bluuebunny/crossref_metadata_2025 huggingface dataset:
Embodied music training can help improve speech imitation and pronunciation skills
Authors: Zhang Yuan , Baills Florence , Prieto Pilar
Published: December 2024

Recent research has shown that music interventions involving body movements are beneficial for reinforcing music learning. Given the reported positive transfer between music training and phonological skills, we investigated, for the first time, the value of an embodied music training program for improving pronunciation skills. In a classroom experiment, 48 Chinese adolescent learners of English participated in three 40-minute sessions of either Dalcroze-inspired embodied music training or treatment-as-usual non-embodied music training. Participants in the embodied music group were involved in a series of activities designed to develop their rhythmic and melodic skills through bodily experiences. Participants in the non-embodied music group followed music lessons designed by their music teacher, appreciating music pieces and receiving music knowledge. Before and after training, participants were tested with a language imitation task using six unfamiliar languages and an oral reading task in second language English. Results show that the embodied music group significantly outperformed the non-embodied music group in both tasks. Overall, our findings suggest that an embodied music training program has beneficial effects on pronunciation skills, supporting an embodied-based language teaching approach.
Drosophila melanogaster: a promising system for space biology research
Authors: Valdivia-Silva Julio Ernesto , Pérez-Tulich Luz , Iza-Zurita Alejandro , Travi-Antonio Giulianna , Ubidia Adolfo , Laván-Quiroz David
Published: December 2024

Drosophila melanogaster has given enormous contributions to Space Biology Research. This organism is an important tool to be manipulated in genetic engineering and molecular experiments in order to understand different biological processes homologous to other multicellular systems, including humans. Their milestone contribution in microgravity conditions and radiation, the two most important variables in space, have allowed new knowledge and perspectives on the positive and negative effects on cellular, molecular and genetic levels. In this review, we expose the historical contribution of Drosophila melanogaster in Astrobiology.
(When) Do Parties Affect Economic Inequality? A Systematic Analysis of 30 Years of Research
Authors: Haselmayer Martin , Horn Alexander
Published: December 2024

Despite 30 years of research on economic inequality, the question of whether government ideology affects inequality remains unresolved. As rising inequality poses a major challenge to contemporary democracies, we ask: (when) do parties matter regarding inequality? Our systematic analysis finds that research is divided, with a tendency toward a pessimistic “no.” We decipher the factors that account for this split in theoretically predictable ways. We assess the roles played by the type of inequality, the time horizon, and the impact of policy channels. Bivariate and multivariate analyses of 393 TSCS-regression findings show how the type of inequality and a neglect of top incomes, a focus on short- rather than long-term effects, and the inclusion of policy channels that absorb the effects of parties strongly codetermine the results. Effects septuple depending on how these factors are combined. We draw three lessons that, when combined, foster a shift toward a more optimistic perspective on the latitude of politics.
Introducing ReChat: A Lab-in-the-Cloud for Text Discussions
Authors: Shen Xiaoxiao , Schulz William Small
Published: December 2024

Text is a major medium of contemporary interpersonal communication but is difficult for social scientists to study unless they have significant resources or the skills to build their own research platform. In this paper, we introduce a cloud-based software solution to this problem: ReChat, an online research platform for conducting experimental and observational studies of live text conversations. We demonstrate ReChat by applying it to a specific phenomenon of interest to political scientists: conversations among co-partisans. We present results from two studies, focusing on (1) self-selection factors that make chat participants systematically unrepresentative and (2) a pre-registered analysis of loquaciousness that finds a significant association between speakers’ ideological extremity and the amount they write in the chat. We conclude by discussing practical implications and advice for future practitioners of chat studies.
Aging, Choosing, … and Regretting
Authors: Nolte Julia , Löckenhoff Corinna E.
Published: December 2024

