Article
Cell Biology
Yitian Guo, Judeah Negre, Gary Eitzen
Summary: When mast cells are stimulated by antigens, they release preformed inflammatory mediators through a process called degranulation. A protein called GEF-H1 is found to be activated during antigen stimulation and plays a role in activating RhoA to promote mast cell spreading and focal adhesion formation. Depletion of GEF-H1 leads to reduced cell spreading, granule movement, and exocytosis, which can be restored by expressing a constitutively active RhoA mutant. Inhibition of Syk kinase, a protein involved in the Fc epsilon RI signaling pathway, also blocks GEF-H1 activation and suppresses cell spreading, granule movement, and exocytosis.
Article
Biochemistry & Molecular Biology
Muhammad S. Hussain, Degang Liu, Warren J. Alilain, Samy O. Meroueh
Summary: RhoA is a GTPase that regulates the actin cytoskeleton and inhibits axon growth. This study found that covalent bond formation at Cys-107 can inhibit RhoA activation. These findings provide starting points for the development of Rho GTPase inhibitors.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Cell & Tissue Engineering
Jie Zhou, Junying Yang, Yuan Dong, Yaru Shi, Endong Zhu, Hairui Yuan, Xiaoxia Li, Baoli Wang
Summary: Our study has for the first time established the direct role of OSMR in regulating osteogenic differentiation of marrow stromal progenitor cells through ERK-mediated autophagy signaling. OSMR thus contributes to bone homeostasis through dual regulation of osteoblasts and osteoclasts. It also suggests that OSMR may be a potential target for the treatment of metabolic disorders such as osteoporosis.
STEM CELL RESEARCH & THERAPY
(2022)
Article
Cell Biology
Xiaoqi Han, Siyuan Jiang, Yinmin Gu, Lihua Ding, Enhao Zhao, Dongxing Cao, Xiaodong Wang, Ya Wen, Yongbo Pan, Xin Yan, Liqiang Duan, Minxuan Sun, Tao Zhou, Yajuan Liu, Hongbo Hu, Qinong Ye, Shan Gao
Summary: In this study, it was found that HUNK inhibits EMT and metastasis of CRC cells through its kinase-dependent interaction with GEF-H1. HUNK directly phosphorylates GEF-H1 at serine 645, leading to activation of RhoA and subsequent phosphorylation of LIMK-1/CFL-1, resulting in stabilization of F-actin and inhibition of EMT. Clinically, decreased levels of HUNK expression and phosphorylation of GEF-H1 at serine 645 were observed in CRC tissues with metastasis, indicating their potential as biomarkers for metastasis.
CELL DEATH & DISEASE
(2023)
Article
Engineering, Biomedical
Zhao Wei, Jingyi Liu, Yuanbo Jia, Meng Lei, Songbai Zhang, Pan Xi, Yufei Ma, Min Zhang, Jinlu Ma, Lin Wang, Hui Guo, Feng Xu
Summary: The fiber structures of tumor microenvironment play crucial roles in tumor cell behaviors, and recent studies have shown that the plastic remolding of the microenvironment can enhance tumor metastasis. However, the relationship between fiber microarchitecture and matrix plasticity has not been well understood in existing in vitro models. This study develops a collagen-alginate hydrogel platform with tunable matrix plasticity and fiber microarchitecture, and demonstrates that tumor cells exhibit more aggressive behavior in high plasticity hydrogels and that fiber structures only have an impact in high plasticity hydrogels. The study further reveals the underlying mechanisms by analyzing force distribution within the matrix and tracking focal adhesions (FAs), showing that highly plastic hydrogels activate FA formation while fiber dispersion controls the maturation and stability of FAs. This study not only provides new insights into the interaction between cells and the tumor microenvironment, but also contributes to the development of engineered hydrogel platforms for in vitro studies of tumor behaviors.
