Supergene Research Articles

Upregulation of TLR2 in keratinocytes activates the MAPK pathway and plays a role in the pathogenesis of FHS

BackgroundMutations in gamma-secretase complex (GSC) genes are associated with hidradenitis suppurativa (HS), and toll-like receptor (TLR) 2 is elevated in HS lesions. However, it remains unclear whether TLR2 is upregulated in the skin lesions of patients with HS with GSC gene variants, and the role of its upregulation in the pathogenesis of this disease are unknown. ObjectiveTo investigate the role of TLR2 upregulation in NCSTN and PSENEN knockdown keratinocytes. MethodsHuman immortalized keratinocyte line (HaCaTs) was treated with potent short-hairpin RNA targeting NCSTN or PSENEN. RNA sequencing was used to assess the effects of PAM2CSK4 treatment on gene expression in HaCaT cells. Altered signaling pathways were confirmed in both HaCaT cells, as well as in skin lesions from patients with HS and in Ncstn keratinocyte-specific knockout (NcstnΔKC) mice. ResultsTLR2 agonist stimulation exacerbated the increased phosphorylation levels of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase (MAPK) in NCSTN- and PSENEN- knockdown keratinocytes. Similar findings were observed in skin lesions from patients with HS and NcstnΔKC mice. ConclusionNovel variations were identified within the GSC gene in Chinese patients with HS. Moreover, our study indicates that TLR2/MAPK signaling pathways play a key role in the pathogenesis of HS associated with GSC gene mutations and represent a crucial therapeutic target.

Characterization of Human Melanoma Skin Cancer Models: A step towards Model-Based Melanoma Research

Advancing 3D in vitro human tissue models is crucial for biomedical research and drug development to address the ethical and biological limitations of animal testing. Recently, 3D skin models have proven to be effective for studying serious skin conditions, such as melanoma. For these advanced models to be applicable in preclinical studies, thorough characterization is essential to understand their applicability and limitations.In this study, we used bioimaging and RNA sequencing to assess the architecture and transcriptomic profiles of skin models, including models with melanoma. Our results indicated that these models closely mimicked skin morphology and gene expression patterns. The full-thickness (FT) model shows a superior resemblance to the human skin, particularly in basement membrane formation and cellular interactions.The integrity of the skin-like properties and gene expression signatures of both skin and melanoma cells were preserved upon the integration of melanoma cells, establishing these models as robust platforms for cancer research. The responsiveness of the FT melanoma models to vemurafenib treatment was successfully monitored, demonstrating their validity as a reliable, reproducible, and humane tool for pharmacological testing and drug development. Furthermore, the transcriptomic data showed that skin models with cancer spheroids had upregulated genes linked to aggressive and resilient cancer behavior compared to spheroids alone. This emphasizes the importance of the microenvironment in cancer progression and suggests that 3D skin models can serve to uncover mechanisms and therapeutic targets that are not detectable in simpler systems. Statement of SignificanceThis study introduces advanced, ethically sound skin and melanoma models as alternatives to animal testing in drug discovery. By thoroughly characterizing these models using bioimaging and RNA sequencing, we demonstrate their close resemblance to human skin, particularly in full-thickness models. These models not only replicate the complex cellular interactions and gene expression patterns of human tissue but also maintain robustness after melanoma integration. Our findings highlight the potential of these models in revealing cancer mechanisms and therapeutic targets, offering a significant impact on melanoma research and preclinical testing.

Manipulation of artificial light environment improves plant biomass and fruit nutritional quality in tomato

