Transition Pathways Research Articles

Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC.

The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with epithelial mesenchymal transition and hallmark pathways of metastasis. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered EphB4 ligands EFNB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggest that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.

Nebulized milk exosomes loaded with siTGF-β1 ameliorate pulmonary fibrosis by inhibiting EMT pathway and enhancing collagen permeability

Pulmonary Fibrosis (PF) is a fatal disease in the interstitial lung associated with high mortality, morbidity, and poor prognosis. Transforming growth factor-β1 (TGF-β1) is a fibroblast-activating protein that promotes fibrous diseases. Herein, an inhalable system was first developed using milk exosomes (M-Exos) encapsulating siRNA against TGF-β1 (MsiTGF-β1), and their therapeutic potential for bleomycin (BLM)-induced PF was investigated. M-siTGF-β1 was introduced into the lungs of mice with PF through nebulization. The collagen penetration effect and lysosomal escape ability were verified in vitro. Inhaled MsiTGF-β1 notably alleviated inflammatory infiltration, attenuated extracellular matrix (ECM) deposition, and increased the survival rate of PF mice by 4.7-fold. M-siTGF-β1 protected lung tissue from BLM toxicity by efficiently delivering specific siRNA to the lungs, leading to TGF-β1 mRNA silencing and epithelial mesenchymal transition pathway inhibition. Therefore, M-siTGF-β1 offers a promising avenue for therapeutic intervention in fibrosis-related disorders.

Understanding Business Models in the Brazilian Context of Electric Mobility: A Proposed Framework

In the transition to electric mobility (EM), business model innovation plays a crucial role in expanding the use of electric vehicles and increasing acceptance of this technology. The transition pathways differ between countries in the largest economies and those in Latin America. Brazil presents a unique scenario, benefiting from an early start with biofuels, the production of flex-fuel vehicles, predominantly renewable electric energy generation (>80%), and the absence of a structured national policy aligned with local governments. This study introduces a framework that surveys and categorizes businesses in EM, relating them to sustainable development aspects and regulatory maturity. It builds a solid conceptual foundation, incorporating data from technical and commercial events, as well as interviews with Brazilian specialists for validation. The proposed framework aids in understanding the Brazilian context, identifying regulatory gaps, and developing a common language to advance studies on business model innovation, contributing to electromobility studies in Latin America. Additionally, it can guide the construction of regional and local public policies and help identify more sustainable projects.

Potential of hydrogen and thermal storage in the long-term transition of the power sector: A case study of China

Hydrogen and thermal storage can reduce cost of long-term and large-scale energy storage with high efficiency and low or even zero carbon emissions. Their potential in the low-carbon transition pathway of an energy system with rapid growth of energy demand, large shifting of energy supply structure and limited investment budget remains unclear. A long-term power generation planning model is proposed in this paper, featuring detailed technical and economic characteristics of hydrogen and thermal storage. The power supply system of China is selected as a case study, due to its urgent need for low-carbon transition and complex spatial characteristics. Results show that the application of hydrogen and thermal storage can benefit the development of volatile renewable power generation technologies, facilitate the transition towards zero or even negative carbon emissions while simultaneously reducing power supply costs. Hydrogen is expected to be mainly produced in spring and consumed in summer while heat is expected to be primarily generated in autumn and consumed in winter. Shifting from thermal storage to hydrogen storage might happen around 2050 in accordance to the low-carbon transition progress.

Combining E-Scores with Scenario Analysis to Evaluate the Impact of Transition Risk on Corporate Client Performance

Scenario analysis is a comprehensive approach to assess the impact of climate-related transition risk on businesses. Environmental, social, and governance (ESG) scores are popular tools with financial institutions (FI’s) for green-scoring practices and since they characterise a company’s performance from an ESG perspective, they have been criticised for enabling “greenwashing” when used within the context of climate risk. Commercially available ESG scores are also available for listed entities, while FI counterparties are often unlisted. This study develops a methodology for creating in-house environmental scores (E-scores), which are then used to effectively choose appropriate transition pathways to be used in company-specific forward-looking scenario analysis. Such scenario analysis can be used to forecast the company’s financial position, including the cost of its greenhouse gas (GHG) emissions, and quantify the impact of transition climate risk on specified metrics. The choice of metrics depends on what the results of the analysis are used for. Two metrics are identified for being useful for risk management and credit decisions: future profitability and weighted average carbon intensity. Finally, the study demonstrates how this process can be implemented with a practical worked example, using only publicly available data.

