory dorsal root ganglia neurons via combinatorial Hi-C, promoter-capture Hi-C, CUT&Tag for H3K27ac and RNA-seq. We find that genes involved in axonal regeneration form long-range, complex chromatin loops, and that cohesin is required for the full induction of the regenerative transcriptional program. Importantly, loss of cohesin results in disruption of chromatin architecture and severely impaired nerve regeneration. Complex enhancer-promoter loops are also enriched in the human fetal cortical plate, where the axonal growth potential is highest, and are lost in mature adult neurons. Together, these data provide an original three-dimensional chromatin map of adult sensory neurons in vivo and demonstrate a role for cohesin-dependent long-range promoter interactions in nerve regeneration.

Brief Communication: Confocal microscopy of oral streptococcal biofilms grown in simulated microgravity using a random positioning machine

Biofilms are a concern for spaceflight missions, given their propensity for biofouling systems and their potential threat to astronaut health. Herein, we describe a random positioning machine-based method for growing fluorescent protein-expressing streptococcal biofilms under simulated microgravity. Biofilms can be subsequently imaged by confocal microscopy without further manipulation, minimizing disruption of architecture. This methodology could be adaptable to other bacteria, potentially standardizing biofilm growth and study under simulated microgravity.

Effect of Vernonia Cinerea Water Extract on the Protection of Liver Tissue in Chronic Nicotine-Treated Rats

Nicotine, a highly toxic alkaloid found in tobacco, is known for its addictive properties and systemic side effects, including carcinogenic potential and multi-organ damage. Recent evidence indicates that nicotine can significantly impair liver function and regeneration by promoting fibrogenesis and oxidative stress. This study aimed to investigate the protective effects of Vernonia cinerea (VC) against nicotine-induced liver damage in Wistar rats, focusing on inflammation and pro-fibrosis markers. Thirty male Wistar rats were divided into three groups: a control group, a nicotine group (1 mg/kg/day), and a nicotine plus VC group (1 mg/kg/day nicotine and 100 mg/kg/day VC). Liver tissues were examined using Hematoxylin and Eosin staining, and Masson's trichrome staining to evaluate histological changes. Kupffer cell counts were determined using a Panoramic digital slide scanner. Statistical analyses were conducted to compare the groups. Nicotine exposure led to significant liver damage, characterized by increased inflammation, collagen deposition, and disruption of liver architecture. VC supplementation ameliorated these effects, reducing inflammation and fibrosis markers. Kupffer cell counts were lower in the nicotine plus VC group compared to the nicotine group alone. Conclusion: VC demonstrates a protective role in mitigating nicotine-induced liver damage, highlighting its potential as a therapeutic agent for preventing liver fibrosis and maintaining liver health in nicotine-exposed individuals.

Mechanism of cigarette smoke in promoting small airway remodeling in mice via STAT 3 / PINK 1-Parkin / EMT

BackgroundAirway remodeling is an important pathological of airflow limitation in chronic obstructive pulmonary disease (COPD).However,its mechanism still needs to be further clarify. MethodsAnimals:Healthy male C57BL/6 mice aged 4–6 weeks were randomly divided into control group and cigarette smoke(CS)group. Mice in the CS group were placed in a homemade glass fumigator, 5 cigarettes/time, 40 min/time, 4 times/day, 5 days/week, for 24 weeks. Mice in the control group were placed in a normal air environment.Cells:BEAS-2B cells were stimulated with 0.1%cigarette smoke extract(CSE).HE staining, immunohistochemical staining and Masson staining were used to observe the pathological of lung tissues, transmission electron microscopy was used to observe the structural of mitochondria in bronchial epithelial cells.Western blotting was used to detect the expression of STAT3,transforming growth factor-β1(TGF-β1),microtubule-associated protein 1A/1B-light chain3(LC3),PINK1,Parkin,E-cadherin,zonula occludens1(ZO-1),vimentin and snail family transcriptional inhibitor1 (Snail1),and MitoSOX Red was used to detect mitochondrial reactive oxygen species(mtROS). ResultsCS exposure causes lung parenchymal destruction and airway remodeling in mice.Compared to the control group,the expression of p-STAT3,TGF-β1 and EMT in the whole lung homogenate of the CS group was increased.Mitochondrial architecture disruption in bronchial epithelial cells of CS mice, with impaired PINK1-Parkin-dependent mitophagy.In vitro experiments showed that CSE exposure led to STAT3 activation, increased TGF-β1,EMT and enhanced PINK1-Parkin-mediated mitophagy.STAT3 inhibition reversed TGF-β1 upregulation induced by CSE and improved CSE-induced EMT and mitophagy.Inhibition of mitophagy improves EMT induced by CSE. Inhibition of mitophagy reduces STAT3-induced EMT. ConclusionCS activates the STAT3,and activated STAT3 promotes EMT in bronchial epithelial cells by enhancing PINK1-Parkin-mediated mitophagy and TGF-β1 signaling.Moreover, activated STAT3 can promote EMT directly.This may be one of the mechanisms by which CS causes small airway remodeling in COPD.