IntroductionThe yield and quality of tomato (Solanum lycopersicum. L) are often decreased when plants suffer from low light intensity and short-photoperiod in winter. Manipulation of the artificial light environment is a feasible technology to promote off-seasonal production and improve fruit nutritional quality in the greenhouse. ObjectivesHere we aim to investigate the appropriate balance between red (R) and blue (B) light to improve tomato yield and quality traits. MethodsBiochemical, molecular and genetic analysis were used to study the photosynthetic traits, pigments, sugar and volatile accumulation pathway genes. ResultsTomato plants subjected to R1B0.8, a ratio between monochromatic red (R) and blue (B) light, for 16 h photoperiod showed significantly increased chlorophyll and biomass accumulation compared to white (W) light treatment. R1B0.8 light treatment enhanced electron transfer efficiency and photosynthetic capacity by improving the light energy utilization rate and inducing photosystem core subunit genes (SlPsaC, SlPsaB, SlPsaA) and light-harvesting complex genes (SlLHCB/A). Compared to W light, R1B0.8 light also induced carotenoid accumulation and accelerated fruit ripening, which was associated with the upregulation of carotenoid biosynthesis genes (SlPSY1, SlPDS) and ethylene biosynthesis genes (SlACS2, SlACO2) in tomato fruits. Moreover, fruits exposed to R1B0.8 light treatments significantly improved fructose and glucose accumulation and the expression of the volatile-related gene (SlAADC1a) and flavor-related gene (SlGORKY). ConclusionOur results showed that R1B0.8 light with a 16 h photoperiod could prominently promote photosynthetic traits, pigments, sugar and volatile accumulation in tomato. Our findings on the manipulation of artificial light environments in protected horticulture offer possibilities for enhancing crop yield and quality to meet the increasing global demand for food.

Drosophila Eye Gene Regulatory Network Inference Using BioGRNsemble: An Ensemble-of-Ensembles Machine Learning Approach

Background: Gene regulatory networks (GRNs) are complex gene interactions essential for organismal development and stability, and they are crucial for understanding gene-disease links in drug development. Advances in bioinformatics, driven by genomic data and machine learning, have significantly expanded GRN research, enabling deeper insights into these interactions. Methods: This study proposes and demonstrates the potential of BioGRNsemble, a modular and flexible approach for inferring gene regulatory networks from RNA-Seq data. Integrating the GENIE3 and GRNBoost2 algorithms, the BioGRNsemble methodology focuses on providing trimmed-down sub-regulatory networks consisting of transcription and target genes. Results: The methodology was successfully tested on a Drosophila melanogaster Eye gene expression dataset. Our validation analysis using the TFLink online database yielded 3703 verified predicted gene links, out of 534,843 predictions. Conclusion: Although the BioGRNsemble approach presents a promising method for inferring smaller, focused regulatory networks, it encounters challenges related to algorithm sensitivity, prediction bias, validation difficulties, and the potential exclusion of broader regulatory interactions. Improving accuracy and comprehensiveness will require addressing these issues through hyperparameter fine-tuning, the development of alternative scoring mechanisms, and the incorporation of additional validation methods.

Different phenotypes with different endings-Telomere biology disorders and cancer predisposition with long telomeres.

Rare germline pathogenic variants (GPVs) in genes essential in telomere length maintenance and function have been implicated in two broad classes of human disease. The telomere biology disorders (TBDs) are a spectrum of life-threatening conditions, including bone marrow failure, liver and lung disease, cancer and other complications caused by GPVs in telomere maintenance genes that result in short and/or dysfunctional telomeres and reduced cellular replicative capacity. In contrast, cancer predisposition with long telomeres (CPLT) is a disorder associated with elevated risk of a variety of cancers, primarily melanoma, thyroid cancer, sarcoma, glioma and lymphoproliferative neoplasms caused by GPVs in shelterin complex genes that lead to excessive telomere elongation and increased cellular replicative capacity. While telomeres are at the root of both disorders, the term TBD is used to convey the clinical phenotypes driven by critically short or otherwise dysfunctional telomeres and their biological consequences.

Post-Flowering Photoperiod Sensitivity of Soybean in Pod-Setting Responses.

The development of soybean (Glycine max) is regulated by the photoperiod, with genes related to photoperiod sensitivity primarily focused on the flowering time. However, their roles in post-flowering reproductive development and the mechanisms by which the photoperiod affects them are not yet determined. In this study, we found that pod formation is sensitive to the photoperiod. Long-day conditions tended to extend the time from flowering to pod formation, and the first wave of flowers tended to fall off. Additionally, the photoperiod affected the pistil morphology; under short-day conditions, the stigma had a curved hook-like structure that facilitated better interaction with the filaments when pollen was released, ultimately influencing the timing of pod formation. Photoperiod-insensitive mutants, lacking E1 family and Evening Complex (EC) genes, showed no difference in the pod formation time under long-day or short-day conditions. Hormone content analysis and transcriptome data analysis indicated that various hormones, reactive oxygen species (ROS) burst pathway signals, and the application of sucrose solution in vitro might influence floral organ abscission.