ADVANCED HEALTHCARE MATERIALS
(2023)
Article
Biochemistry & Molecular Biology
Yanli Zhang, Yingting Pang, Weixi Feng, Yuxi Jin, Sijia Chen, Shixin Ding, Ze Wang, Ying Zou, Yun Li, Tianqi Wang, Peng Sun, Junying Gao, Yi Zhu, Xiaoyan Ke, Charles Marshall, Huang Huang, Chengyu Sheng, Ming Xiao
Summary: Research has found that patients with autism spectrum disorder (ASD) have higher levels of miR-124, which may be related to brain development and social isolation. Animal models indicate that the miR-124 signaling pathway is involved in regulating myelination in brain regions associated with early social experiences, and could be a potential therapeutic target for neuropsychiatric disorders related to social neglect or social isolation.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Neurosciences
Yanyu Ding, Fang Fang, Xiaolong Liu, Shuyan Sheng, Xueyan Li, Xiaojiao Yin, Zhiwu Chen, Jiyue Wen
Summary: This study investigated the role of hydrogen sulfide (H2S) in the phenotypic change of astrocytes following cerebral ischemia/reperfusion (I/R) in mice. The results showed that H2S could regulate the transformation of astrocytes to A2 phenotype following cerebral I/R, which is beneficial for neuronal recovery. Furthermore, H2S exerts its neuroprotective effect by inhibiting the RhoA/ROCK pathway.
MOLECULAR NEUROBIOLOGY
(2023)
Review
Pharmacology & Pharmacy
Xiaoli Pan, Junping Pei, Aoxue Wang, Wen Shuai, Lu Feng, Faqian Bu, Yumeng Zhu, Lan Zhang, Guan Wang, Liang Ouyang
Summary: This review provides an overview of the roles of the ERKs signaling pathway in cancer and the structure-activity relationships of small molecule inhibitors targeting ERKs. It offers important insights for drug design and optimization as well as potential therapeutic strategies to overcome drug resistance.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Cell Biology
Arun A. Chandrakumar, Etienne Coyaud, Christopher B. Marshall, Mitsuhiko Ikura, Brian Raught, Robert Rottapel
Summary: Rab11 GTPase proteins play important roles in cytokinesis, ciliogenesis, and lumenogenesis; SH3BP5 and SH3BP5L are crucial for the activation of Rab11a and cyst lumen formation; Tankyrase regulates epithelial polarity and lumen formation by inhibiting SH3BP5 and SH3BP5L, which is counteracted by RNF146.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Cell Biology
Silvio Holzner, Sophie Bromberger, Judith Wenzina, Karin Neumuller, Tina-Maria Holper, Peter Petzelbauer, Wolfgang Bauer, Benedikt Weber, Klaudia Schossleitner
Summary: The study reveals that cingulin strengthens vascular barrier integrity by interacting with GEF-H1, attenuating myosin light chain 2 phosphorylation and protecting barrier function in blood endothelial cells during disease.
JOURNAL OF CELL SCIENCE
(2021)
Article
Biotechnology & Applied Microbiology
Chuping Luo, Jiachen Liu, Muhammad Bilal, Xuehui Liu, Xiaohua Wang, Fei Dong, Yuan Liu, Shanshan Zang, Xiulian Yin, Xueting Yang, Tao Zhu, Shuangyu Zhang, Weifeng Zhang, Bin Li
Summary: This study proposed a novel molecular mechanism for triggering multicellularity in B. velezensis Bs916 through an endogenous cyclic lipopeptide, bacillomycin L. The disruption of gene cluster caused genome-wide effect on gene expression, leading to changes in swarming motility and complex biofilm formation. Bacillomycin L acted as a tuning signal by indirectly regulating the expression levels of some two-component systems connector genes, particularly those that potentially regulate the phosphorylation levels of major regulators ComA, DegU, and Spo0A.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Mengling Chang, Lei Yi, Zengding Zhou, Xin Yi, Hongsai Chen, Xiao Liang, Rui Jin, Xiaoqin Huang
Summary: One of the key targets of the inflammatory response in acute lung injury (ALI) is human pulmonary microvascular endothelial cells (HPMVECs). CD40L plays an important role in the pathogenesis of ALI by triggering NF-κB-dependent gene expression on endothelial cells. This study found that CD40L stimulates the transactivation of NF-κB and the expression of downstream cytokines in HPMVECs through a p38 MAPK-dependent mechanism. The GEF-H1/RhoA signaling pathway is involved in the CD40L-induced inflammatory responses in the lung.