Abstract: This review examines how age-related differences in the experience of regrets relate to decision making with particular emphasis on memory-based and anticipatory processes. First, we summarize how reports of different types of regrets vary across the lifespan. For long-term/life regrets, older (vs. younger) adults tend to recall more intense and omission-based regrets, but not a higher number of regrets. For short-term/everyday regrets, older (vs. younger) adults tend to recall fewer and less intense regrets as well as similar or higher levels of decision satisfaction. For anticipated or future regrets, older adults are typically as accurate as younger adults in forecasting feelings, but they expect to experience lower levels of negative affect after missing out on desirable decision outcomes. Second, we link age-related differences in the experience of regrets to potential neural, cognitive, emotional, and motivational mechanisms. With respect to neural and cognitive processes, age-related cognitive changes may alter older adults’ ability to process regret-related information and to engage in counterfactual thinking. With respect to affect, older adults tend to attend more strongly to positive decision-relevant information and remember past decisions and experiences as more positively than they initially experienced them. Finally, with respect to motivation, older age is typically associated with a shift toward maintenance and loss prevention goals. In addition, older adults focus more on controlling their response to regrets rather than the regrettable decision itself. We conclude our review by identifying limitations of the extant literature and making suggestions for future research directions on the topic.
Climate Change‐Driven Long‐Term Stability Risks of Ubiquitous Moraine Dams in Glacial Lakes on Qinghai‐Tibet Plateau: A Multiphysics Coupling Evolution Perspective
Authors: Zhou Jia‐Qing , Li Qi‐Long , Chen Yi‐Feng , Li Changdong , Jiao Jiu Jimmy , Tang Huiming
Published: December 2024

Glacial lake‐moraine dam systems are widespread in cold alpine environments such as the Qinghai‐Tibet Plateau (QTP). Without climate change, the lake‐dam system exhibits stably dynamic evolution on a hydrological annual cycle. However, climate change may drive subtle alterations in the system's evolution. We developed a fully coupled Thermal‐Hydraulic‐Mechanical simulation platform considering ice‐water phase change, showing robust performance under CMIP6‐derived boundary conditions. Using this platform, we simulated climate warming‐driven multiphysics responses and dam stability evolutions of a homogeneous, simplified conceptual model of the lake‐dam system. We identified critical temperature thresholds for permanently frozen area thawing and abrupt changes in dam stability of this lake‐dam system. Considering the current slope stability situations on the QTP, the SSP 5–8.5 climate warming scenario is conservatively anticipated to pose significant geological safety risks due to potential disaster chains from glacial lake failures. Our study provides insights into profound geological process evolutions driven by climate change.
Continuous Holocene Streamflow Rise and ENSO Linked Floods in the Upper Reaches of Yarlung Tsangpo
Authors: Sun Zhe , Hou Xiaohuan , Ji Kejia , Li Can‐Ge , Wang Mingda , Yuan Kan , Gao Xiaoxue , Hou Juzhi
Published: December 2024

Understanding the long‐term streamflow variability of the Yarlung Tsangpo (called the Brahmaputra River in downstream) is critical for water resources management due to its provision of freshwater for millions of people and its flood risk. However, previous streamflow reconstructions, based on dendrochronology and palaeo‐flood sediments, are either discontinuous or cover only a few hundred years. Here, we provide a continuous palaeolimnological record of the streamflow of the Yarlung Tsangpo upstream. Our results reveal an unexpected streamflow rise after 6,000 years ago, indicating the Westerlies and glacier meltwater replaced Indian Summer Monsoon as the dominant driver of runoff. Furthermore, the relatively frequent palaeo‐flood events during the early and late Holocene may be attributed to El Niño‐Southern Oscillation (ENSO) variance. These findings suggest the future occurrence of unsustainable streamflow and an increased flooding risk, as a result of weakening Westerlies, reduced glaciers, and strengthened ENSO activity under climatic warming.
The Spatiotemporal Structure of Induced Magnetic Fields in Callisto's Plasma Environment Due to Their Propagation With MHD Modes
Authors: Strack David , Saur Joachim
Published: December 2024