Differential Host Gene Expression in Response to Infection by Different Mycobacterium tuberculosis Strains-A Pilot Study.

Tuberculosis (TB) represents a global public health threat and is a leading cause of morbidity and mortality worldwide. Effective control of TB is complicated with the emergence of multidrug resistance. Yet, there is a fundamental gap in understanding the complex and dynamic interactions between different Mycobacterium tuberculosis strains and the host. In this pilot study, we investigated the host immune response to different M. tuberculosis strains, including drug-sensitive avirulent or virulent, and rifampin-resistant or isoniazid-resistant virulent strains in human THP-1 cells. We identified major differences in the gene expression profiles in response to infection with these strains. The expression of IDO1 and IL-1β in the infected cells was stronger in all virulent M. tuberculosis strains. The most striking result was the overexpression of many interferon-stimulated genes (ISGs) in cells infected with the isoniazid-resistant strain, compared to the rifampin-resistant and the drug-sensitive strains. Our data indicate that infection with the isoniazid-resistant M. tuberculosis strain preferentially resulted in cGAS-STING/STAT1 activation, which induced a characteristic host immune response. These findings reveal complex gene signatures and a dynamic variation in the immune response to infection by different M. tuberculosis strains.

A novel gene editing lexicon strategy for the haemophilia community: Research plan for development and preliminary results.

Despite the progress in gene editing platforms like CRISPR/Cas9 with thepotential to transform the standard of care for haemophilia, the language used to explain and discuss gene editing is not aligned across the haemophilia community. Here, we present the objective and rationale for developing a clear, consistent, and globally aligned gene editing lexicon to address these communication gaps. Effectively communicating complex gene editing concepts requires a clear and consistent vocabulary. Through collaboration with a diversity of haemophilia stakeholders, our main goal is to develop an accurate, informative lexicon which avoids overpromising or highly technical terminology. Using an innovative process, representatives from several patient and scientific haemophilia organizations and select biotechnology companies will develop and refine language concepts to be tested with approximately seventy participants across the United States of America, United Kingdom, and Germany. Participants will include lived experience experts (LEEs) and haematologists. The process will be overseen by the Lexicon Steering Committee of global experts from leading scientific and patient organizations in the haemophilia and gene editing fields. Initial feedback provided a robust foundation and rationale for building clear, consistent language around gene editing. This lexicon development framework will allow for increased understanding across the haemophilia community, including thedevelopment of valid informed consent and shared decision-making materials. Results provide important building blocks for stimuli development and highlight the need for a novel gene editing lexicon. In the next phase, language stimuli will be tested with LEEs and haematologists to better understand audience preferences and help shape the final lexicon.

Epidemiology and biological characteristics of influenza A (H4N6) viruses from wild birds

ABSTRACT During the active surveillance, we isolated nine H4N6 subtype influenza A viruses from wild birds in China. To reveal the epidemiology and biology characteristics of H4 subtype influenza A virus from wild birds, we investigated H4 subtype viruses available in the public source, and found that the H4 viruses have been detected in at least 37 countries to date, and more than 73.6% of the viruses were from wild Anseriformes. Bayesian phylogeographic analysis showed that Mongolia worked as the important transmission centre for Eurasian lineage H4 viruses spreading. Phylogenetic analysis of HA genes indicated that global H4 influenza A viruses were divided into Eurasian and North American lineage, our nine H4N6 isolates fell into the Eurasian lineage. Recombination analysis suggested that nine H4N6 isolates underwent complex gene recombination with various subtypes of influenza A viruses and formed two genotypes. Notably, nine H4N6 isolates acquired mammalian virulence-increasing residues. Two representative H4N6 viruses possessed dual receptor binding specificity, they could efficiently replicate in MDCK and 293 T cells in vitro infection, also could cross the species barrier to infect mice directly without prior adaption in vivo experiments. These findings emphasize the public health issues represented by H4 viruses, and highlight the need to strengthen the active surveillance of H4 viruses from wild birds.