Inverse mapping of quantum properties to structures for chemical space of small organic molecules

Computer-driven molecular design combines the principles of chemistry, physics, and artificial intelligence to identify chemical compounds with tailored properties. While quantum-mechanical (QM) methods, coupled with machine learning, already offer a direct mapping from 3D molecular structures to their properties, effective methodologies for the inverse mapping in chemical space remain elusive. We address this challenge by demonstrating the possibility of parametrizing a chemical space with a finite set of QM properties. Our proof-of-concept implementation achieves an approximate property-to-structure mapping, the QIM model (which stands for “Quantum Inverse Mapping”), by forcing a variational auto-encoder with a property encoder to obtain a common internal representation for both structures and properties. After validating this mapping for small drug-like molecules, we illustrate its capabilities with an explainability study as well as by the generation of de novo molecular structures with targeted properties and transition pathways between conformational isomers. Our findings thus provide a proof-of-principle demonstration aiming to enable the inverse property-to-structure design in diverse chemical spaces.

HIV-1-envelope trimer transitions from prefusion-closed to CD4-bound-open conformations through an occluded-intermediate state.

HIV-1 infection is initiated by the interaction between the gp120 subunit in the envelope (Env) trimer and the cellular receptor CD4 on host cells. This interaction induces substantial structural rearrangement of the Env trimer. Currently, static structural information for prefusion-closed trimers, CD4-bound prefusion-open trimers, and various antibody-bound trimers is available. However, dynamic features between these static states (e.g., transition structures) are not well understood. Here, we investigate the full transition pathway of a site specifically glycosylated Env trimer between prefusion-closed and CD4-bound-open conformations by collective molecular dynamics and single-molecule Förster resonance energy transfer (smFRET). Our investigations reveal and confirm important features of the transition pathway, including movement of variable loops to generate a glycan hole at the trimer apex and formation or rearrangements of α-helices and β-strands. Notably, by comparing the transition pathway to known Env-structures, we uncover evidence for a transition intermediate, with four antibodies, Ab1303, Ab1573, b12, and DH851.3, recognizing this intermediate. Each of these four antibodies induce population shifts of Env to occupy a newly observed smFRET state: the "occluded-intermediate" state. We propose this occluded-intermediate state to be both a prevalent state of Env and an on-path conformation between prefusion-closed and CD4-bound-open states, previously overlooked in smFRET analyses.

Exploring barriers in the transition toward an established e-waste management system in Brazil: a multiple-case study of the formal sector

AbstractBrazil is the largest generator of electrical and electronic waste (e-waste) in Latin America but faces significant challenges with its management. This study investigates barriers to the growth of the formal sector in transitioning toward an established e-waste management system in the country. Driven by sustainability transitions research, it applies a transition management approach to e-waste management. The study presents the results of field studies conducted in four organizations with different levels of recycling operations. The results show several barriers, for instance, a lack of processes for the complete separation of metals, high reverse logistics cost, a lack of transparency throughout the supply chains, concern with data security, and a lack of financial incentives and policy integration. The study highlights various initiatives from the organizations that assist in tackling some of the identified barriers and shed light on possible transition pathways. The study provides a perspective from e-waste management organizations and policy insights to strengthen e-waste management in the country.

Assessing Transition Pathways of Hydrogen Production in China with a Probabilistic Framework.