We investigate how the spatiotemporal structure of induced magnetic fields outside of Callisto is affected by their propagation with the magnetohydrodynamic (MHD) modes. At moons that are surrounded by dense magnetized plasmas like the Galilean moons, low‐frequency induced magnetic fields cannot propagate with the ordinary electromagnetic mode as is implicitly used by standard analytical expressions. Instead, the induced magnetic fields propagate with the MHD modes, which exhibit anisotropic propagation properties and have finite velocities. Using an MHD framework, we model the spatiotemporal effects of the transport on the induced signals and analyze their contribution to Galileo's C03 and C09 flyby observations. We find that the induced magnetic field in Callisto's plasma environment is asymmetric with a pronounced upstream/downstream asymmetry. By neglecting the transport effects, the amplitude of the induced magnetic field is under‐ or overestimated by up to tens of percent, respectively. Additionally, we find that MHD wave and convection velocities are strongly reduced in Callisto's local plasma environment, resulting in an additional temporal delay between the emergence of the induced field at the surface of Callisto or the top of its ionosphere and the measurements at spacecraft location. The associated phase shift depends on the location of the observer and can reach values of several to tens of degrees of the phase of the primary inducing frequency. Transport effects impact the observed induction signals and are consistent with the C03 and C09 magnetic field measurements.
Atmospheric and Surface Dynamics During Winter Warm Spells in the Southern Great Plains: Insights From the 2021 Case Study
Authors: Grace Taylor M. , Pegion Kathleen , Basara Jeffrey B.
Published: December 2024

Two 2021 winter warm spell events experienced near record extreme surface temperatures, anomalies exceeding C, during the winter season in 2021 across the Southern Great Plains (SGP). Extreme heat during the winter season results in similar detrimental socioeconomic impacts compared to their counterpart summer heat wave events. Winter warm spell events across the SGP have been historically increasing over the last several decades, and as such, it is crucial to investigate the drivers of these extreme events. In this study, we use ERA‐5 reanalysis data to investigate the atmospheric and surface characteristics associated with these two extreme events (i.e., (a) 29 November–17 December 2021 and (b) 22 December–31 December 2021). A prolonged period of positive geopotential height anomalies amplified subsidence in combination with increased incoming solar radiation and surface heat fluxes aiding extreme surface temperatures during the first winter warm spell event. However, a more prominent atmospheric blocking high (i.e., Alaskan Ridge) initiated and intensified the extreme heat during the second winter warm spell. Increased incoming solar radiation and positive sensible heat flux due to a dry surface fostered extreme heat during the second winter warm spell event. Warm air advection throughout both winter warm spell events supported the extreme surface temperatures. Discovering potential crucial drivers to winter warm spells identifies the sources of predictability to improve prediction of these extreme heat events.
The clinically relevant MEK inhibitor mirdametinib combined with D-cycloserine and prediction error disrupts fear memory in PTSD models
Authors: Raut Sanket B. , Joly Fanny , Haass Nikolas K. , Eri Rajaraman , Canales Juan J. , Benedek David M. , Ursano Robert J. , Johnson Luke R.
Published: December 2024

This study establishes mirdametinib as the first MEK inhibitor that can undergo clinical development for psychiatric indications such as post-traumatic stress disorder (PTSD). PTSD is characterized by persistent traumatic memories with limited effective treatment options. A body of evidence suggests that memory storage is dynamic and constantly updated through post-retrieval modification a process termed reconsolidation. Although ERK/MAPK signaling plays a central role in fear memory consolidation, no clinically translatable MEK inhibitor has been tested in experimental models or in clinical trials to disrupt this process. Furthermore, there is need to develop pharmacological and behavioral strategies to labilize the memory to make it susceptible for disruption. Here, we disrupted fear memory reconsolidation with the clinically relevant MEK inhibitor mirdametinib in C57BL/6 mice and tested memory destabilization strategies using an auditory fear conditioning paradigm, with drugs administered following reactivation of memory. We found prediction error effective in labilizing weak fear memory and combined D-cycloserine (DCS) and predication error effective in labilizing strong fear memory. Mirdametinib disrupted the weak fear memory and reduced ERK phosphorylation in lateral amygdala when coupled with prediction error at the time of memory reactivation but required coordinated combination of DCS, prediction error and mirdametinib to disrupt strong fear memory. Barnes maze spatial memory test and open field test revealed that mirdametinib did not affect retrieval of other forms (spatial) of long-term memory and locomotor activity. Furthermore, the effect of mirdametinib was specific to reconsolidation as it had no effect on fear memory when given without reactivation. These translational findings identify a new drug that can be adapted for the treatment of PTSD.
Targeted memory reactivation during sleep improves emotional memory modulation following imagery rescripting
Authors: Recher Dominique , Rohde Judith , Da Poian Giulia , Henninger Mirka , Brogli Luzius , Huber Reto , Karlen Walter , Lustenberger Caroline , Kleim Birgit
Published: December 2024