WRKY Transcription Factors (TFs) as Key Regulators of Plant Resilience to Environmental Stresses: Current Perspective

Plants encounter various stresses in their natural environments and can effectively respond to only one stress at a time. Through a complex gene network, transcription factors (TFs) such as WRKY TFs regulate a diverse array of stress responses. The clarification of the structural characteristics of WRKY proteins, along with recent advancements in molecular dynamics simulations, has shed light on the formation, stability, and interactions of DNA–protein complexes. This has provided a novel viewpoint regarding the control of WRKY TFs. The investigation of superfamilies, encompassing their historical development, diversity, and evolutionary patterns, has become feasible due to the transcriptome approach’s capacity to provide extensive and comprehensive transcripts. The significance of WRKY TFs lies in their pivotal role within several signaling cascades and regulatory networks that influence plant defense responses. The present review summarizes the functional aspects of the high-volume sequence data of WRKY TFs from different species studied to date. Moreover, a comparative analysis approach was utilized to determine the functions of the identified WRKY TFs in response to both abiotic and biotic stresses, as revealed through numerous studies on different plant species. The results of this review will be pivotal in understanding evolutionary events and the significance of WRKY TFs in the context of climate change, incorporating new scientific evidence to propose an innovative viewpoint.

Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing.

Skin wound healing involves a complex gene expression program that remains largely undiscovered in humans. Circular RNAs (circRNAs) and microRNAs (miRNAs) are key players in this process. To understand the functions and potential interactions of circRNAs and miRNAs in human skin wound healing. CircRNA, linear RNA, and miRNA expression in human acute and chronic wounds were analyzed using RNA sequencing and qRT-PCR. The roles of circASH1L(4,5) and miR-129-5p were studied in human primary keratinocytes (proliferation and migration assays, microarray analysis) and ex vivo wound models (histological analysis). The interaction between circASH1L(4,5) and miR-129-5p was examined using luciferase reporter and RNA pull-down assays. We identified circASH1L(4,5) and its interaction with miR-129-5p, both of which increased during human skin wound healing. Unlike typical miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting it from target-directed degradation triggered by NR6A1 mRNA. TGF-β signaling, crucial in wound healing, promoted circASH1L expression while suppressing NR6A1, thereby increasing miR-129 abundance at the post-transcriptional level. CircASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds. Our study uncovers a novel role for circRNAs as protectors of miRNAs and highlights the importance of regulated miRNA degradation in skin wound healing.

Autism: A review

Reduced eye contact, facial expressions, and body movements during the first three years of life are among the social behaviors and nonverbal interactions that define autism spectrum disorder (ASD), a collection of neurodevelopmental diseases. It is generally accepted that this condition is a multifactorial disorder resulting from the combination of both hereditary and non-genetic risk factors. It is not a single disorder. Studies on the genetics of ASD have found mutations that disrupt normal neurodevelopment from infancy through childhood. Axon mobility and synaptogenesis have been linked to these gene complexes. Advances in neuroimaging research have yielded numerous significant insights into the pathological alterations that take place in the brains of individuals with ASD while they are living their lives. Numerous neuropathological and neuroimaging studies have demonstrated the significance of the amygdala, a key component of the limbic system and the affective loop of the cortico-striatothalamo-cortical circuit, in cognition and ASD. The nucleus accumbens is seen as another important structure associated with the social reward response in ASD, in addition to the amygdala. While behavioral and educational interventions have traditionally been the cornerstones of ASD care, pharmaceutical and interventional therapies have also demonstrated some promise in ASD patients. Additionally, a small number of individuals have reportedly improved following deep brain stimulation, one of the interventional treatments.

Identification of Novel Genetic Risk Variants Associated with Hidradenitis Suppurativa in an Exome Sequencing Cohort of 92,455 Individuals