MOLECULAR IMMUNOLOGY
(2023)
Article
Cell Biology
Leonardo Lupori, Sara Cornuti, Raffaele Mazziotti, Elisa Borghi, Emerenziana Ottaviano, Michele Dei Cas, Giulia Sagona, Tommaso Pizzorusso, Paola Tognini
Summary: Exposing animals to an enriched environment (EE) has significant effects on brain structure, function, and plasticity, which are believed to be mediated by signals from the gut microbiota. This study reveals differences in gut bacterial composition and higher levels of short-chain fatty acids (SCFA) in EE mice compared to standard rearing (ST) mice. Depletion of gut microbiota in EE mice reduces SCFA levels and prevents activation of brain plasticity. Treatment with SCFA in ST mice mimics the effects of EE on brain plasticity. Importantly, transferring the gut microbiota from EE mice to ST mice activates brain plasticity. Therefore, changes in gut microbiota due to environmental enrichment play a crucial role in regulating brain plasticity.
Article
Cell Biology
Shumpei Nakashima, Takahide Matsui, Mitsunori Fukuda
Summary: Vps9d1 is identified as a novel Rab22A-GEF, which promotes the formation of tubular endosomes by specifically activating Rab22A. Depletion of Vps9d1 leads to impaired tubular endosome structures and altered distribution and recycling of clathrin-independent endocytosed cargos.
JOURNAL OF CELL SCIENCE
(2023)
Article
Medicine, Research & Experimental
Wan-Hsin Lin, Ryan W. Feathers, Lisa M. Cooper, Laura J. Lewis-Tuffin, Jiaxiang Chen, Jann N. Sarkaria, Panos Z. Anastasiadis
Summary: The Rho family guanine nucleotide exchange factor Syx promotes GBM cell growth by regulating cell cycle progression, DNA damage, and therapy resistance. Depletion of Syx leads to prolonged mitosis, increased DNA damage, cell cycle arrest, and cell apoptosis. Targeting the Syx signaling pathway may provide a potential treatment option for GBM.
Article
Cell Biology
Tae Chung, Taylor Bopp, Chris Ward, Francesca M. Notarangelo, Robert Schwarcz, Reyhan Westbrook, Qian-Li Xue, Jeremy Walston, Ahmet Hoke
Summary: Decline in neuromuscular function is a major factor contributing to disability and mortality in the elderly, but the neurobiology of age-associated muscle weakness is not well understood. This study used a mouse model with a deletion of the QPRT gene to examine the neurobiology of neurotoxic metabolites. The findings suggest that the kynurenine pathway may play an important role in frailty and age-associated muscle weakness.
Letter
Critical Care Medicine
Chris Ward, Hafez Al Momani, Melissa J. McDonnell, Desmond M. Murphy, Laura Walsh, John Mac Sharry, Mike Griffin, Ian A. Forrest, Rhys Jones, Amaran Krishnan, Jeffrey Pearson, Robert M. Rutherford
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2023)
Article
Otorhinolaryngology
C. D. Campbell, P. C. Ridge, M. J. McDonnell, C. Ward, M. J. Harrison, C. Collins, R. M. Rutherford
Article
Respiratory System
Jason Powell, Steven Powell, Michael W. Mather, Lauren Beck, Andrew Nelson, Pawel Palmowski, Andrew Porter, Jonathan Coxhead, Ann Hedley, Jonathan Scott, Anthony J. Rostron, Thomas P. Hellyer, Fatima Zaidi, Tracey Davey, James P. Garnett, Rachel Agbeko, Chris Ward, Christopher J. Stewart, Clifford C. Taggart, Malcolm Brodlie, A. John Simpson
Summary: This study aimed to characterize airway host defense in tracheostomized children using serial molecular analyses. The results showed that long-term tracheostomy was associated with airway neutrophilic inflammation and the ongoing presence of potential respiratory pathogens. These findings suggest neutrophil recruitment and activation as potential therapeutic targets in preventing recurrent airway complications in this vulnerable group of patients.