The transition of China's hydrogen production system to meeting carbon neutrality is considerably uncertain. This study uses a probabilistic framework to assess the transition pathways of hydrogen production in China to meet the goal of carbon neutrality and reveals the key technology selection mechanism. Three strategies for hydrogen production transition were considered: delayed, orderly, and radical, corresponding to the green hydrogen shares between 70 and 95% in 2060. More ambitious strategies tended to result in greater uncertainty of green hydrogen production and introduce higher system costs and cost uncertainty. The different strategies showed notable differences in carbon dioxide (CO2) reduction pathways. The cumulative CO2 emissions of the delayed strategy may reach 3 times that of the radical strategy, and the CO2 reduction uncertainty of the orderly strategy may be twice that of the other strategies. Alkaline electrolyzers were predicted to dominate green hydrogen production until being surpassed by proton exchange membrane electrolyzers (PEM) after 2060. The synergy of the solar-energy storage-PEM technology combination was notable because expensive electrolyzers tended to increase utilization, thereby diluting fixed costs. Our results underscore the importance of studying the impact of uncertainty and technology selection mechanisms on transition pathways.

Subnational perspectives on energy transition pathways for Mexico's electricity grid

This study utilizes a state-level approach to explore the economic implications of decarbonizing Mexico's electricity grid. By modeling the costs of four power generation mix scenarios for 2060, the research highlights the diverse renewable energy potentials and current power generation mixes across Mexican states. While transitions to natural gas or nuclear power emerge as the most economically attractive options, the study underscores the environmental and political benefits of renewable energy pathways. States with significant renewable resources are prime candidates for early adoption of wind and solar power. The analysis emphasizes the importance of a decentralized approach to energy policy, allowing states to tailor strategies to their unique circumstances.

Conceptualizing transgender experiences in psychology: Do we have a 'true' gender?

Psychological research has acknowledged that the commonly accepted definitions of 'transgender', 'sex' and 'gender' within psychological research have resulted in limitations in accounting for the lived realities of transgender individuals. Such limitations include, but are not limited to, the continued pathologization of transgender experiences through idealizing sex and gender congruence and incapacity to account for non-normative and non-binary transition pathways. This paper provides a review of these limitations to first demonstrate how the incongruence definition of 'transgender' is reliant on the idea of a 'true' gender, and next suggest that problematising the idea of a 'true' gender allows new conceptions of transgender experiences to be advanced. To undertake this problematization, the work of Judith Butler and Sara Ahmed is used to consider how gender could be conceptualized otherwise in psychology and then applied to transgender experiences. In all, this paper theorizes transgender experiences without a reliance on the assertion of a true gender, to suggest instead a focus on contextualized transgender experiences. Last, the limitations and implications of this definition of transgender are briefly discussed. Overall, transgender experiences are conceptualized as those experiences that run counter to the dominant (re)production of binary sexed gender.

Transition from child to adult health services for young people with cerebral palsy in Ireland; implications from a mixed-methods study

Background Poor transition from child- to adult-oriented healthcare may lead to negative outcomes and dissatisfaction with services in adulthood. The aim of the study was to examine how transition is provided to and experienced by young people with CP in Ireland. This report provides integrated quantitative and qualitative findings and implications based on the totality of knowledge generated. Methods A convergent parallel mixed-methods study was conducted. Data were collected from people with CP aged 16-22 years, parents, and health professionals using surveys and semi-structured interviews, informed by a framework of nine key transition practices. Quantitative and qualitative findings were integrated at the interpretation stage of the research using integration through joint displays. Implications were developed through discussions with health professionals, young people, and parents. Results Surveys were completed by 75 young people/parents and 108 health professionals. Interviews were conducted with 13 young people, 14 parents, and 27 health professionals. There was complementarity between quantitative and qualitative findings indicating lack of a named worker, limited information provision, insufficient self-management support, no opportunity to meet the adult team, limited contact with the GP, and no opportunity for attending formal life skills training. There was dissonance between quantitative and qualitative findings regarding appropriate level of parental involvement. There was silence between quantitative and qualitative findings for promotion of health self-efficacy and senior manager responsible for transition, with quantitative findings indicating these were not present for most young people, but qualitative findings not describing these practices Conclusion Implications of integrated findings include the need for a standardised transition pathway, intentional actions to enable parents and young people to adapt to changing roles, provision of information in a collaborative and phased approach, a common understanding of self-management between young people, parents and health professionals, and the need to involve adults’ services and GPs in transition.