Introduction: Hidradenitis suppurativa (HS) is a prevalent and persistent inflammatory skin disorder, lacking a known cure or effective biomarkers for early diagnosis at present. The genetic determinants of HS have not been fully documented, but it is believed to result from a combination of genetic and environmental factors. Methods: To identify relevant HS gene variants in sporadic HS patients, this study utilized longitudinal electronic health records (EHRs) and whole-exome sequencing. DNA exome sequencing data from 92,455 participant samples in the MyCode biobank, linked to Geisinger’s EHR, were analyzed. This cohort included 1,092 HS cases and 91,363 healthy controls. The MyCode EHR has a median longitudinal follow-up of 15 years per participant, with an average of 87 clinical encounters, 687 laboratory tests, and 7 procedures. Results: There were 1,092 (901 females and 191 males) participants aged 14–89 years (median 47 years) with HS (L73.2), indicating a 1.18% prevalence and accounting for a 4.7:1 female-to-male ratio among the individuals presenting for clinical care. γ-secretase complex, syndromic, and autoinflammatory gene variants were assessed. Potential pathogenic variants were identified among 66 individuals in the HS genes studied. Molecularly, the estimated HS variant prevalence was 1:1,400 in the cohort, 12.3% of variant carriers had HS diagnosis in EHR. Conclusions: Using longitudinal EHR data, genomic screening identified HS-associated gene variants in a defined group of sporadic HS patients to augment the clinical diagnosis, particularly in cases of ambiguity. Based on this study, the field of skin disorders can benefit from a personalized approach to HS diagnosis using large-scale sequencing.

Integrating Metabolic RNA Labeling-Based Time-Resolved Single-Cell RNA Sequencing with Spatial Transcriptomics for Spatiotemporal Transcriptomic Analysis.

Metabolic RNA labeling-based time-resolved single-cell RNA sequencing (scRNA-seq) has provided unprecedented tools to dissect the temporal dynamics and the complex gene regulatory networks of gene expression. However, this technology fails to reveal the spatial organization of cells in tissues, which also regulates the gene expression by intercellular communication. Herein, it is demonstrated that integrating time-resolved scRNA-seq with spatial transcriptomics is a new paradigm for spatiotemporal analysis. Metabolic RNA labeling-based time-resolved Well-TEMP-seq is first applied to profile the transcriptional dynamics of glioblastoma (GBM) cells and discover two potential pathways of EZH2-mediated mesenchymal transition in GBM. With spatial transcriptomics, it is further revealed that the crosstalk between CCL2+ malignant cells and IL10+ tumor-associated macrophages in the tumor microenvironment through an EZH2-FOSL2-CCL2 axis contributes to the mesenchymal transition in GBM. These discoveries show the power of integrative spatiotemporal scRNA-seq to elucidate the complex gene regulatory mechanism and advance the understanding of cellular processes in disease.

Effect of Lactobacillus supernatant on swarming-related gene expression in Proteus mirabilis isolated from urinary tract infections

Proteus mirabilis isolates have been intensively researched for their capacity to cause urinary tract infections (UTIs) and their swarming motility, although little is known about this phenomenon. Probiotic Lactobacillus species, which are beneficial bacteria, are being studied worldwide as therapeutic and preventative agents against bacterial infections. This study investigated Lactobacillus supernatants as a potential new treatment against Proteus mirabilis. In addition to testing their antimicrobial and anti-swarming activities, the research also aimed to understand the genetic mechanisms behind the observed phenotypic changes. Methods. A total of 150 urine specimens were collected from UTI patients at various hospitals in Baghdad. Direct culture was performed by streaking the specimens on differential media. RNA was extracted and purified from the bacterial isolates, and then reverse transcription and quantitative PCR were used to evaluate swarming-related gene expression. Gene expression was assessed relative to a reference gene to reveal how probiotics regulate swarming behavior at the genetic level. Gene expression patterns varied, indicating complex genomic responses to Lactobacillus exposure. Results. UTIs affected 50 males (33.33%) and 100 females (66.66%) of various ages. Proteus mirabilis was identified in 30 (20%) of the 150 samples. Resistance was observed in 25 (83.33%) isolates for azithromycin and amoxicillin/clavulanic acid, and in 22 (73.33%) isolates for meropenem. Real-time PCR showed significant alterations in the expression of four swarming-related genes (rsbA, umoD, ZapA, and FliL). The rsbA gene showed a notable increase in expression, while another sample displayed a decrease. The umoD gene exhibited the largest change, with expression doubling in some cases. ZapA showed the greatest increase, nearly tripling in expression in one sample. FliL expression also rose in multiple isolates. Swarming activity was positively correlated with gene expression levels for rsbA (r = 0.8, p = 0.009), umoD (r = 0.635, p = 0.045), ZapA (r = 0.942, p = 0.001), and FliL (r = 0.894, p = 0.001). Conclusions. The study reveals a complex gene network regulating the swarming motility of Proteus mirabilis. It suggests that Lactobacillus acidophilus supernatants can modify gene expression and bacterial motility, potentially aiding in the treatment of UTIs.