Article
Multidisciplinary Sciences
Hafez Al-Momani, Dua'a Al Balawi, Saja Hamed, Borhan Aldeen Albiss, Muna Almasri, Hadeel AlGhawrie, Lujain Ibrahim, Hadeel Al Balawi, Sameer Al Haj Mahmoud, Jeffrey Pearson, Christopher Ward
Summary: In this study, the antibacterial properties of Zinc Oxide nanoparticles (ZnO NPs) were evaluated against Pseudomonas aeruginosa (PA) strains. The biosynthesized ZnO NPs were found to inhibit the growth and biofilm formation of PA strains, and reduce the expression of quorum sensing genes. The results suggest that ZnO NPs can be a potential treatment for PA and other antibiotic resistant bacteria.
SCIENTIFIC REPORTS
(2023)
Article
Multidisciplinary Sciences
Hafez Al-Momani, Muna Almasri, Dua'A. Al Balawi, Saja Hamed, Borhan Aldeen Albiss, Nour Aldabaibeh, Lugain Ibrahim, Hadeel Albalawi, Sameer Al Haj Mahmoud, Ashraf I. Khasawneh, Muna Kilani, Muneef Aldhafeeri, Muayyad Bani-Hani, Matthew Wilcox, Jeffrey Pearson, Christopher Ward
Summary: This study evaluated the antibacterial and antibiofilm effectiveness of biosynthesized silver nanoparticles (Ag NPs) against biofilm-forming clinical isolates of Pseudomonas aeruginosa (PA). Ag NPs showed significant inhibitory effects on growth and biofilm formation of PA strains, as well as reduced expression of biofilm-encoding genes. The findings demonstrate the potential of Ag NPs in the treatment of PA infections.
SCIENTIFIC REPORTS
(2023)
Article
Multidisciplinary Sciences
Luis F. Iglesias-Martinez, Nora Rauch, Kieran Wynne, Brendan McCann, Walter Kolch, Jens Rauch
Summary: RAF kinases are important in cancer, particularly the BRAFV600E mutants. Although potent kinase inhibitors exist, their effects vary in different cancer types and can even induce paradoxical RAF kinase activation. Enhanced dimerization between RAF1 and BRAF contributes to both paradoxical activation and drug resistance. Mapping the interactomes of RAF1 monomers, RAF1-BRAF, and RAF1-BRAFV600E dimers, we identified and quantified over 1,000 proteins. Additionally, we analyzed the effects of vemurafenib and sorafenib, two clinically used RAF inhibitors, and found overlapping core interactomes with distinct condition-specific differences. Understanding these dynamic interactome changes may provide insights into RAF signaling and resistance mechanisms.
Article
Multidisciplinary Sciences
Ana Martin-Vega, Laura Ruiz-Peinado, Rocio Garcia-Gomez, Ana Herrero, Dalia de la Fuente-Vivas, Swetha Parvathaneni, Ruben Caloto, Marta Morante, Alex von Kriegsheim, Xose R. Bustelo, David B. Sacks, Berta Casar, Piero Crespo
Summary: RAS-ERK pathway signals are regulated by scaffold proteins, and it is revealed that scaffold proteins can interact with each other and undergo phosphorylation reactions. The trans-phosphorylation process participates in KSR1-regulated adipogenesis and the cytotoxicity exhibited by KSR-directed inhibitors. This finding has implications in signaling and the design of scaffold protein-aimed therapeutics.