Achieving net-zero U.S. ammonia: Technology and policy options and their emissions, investment, and cost tradeoffs

Ammonia production is responsible for around 35% of the CO2 emissions associated with the global chemical sector. In this study, a bottom-up model with high technical and economic resolution is implemented to assess potential least-cost pathways to achieve a net-zero U.S. ammonia industry by 2050. Results indicate that natural gas reformers equipped with carbon capture technologies may play a key role in decarbonizing U.S. ammonia production in the near term, while water electrolysis will be required in the long term to achieve net-zero emissions. Technical improvements and cost reductions in electrolyzers and lower-cost renewable electricity will be needed to accelerate the adoption of water electrolysis. Furthermore, two key policy interventions were investigated (carbon pricing and production tax credits) and were found to hold significant potential for accelerating low-carbon ammonia production technologies and for further reducing the cumulative carbon emissions. The methodology and analyses presented in this study provide important insights into available transition pathways to decarbonized U.S. ammonia production, providing fundamental insights for policy makers on required actions and investments to achieve the net-zero emissions targets.

Boric Acid Matrix‐Activated nπ* Transition of Guest Chromophores: from Pure Fluorescence to Efficient Afterglow

AbstractEl‐Sayed rule highlights the important role of heteroatoms (e.g., N, O, and S) and the corresponding nπ* transition in designing efficient organic phosphors. Nevertheless, for some heteroatom‐rich fluorophores, their phosphorescence is quite weak (e.g., fluorescein), since the nπ* components are absent in the whole transitions. Here, these chromophores (mainly with n electron‐containing twisted structure) are found doping into the boric acid (BA) matrix can activate the nπ* transition for efficient afterglow luminescence. For example, doping purely green‐emitting fluorescein into BA yielded a high afterglow quantum yield (≈24%) and a long‐lasting, blue‐shifted cyan afterglow (>10 s). The covalent/non‐covalent interactions between the BA matrix and the guests resulted in twisting the n electron‐containing structure to promote the spin‐orbit coupling process, leading to the generation of new excited state triplet transition pathways. Since the guest chromophores feature visible light absorption, a series of multi‐color afterglow phosphors with visible or white light excitation are successfully constructed.

Myofibroblasts derived type V collagen promoting tissue mechanical stress and facilitating metastasis and therapy resistance of lung adenocarcinoma cells

Lung cancer is a leading cause of cancer-related mortality globally, with a dismal 5-year survival rate, particularly for Lung Adenocarcinoma (LUAD). Mechanical changes within the tumor microenvironment, such as extracellular matrix (ECM) remodeling and fibroblast activity, play pivotal roles in cancer progression and metastasis. However, the specific impact of the basement membrane (BM) on the mechanical characteristics of LUAD remains unclear. This study aims to identify BM genes influencing internal mechanical stress in tumors, elucidating their effects on LUAD metastasis and therapy resistance, and exploring strategies to counteract these effects. Using Matrigel overlay and Transwell assays, we found that mechanical stress, mimicked by matrix application, augmented LUAD cell migration and invasion, correlating with ECM alterations and activation of the epithelial-mesenchymal transition (EMT) pathway. Employing machine learning, we developed the SVM_Score model based on relevant BM genes, which accurately predicted LUAD patient prognosis and EMT propensity across multiple datasets. Lower SVM_Scores were associated with worse survival outcomes, elevated cancer-related pathways, increased Tumor Mutation Burden, and higher internal mechanical stress in LUAD tissues. Notably, the SVM_Score was closely linked to COL5A1 expression in myofibroblasts, a key marker of mechanical stress. High COL5A1 expression from myofibroblasts promoted tumor invasiveness and EMT pathway activation in LUAD cells. Additionally, treatment with Sorafenib, which targets COL5A1 secretion, attenuated the tumor-promoting effects of myofibroblast-derived COL5A1, inhibiting LUAD cell proliferation, migration, and enhancing chemosensitivity. In conclusion, this study elucidates the complex interplay between mechanical stress, ECM alterations, and LUAD progression. The SVM_Score emerges as a robust prognostic tool reflecting tumor mechanical characteristics, while Sorafenib intervention targeting COL5A1 secretion presents a promising therapeutic strategy to mitigate LUAD aggressiveness. These findings deepen our understanding of the biomechanical aspects of LUAD and offer insights for future research and clinical applications.