Targeted Memory Reactivation (TMR) during sleep benefits memory integration and consolidation. In this pre-registered study, we investigated the effects of TMR applied during non-rapid eye movement (NREM) sleep following modulation and updating of aversive autobiographical memories using imagery rescripting (ImR). During 2–5 nights postImR, 80 healthy participants were repeatedly presented with either idiosyncratic words from an ImR updated memory during sleep (experimental group) or with no or neutral words (control groups) using a wearable EEG device (Mobile Health Systems Lab-Sleepband, MHSL-SB) [1] implementing a close-loop cueing procedure. Multivariate analysis were conducted to assess change score trajectories in five key emotional memory characteristics (positive and negative valence, emotional distress, arousal, and vividness) across assessments (timepoints, t) and between the study groups (TMR condition). While ImR showed significant effects on all memory characteristics (d = 0.76–1.66), there were significant additional improvements in the experimental group. Memories were significantly less vivid and afflicted with less emotional distress and arousal following ImR-words cueing. TMR during sleep in individuals’ homes was feasible and further improved some ImR’s adaptive memory effects. If replicated in clinical samples, TMR may be utilized to augment the effects of ImR and other clinical memory modulation procedures and create personalized treatment options. Such advances in emotional memory treatments are direly needed, as aversive memories are a salient feature across mental disorders, such as post-traumatic stress disorder (PTSD).
Prefrontal cortex stimulation normalizes deficient adaptive learning from outcome contingencies in low mood
Authors: Sarrazin Verena , Overman Margot Juliëtte , Mezossy-Dona Luca , Browning Michael , O’Shea Jacinta
Published: December 2024

Depression and anxiety are associated with deficits in adjusting learning behaviour to changing outcome contingencies. This is likely to drive and maintain symptoms, for instance, by perpetuating negative biases or a sense of uncontrollability. Normalising such deficits in adaptive learning might therefore be a novel treatment target for affective disorders. The aim of this experimental medicine study was to test whether prefrontal cortex transcranial direct current stimulation (tDCS) could normalise these aberrant learning processes in depressed mood. To test proof-of-concept, we combined tDCS with a decision-making paradigm that manipulates the volatility of reward and punishment associations. 85 participants with low mood received tDCS during (or before) the task. In two sessions participants received real or sham tDCS in counter-balanced order. Compared to healthy controls (n = 40), individuals with low mood showed significantly impaired adjustment of learning rates to the volatility of loss outcomes. Prefrontal tDCS applied during task performance normalised this deficit, by increasing the adjustment of loss learning rates. As predicted, prefrontal tDCS before task performance (control) had no effect. Thus, the effect was cognitive-state dependent. Our study shows, for the first time, that a candidate depression treatment, prefrontal tDCS, when paired with a task, can reverse deficits in adaptive learning from outcome contingencies in low mood. Thus, combining neurostimulation with a concurrent cognitive manipulation is a potential novel strategy to enhance the effect of tDCS in depression treatment.
Fludarabine melphalan reduced intensity conditioning vs radiation-based myeloablative conditioning in patients undergoing allogeneic transplantation for acute myeloid leukemia with measurable residual disease
Authors: Blackmon Amanda , Afkhami Michelle , Yang Dongyun , Mokhtari Sally , Samara Yazeed , Pourhassan Hoda , Ball Brian , Salhotra Amandeep , Agrawal Vaibhav , Sandhu Karamjeet , Desai Amrita , Otoukesh Salman , Arslan Shukaib , Amanam Idoroenyi , Koller Paul , Tinajero Jose , Aribi Ahmed , Aldoss Ibrahim , Becker Pamela , Artz Andy , Ali Haris , Stein Anthony , Smith Eileen , Pullarkat Vinod , Forman Stephen J. , Marcucci Guido , Nakamura Ryotaro , Al Malki Monzr M.
Published: December 2024