Letter
Medicine, Research & Experimental
Adil Aldhahrani, Jeffrey Pearson, Chris Ward
Article
Multidisciplinary Sciences
Cemal Erdem, Sean M. M. Gross, Laura M. M. Heiser, Marc R. R. Birtwistle
Summary: A problem in network biology is the identification of context-specific networks. In this study, the authors introduce MOBILE (Multi-Omics Binary Integration via Lasso Ensembles) as a method to nominate molecular features associated with cellular phenotypes and pathways. They use MOBILE to investigate interferon-γ regulated PD-L1 expression and compare networks activated by related family members TGF-β1 and BMP2. The authors also demonstrate the broad applicability of MOBILE by analyzing publicly available molecular datasets to study breast cancer subtype specific networks.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Thomas Schwarzl, Andrea Keogh, Georgina Shaw, Aleksandar Krstic, Elizabeth Clayton, Desmond G. Higgins, Walter Kolch, Frank Barry
Summary: Articular cartilage has limited regenerative capacities in humans, and tissue engineering techniques for producing hyaline cartilage are also limited. Differentiating multipotent stem cells into mature cartilage cells could be a potential solution for repairing damaged cartilage. However, chondrogenesis is a complex and inefficient process.
Article
Oncology
Aoife Nolan, Cinzia Raso, Walter Kolch, Alex von Kriegsheim, Kieran Wynne, David Matallanas
Summary: RAS proteins play a crucial role in cell signalling, regulating cell functions such as proliferation, differentiation, and death. Mutations in genes of this family, particularly KRAS, are common and were believed to constitutively activate KRAS. However, recent findings show that some mutants can switch between active and inactive states. This, along with the development of covalent KRASG12C inhibitors, has led to the emergence of KRAS inhibitors in clinical use. Despite this, resistance to targeted therapies remains a challenge, and effective treatments for other KRAS mutants are lacking. To overcome these hurdles and accelerate RAS targeting therapies, a comprehensive understanding of the molecular mechanisms underlying KRAS signalling networks and the differences in downstream signalling of KRAS mutants is needed. This study employed affinity purification mass-spectrometry proteomics to analyze the interactome of KRAS wild-type and three KRAS mutants. Through bioinformatic analysis and experimental validation, the researchers mapped the signalling network mediated by different KRAS proteins. The study also revealed novel crosstalk between KRAS and effector pathways, including AKT and JAK-STAT signalling modules.
Article
Pharmacology & Pharmacy
Khadeijah Almarshoodi, Carlos Echevarria, Abeer Kassem, Bassam Mahboub, Laila Salameh, Chris Ward
Summary: The DECAF score is a strong predictor of inpatient death, 30-day mortality, and 90-day readmission in patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) in the United Arab Emirates (UAE). It can help clinicians make appropriate clinical decisions and improve patient outcomes.
Article
Biochemistry & Molecular Biology
Zhi Liu, Aleksandar Krstic, Ashish Neve, Cristina Casalou, Nora Rauch, Kieran Wynne, Hilary Cassidy, Amanda McCann, Emma Kavanagh, Brendan McCann, Alfonso Blanco, Jens Rauch, Walter Kolch
Summary: KSR1 plays a critical role in mutant BRAF transformation, and its loss results in impaired cell proliferation and migration, cell cycle abnormalities, cellular senescence, and apoptosis. The study reveals that KSR1 directs ERK to phosphorylate substrates essential for cell survival, and its loss activates p38 MAPK pathway leading to cell cycle aberrations and senescence.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Allergy
Laura J. Walsh, Ashley Sullivan, Christopher Ward, Liam J. Fanning, Paul M. O'Byrne, John A. MacSharry, Desmond M. Murphy
Summary: The presence of virus in non-exacerbating asthmatic patients may lead to poorer asthma control and altered airway cytokine composition. Further research is needed to understand the role of viruses in the lung microbiota and their impact on asthma.
ALLERGY ASTHMA & IMMUNOLOGY RESEARCH
(2023)