Impact of electronic correlation on strong laser-induced bound-state transitions

Electron correlation (EC) plays a crucial role in all multi-electron systems and dynamic processes. In this work, we focus on strong laser-induced bound-bound transitions (BBT), which are fundamental to optical absorption measurements. We use the helium atom, the simplest two-electron system, as our test case, utilizing the ab initio code package HeTDSE. We examined the bound state energy levels, transition dipole moments (TDMs), and the dynamics of strong laser-induced BBT, both with and without considering EC. Our results indicate that EC significantly impacts the energy levels of the bound states and the TDMs. These effects collectively influence the transition dynamics of the excited states. Although EC does not alter the quantum transition pathways between resonance states, it generally increases the probability of resonance transitions in most cases. Our findings provide a quantitative description of EC in laser-induced BBT.

Cytoplasmic Lipid Droplets Predict Worse Prognosis in Diffuse Large B-Cell Lymphoma: Next-Generation Sequencing Deciphering Lipogenic Genes.

Burkitt lymphoma is characterized by high cell turnover and numerous cytoplasmic vacuoles that are demonstrated to be lipid droplets (LDs) decorated by adipophilin. By contrast, cytoplasmic vacuoles are variably observed in diffuse large B-cell lymphoma (DLBCL) and less well characterized. In this study, we first validated in DLBCL that cytoplasmic vacuoles are indeed LDs by Oil-red-O stain, Bodipy fluorescent stain, and electron microscopy. Second, in a cohort of DLBCL patients (n=52) we showed that LDs in effusional lymphoma cells were associated with a poorer prognosis (P=0.029, log-rank test) and higher International Prognostic Index (IPI) score (94% vs. 66%, P=0.026) than those without. Moreover, using adipophilin as a surrogate marker for LDs, we found in another cohort of biopsy specimen (n=85) that expression of adipophilin by lymphoma cells predicted a poorer prognosis (P=0.007, log-rank test) and higher IPI score (63% vs. 30%, P=0.005). In addition, whole exome sequencing of effusional DLBCL cells showed LD-positive DLBCL shared genetic features with the MCD (MYD88 and CD79B mutations) subtype and highlighted OSBPL10 and CUBN as the most frequently mutated genes involved in lipogenesis. Whole transcriptome analysis by comparing effusional DLBCL cells with versus without LDs showed upregulation of EHHADH, SLC1A1, CD96, INPP4B, and RNF183 relevant for lymphoma lipogenesis and upregulation of epithelial-mesenchymal transition and KRAS signaling pathways. Higher expression of EHHADH and CD96 were validated in LD-positive clinical samples and LD-rich cell lines than LD-poor cells along with the known lipogenic gene, FASN. Our findings highlight the roles of LDs and adipophilin expression in DLBCL, suggest that these markers may predict prognosis and show that lipogenic genes may be potential therapeutic targets.

Mathematical optimization modeling for scenario analysis of integrated steelworks transitioning towards hydrogen-based reduction

To reduce carbon dioxide emissions from the steel industry, efforts are made to introduce a steelmaking route based on hydrogen reduction of iron ore instead of the commonly used coke-based reduction in a blast furnace. Changing fundamental pieces of steelworks affects the functions of most every system unit involved, and thus warrants the question of how such a transition could optimally take place over time, and no rigorous attempts have until now been made to tackle this problem mathematically. This article presents a steel plant optimization model, written as a mixed-integer non-linear programming problem, where aging blast furnaces and basic oxygen furnaces could potentially be replaced with shaft furnaces and electric arc furnaces, minimizing costs or emissions over a long-term time horizon to identify possible transition pathways. Example cases show how various parameters affect optimal investment pathways, stressing the necessity of appropriate planning tools for analyzing diverse cases.