Semaphorin heterodimerization in cis regulates membrane targeting and neocortical wiring

Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations of SATB2 cause SATB2 Associated Syndrome (SAS), a multisymptomatic syndrome involving epilepsy, intellectual disability, speech delay, and craniofacial defects. Here we show that Satb2 controls neuronal migration and callosal axonal outgrowth during murine neocortical development by inducing the expression of the GPI-anchored protein, Semaphorin 7A (Sema7A). We find that Sema7A exerts this biological activity by heterodimerizing in cis with the transmembrane semaphorin, Sema4D. We could also observe that heterodimerization with Sema7A promotes targeting of Sema4D to the plasma membrane in vitro. Finally, we report an epilepsy-associated de novo mutation in Sema4D (Q497P) that inhibits normal glycosylation and plasma membrane localization of Sema4D-associated complexes. These results suggest that neuronal use of semaphorins during neocortical development is heteromeric, and a greater signaling complexity exists than was previously thought.

Maintenance of germline stem cell homeostasis despite severe nuclear distortion

Stem cell loss in aging and disease is associated with nuclear deformation. Yet, how nuclear shape influences stem cell homeostasis is poorly understood. We investigated this connection using Drosophila germline stem cells, as survival of these stem cells is compromised by dysfunction of the nuclear lamina, the extensive protein network that lines the inner nuclear membrane and gives shape to the nucleus. To induce nuclear distortion in germline stem cells, we used the GAL4-UAS system to increase expression of the permanently farnesylated nuclear lamina protein, Kugelkern, a rate limiting factor for nuclear growth. We show that elevated Kugelkern levels cause severe nuclear distortion in germline stem cells, including extensive thickening and lobulation of the nuclear envelope and nuclear lamina, as well as alteration of internal nuclear compartments. Despite these changes, germline stem cell number, proliferation, and female fertility are preserved, even as females age. Collectively, these data demonstrate that disruption of nuclear architecture does not cause a failure of germline stem cell survival or homeostasis, revealing that nuclear deformation does not invariably promote stem cell loss.

1H-Pyrrole-2,5-dicarboxylic acid, a quorum sensing inhibitor from one endophytic fungus in Areca catechu L., acts as antibiotic accelerant against Pseudomonas aeruginosa.

Pseudomonas aeruginosa has already been stipulated as a "critical" pathogen, emphasizing the urgent need for researching and developing novel antibacterial agents due to multidrug resistance. Bacterial biofilm formation facilitates cystic fibrosis development and restricts the antibacterial potential of many current antibiotics. The capacity of P. aeruginosa to form biofilms and resist antibiotics is closely correlated with quorum sensing (QS). Bacterial QS is being contemplated as a promising target for developing novel antibacterial agents. QS inhibitors are a promising strategy for treating chronic infections. This study reported that the active compound PT22 (1H-pyrrole-2,5-dicarboxylic acid) isolated from Perenniporia tephropora FF2, one endophytic fungus from Areca catechu L., presents QS inhibitory activity against P. aeruginosa. Combined with gentamycin or piperacillin, PT22 functions as a novel antibiotic accelerant against P. aeruginosa. PT22 (0.50 mg/mL, 0.75 mg/mL, and 1.00 mg/mL) reduces the production of QS-related virulence factors, such as pyocyanin and rhamnolipid, and inhibits biofilm formation of P. aeruginosa PAO1 instead of affecting its growth. The architectural disruption of the biofilms was confirmed by visualization through scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Real-time quantitative PCR (RT-qPCR) indicated that PT22 significantly attenuated the expression of QS-related genes followed by docking analysis of molecules against QS activator proteins. PT22 dramatically increased the survival rate of Galleria mellonella. PT22 combined with gentamycin or piperacillin presents significant inhibition of biofilm formation and eradication of mature biofilm compared to monotherapy, which was also confirmed by visualization through SEM and CLSM. After being treated with PT22 combined with gentamycin or piperacillin, the survival rates of G. mellonella were significantly increased compared to those of monotherapy. PT22 significantly enhanced the susceptibility of gentamycin and piperacillin against P. aeruginosa PAO1. Our results suggest that PT22 from P. tephropora FF2 as a potent QS inhibitor is a candidate antibiotic accelerant to combat the antibiotic resistance of P. aeruginosa.