Using bioinformatics to investigate functional diversity: a case study of MHC diversity in koalas.

Conservation genomics can greatly improve conservation outcomes of threatened populations, including those impacted by disease. Understanding diversity within immune gene families, including the major histocompatibility complex (MHC) and toll-like receptors (TLR), is important due to the role they play in disease resilience and susceptibility. With recent advancements in sequencing technologies and bioinformatic tools, the cost of generating high-quality sequence data has significantly decreased and made it possible to investigate diversity across entire gene families in large numbers of individuals compared to investigating only a few genes or a few populations previously. Here, we use the koala as a case study for investigating functional diversity across populations. We utilised previous target enrichment data and 438 whole genomes to firstly, determine the level of sequencing depth required to investigate MHC diversity and, secondly, determine the current level of diversity in MHC genes in koala populations. We determined for low complexity, conserved genes such as TLR genes 10 × sequencing depth is sufficient to reliably genotype more than 90% of variants, whereas for complex genes such as the MHC greater than 20 × and preferably 30 × sequencing depth is required. We used whole genome data to identify 270 biallelic SNPs across 24 MHC genes as well as copy number variation (CNV) within class I and class II genes and conduct supertype analysis. Overall, we have provided a bioinformatic workflow for investigating variation in a complex immune gene family from whole genome sequencing data and determined current levels of diversity within koala MHC genes.

8636 Characterization Of The Role Of Neutrophils In Promoting Progression Of Lymphangioleiomyomatosis

Abstract Disclosure: T.R. Henson: None. B. Minor: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a rare, multisystemic disease that is associated with cystic lung destruction. LAM is caused by small smooth muscle cell-like tumors throughout the lung that contain deleterious mutations in the tuberous sclerosis complex genes TSC1 or TSC2. This attenuates the activity of the mammalian target of rapamycin complex 1 (mTORC1) causing increased proliferation of the smooth muscle cells. LAM is a sexually dimorphic disease that primarily affects genetic females. Clinical observations implicate the role of estrogen in disease progression, as it is exacerbated during pregnancy and by use of exogenous estrogens in birth control. LAM tumor-derived cells lines have shown that direct estrogen stimulation of cell proliferation is modest compared to the dramatic in vivo effects of estradiol (E2) stimulation in a uterine-specific TSC2-null mouse model. Creation of a monoclonal cell line from these mice resulted in the generation of the LTM3 cell line, which also demonstrates low response to direct estrogen stimulation in vitro. This indicates that direct E2 stimulation may act upon other cell types in the tumor microenvironment. Immunophenotyping of uterine-specific TSC2-null mice has shown that the tumor microenvironment is enriched with myeloid cells specifically neutrophils. Functional analysis of neutrophil suppression in vivo has shown a reduction in myometrial growth in the uterine-specific TSC2-null mice, indicating a key role for neutrophil-mediated LAM tumor growth. Altered transcriptional regulation of neutrophils further highlights the importance of neutrophils in LAM progression. Bulk messenger RNA sequencing revealed E2 dependent increase in the neutrophil derived serine protease neutrophil elastase (NE). NE in vitro has been shown to increase migration, invasion, and proliferation of LAM cell lines, while inhibition in vivo has shown a reduction to the myometrial growth. Previously published data by the lab has shown that E2 increases tumor induced expansion of neutrophils in the bone marrow. Isolation and purification of Neutrophils from mouse bone marrow stimulated with tumor conditioned media from the LTM3 cells has shown signs of activation via upregulated gene expression. The focus of the current research has been the characterization of bone marrow derived neutrophils. Currently working with an in vitro system to study the proliferation of LTM3 and the rat leiomyoma (ELT3) cell lines when they are co-cultured with neutrophils. Understanding the mechanism by which neutrophils are activated and interact with LAM cells can give understanding to disease progression may provide insight into future treatment options. Presentation: 6/3/2024

Recording morphogen signals reveals mechanisms underlying gastruloid symmetry breaking.