PP2A B55α inhibits epithelial-mesenchymal transition via regulation of Slug expression in non-small cell lung cancer

PP2A B55α, encoded by PPP2R2A, acts as a regulatory subunit of the serine/threonine phosphatase PP2A. Despite a frequent loss of heterozygosity of PPP2R2A in cases of non-small cell lung cancer (NSCLC), research on PP2A B55α′s functions remains limited and controversial. To investigate the biological roles of PP2A B55α, we conducted bulk RNA-sequencing to assess the impact of PPP2R2A knockdown using two shRNAs in a NSCLC cell line. Gene set enrichment analysis (GSEA) of the RNA-sequencing data revealed significant enrichment of the epithelial-mesenchymal transition (EMT) pathway, with SNAI2 (the gene encoding Slug) emerging as one of the top candidates. Our findings demonstrate that PP2A B55α suppresses EMT, as PPP2R2A deficiency through knockdown or homozygous or hemizygous depletion promotes EMT and metastatic behavior in NSCLC cells, as evidenced by changes in EMT biomarkers, invasion and migration abilities, as well as metastasis in a tail vein assay. Mechanistically, PP2A B55α inhibits EMT by downregulating SNAI2 expression via the GSK3β-β-catenin pathway. Importantly, PPP2R2A deficiency also slows cell proliferation by disrupting DNA replication, particularly in PPP2R2A−/− cells. Furthermore, PPP2R2A deficiency, especially PPP2R2A−/− cells, leads to an increase in the cancer stem cell population, which correlates with enhanced resistance to chemotherapy. Overall, the decrease in PP2A B55α levels due to hemizygous/homozygous depletion heightens EMT and the metastatic or stemness/drug resistance potential of NSCLC cells despite their proliferation disadvantage. Our study highlights the significance of PP2A B55α in EMT and metastasis and suggests that targeting EMT/stemness could be a potential therapeutic strategy for treating PPP2R2A-deficient NSCLC.

SEC61 translocon gamma subunit is correlated with glycolytic activity, epithelial mesenchymal transition and the immune suppressive phenotype of lung adenocarcinoma.

Lung adenocarcinoma (LUAD) remains a predominant cause of cancer-related mortality globally, underscoring the urgency for targeted therapeutic strategies. The specific role and impact of the SEC61 translocon gamma subunit (SEC61G) in LUAD progression and metastasis remain largely unexplored. In this study, we use a multifaceted approach, combining bioinformatics analysis with experimental validation, to elucidate the pivotal role of SEC61G and its associated molecular mechanisms in LUAD. Our integrated analyses reveal a significant positive correlation between SEC61G expression and the glycolytic activity of LUAD, as evidenced by increased fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)/CT scans. Further investigations show the potential influence of SEC61G on metabolic reprogramming, which contributes to the immunosuppressive tumor microenvironment (TME). Remarkably, we identify a negative association between SEC61G expression levels and the infiltration of critical immune cell populations within the TME, along with correlations with immune checkpoint gene expression and tumor heterogeneity scores in LUAD. Functional studies demonstrate that SEC61G knockdown markedly inhibits the migration of A549 and H2030 LUAD cells. This inhibitory effect is accompanied by a significant downregulation of key regulators of tumor progression, including hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A, and genes involved in the epithelial-mesenchymal transition pathway. In conclusion, our comprehensive analyses position SEC61G as a potential prognostic biomarker intricately linked to glycolytic metabolism, the EMT pathway, and the establishment of an immune-suppressive phenotype in LUAD. These findings underscore the potential of SEC61G as a therapeutic target and predictive marker for immunotherapeutic responses in LUAD patients.