Aggregates of stem cells can break symmetry and self-organize into embryo-like structures with complex morphologies and gene expression patterns. Mechanisms including reaction-diffusion Turing patterns and cell sorting have been proposed to explain symmetry breaking but distinguishing between these candidate mechanisms of self-organization requires identifying which early asymmetries evolve into subsequent tissue patterns and cell fates. Here we use synthetic 'signal-recording' gene circuits to trace the evolution of signalling patterns in gastruloids, three-dimensional stem cell aggregates that form an anterior-posterior axis and structures resembling the mammalian primitive streak and tailbud. We find that cell sorting rearranges patchy domains of Wnt activity into a single pole that defines the gastruloid anterior-posterior axis. We also trace the emergence of Wnt domains to earlier heterogeneity in Nodal activity even before Wnt activity is detectable. Our study defines a mechanism through which aggregates of stem cells can form a patterning axis even in the absence of external spatial cues.

ADC Value of Optic Nerve in Multiple Sclerosis

Abstract Background Multiple sclerosis (MS) is the commonest non-traumatic disabling disease to affect young adults. The incidence of MS is increasing worldwide, together with the socioeconomic impact of the disease. The underlying cause of MS and mechanisms behind this increase remain opaque, although complex gene–environment interactions almost certainly play a significant role. Aim of the Work To investigate diffusion alteration by measuring ADC values in optic nerve in multiple sclerosis in comparison to the healthy controls. The ADC values of optic nerve may have potential for MS patients as it predict the patients at risk of optic nerve disease and assess the long term effect of MS on optic nerve. Patients and Methods This study is a retrospective study. The study was conducted at Ain Shams University Hospitals over a course of 8 months from December 2022 to July 2023 and the main source of data for this study was the archived MRI imaging of the patients referred to the department of Radiology, Ain Shams University Hospitals. Results Our study included a heterogeneous group of adult patients older than 18 years old. Male patients= 50 (33.8%) and female patients= 98 (66.2%). Multiple sclerosis was found to be associated with risk of optic nerve disease and atrophy due to axonal loss as presented by facilitated diffusion of optic nerve indicated by increase of mean ADC value in MS patients as compared to optic nerve of normal controls. It was found that there is positive correlation between disease duration and optic nerve affection, The mean value of disease duration was found to be 6.18 +/- 5.29 years ranged from 1 to 26 years, Although it was statistically significant weak positive correlation yet it was a good indication to put eye upon the optic nerve affection in MS patients regardless of their clinical presentation, suggesting subclinical optic neuritis in MS. Conclusion Changes detected in ADC value of optic nerve could be helpful in early detection of subclinical optic neuritis even before it presented clinically, this necessitate some modifications in the treatment strategies to prevent or even delay the possibility of optic nerve axonal damage.

Paired transcriptional analysis of periodontitis and peri-implantitis within same host: A pilot study

BackgroundPeri-implantitis, a plaque-associated pathological condition, has been on the rise with the increasing prevalence of dental implants. Despite its similarities to periodontitis, peri‑implantitis is difficult to control completely and has high relapse rates. This has sparked interest in exploring the pathogenic differences between the two conditions. MethodsThis cross-sectional study involved 10 participants to concurrently examine periodontitis and peri‑implantitis within the same patients, thereby minimizing inter-individual variation. Gingival tissue samples were collected from each participant, comprising 10 periodontitis and 10 peri‑implantitis tissues, and RNAs were extracted. Using RNA sequencing and bioinformatics analysis, we investigated complex gene interactions, immune responses, and the role of the extracellular matrix in both conditions. We identified hub genes in each enhanced Protein-Protein Interaction network, providing crucial insights into these diseases’ pathogenesis. ResultsOur findings highlighted the potential involvement of activated fibroblasts in the pathogenesis of peri‑implantitis, identifying three marker genes (ACTA2, FAP, and PDGFRβ) overexpressed in peri‑implantitis, thus highlighting their potential as disease-specific biomarkers. ConclusionsOur study uncovered a novel connection between peri‑implantitis and activated fibroblasts, examining specific markers and microbial differences between periodontitis and peri‑implantitis. These insights improve our understanding of peri‑implantitis pathogenesis, encouraging future research for better management and prevention strategies. Clinical SignificanceThis study identifies key insights into the pathogenesis of peri‑implantitis compared to periodontitis. These findings promise to advance clinical approaches for better managing and preventing peri‑implantitis, addressing its complexities and high relapse rates effectively.