Patients with AML and measurable residual disease (MRD) undergoing allogeneic hematopoietic cell transplantation (HCT) may benefit from myeloablative conditioning (MAC) when feasible to reduce relapse risk. Fludarabine-Melphalan (FluMel) is a common reduced intensity conditioning (RIC) regimen; however, data in MRD+ patients is sparse. We performed a retrospective review of AML patients who underwent their first HCT (2016–2021) without morphologic disease at City of Hope who had pre-transplant marrow evaluated for MRD using multicolor flow cytometry (MFC) and received radiation-based MAC or FluMel conditioning. We identified 312 patients; 44 with MRD+ disease pre-HCT. The 24-month overall survival (OS), leukemia-free survival (LFS) and cumulative incidence of relapse (CIR) were 47.7%, 40.9%, and 38.6% in MRD+, and 78.0%, 73.9%, and 14.6% in MRD− patients. Radiation-based MAC was given to 136 (43.5%) patients (n = 20 with MRD+) and FluMel was given to 174 (55.8%) patients (n = 24 with MRD+). In patients with MRD+, there was no statistically significant difference between those who received MAC vs. FluMel in 24-month OS (60% vs. 38%, p = 0.21), or CIR (35% vs. 42%, p = 0.59), respectively. Our data substantiates the adverse impact of MRD in patients with AML undergoing HCT; FluMel is a reasonable option for MRD+ patients unfit for MAC.
MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress
Authors: Yang Zhengmeng , Hou Nan , Cheng Wenxiang , Lu Xuan , Wang Ming , Bai Shanshan , Lin Yuejun , Wang Yaofeng , Lin Sien , Zhang Peng , Tortorella Micky D. , Feng Lu , Li Gang
Published: December 2024

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by pain, inflammation, and discomfort in the synovial joints. It is critical to understand the pathological mechanisms of RA progression. MicroRNA-378 (miR-378) is highly expressed in the synovium of RA patients and positively correlated with disease severity, but its function and underlying mechanisms remain poorly understood. In this study, miR-378 transgenic (miR-378high) mice were used to construct the collagen-induced arthritis (CIA) model for exploring the role of miR-378 in RA development. miR-378high CIA mice showed accelerated RA development, as evidenced by exaggerated joint swelling and bone structural deformities. More severe endoplasmic reticulum (ER) stress and the consequent angiogenesis and osteoclastogenesis were also activated in the synovial tissue and calcaneus, respectively, in the miR-378high group, suggesting that ER plays a significant role in miR-378-mediated RA pathogenesis. Upon in vitro RA induction, fibroblast-like synoviocytes (FLSs) isolated from miR-378high mice showed a higher expression level of ER stress markers. The conditioned medium (CM) from RA-FLSs of miR-378high mice stimulated more intensive angiogenesis and osteoclastogenesis. The ER stress-related protein Crebrf was identified as a downstream target of miR-378. Crebrf knockdown diminished the promoting effect of miR-378 on ER stress, as well as its downstream angiogenesis and osteoclastogenesis activities. Tail vein injection of anti-miR-378 lentivirus in an established RA mouse model was shown to ameliorate RA progression. In conclusion, miR-378 amplified RA development by promoting ER stress and downstream angiogenesis and osteoclastogenesis, thus indicating that miR-378 may be a potential therapeutic target for RA treatment.
Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis
Authors: Su Xin , Bai Mi , Shang Yaqiong , Du Yang , Xu Shuang , Lin Xiuli , Xiao Yunzhi , Zhang Yue , Chen Huimei , Zhang Aihua
Published: December 2024

Acute kidney injury (AKI) is a significant global health issue, which is often caused by cisplatin therapy and characterized by mitochondrial dysfunction. Restoring mitochondrial homeostasis in tubular cells could exert therapeutic effects. Here, we investigated Slc25a21, a mitochondrial carrier, as a potential target for AKI intervention. Renal Slc25a21 expression is negatively associated with kidney function in both AKI patients and cisplatin-induced murine models. Sustaining renal expression of Slc25a21 slowed down AKI progression by reducing cellular apoptosis, necroptosis, and the inflammatory response, likely through its regulation of 2-oxoadipate conversion. Slc25a21 is highly expressed in proximal tubular epithelial cells, and its down-regulation contributes to compromised mitochondrial biogenesis and integrity, as well as impaired oxidative phosphorylation. Mechanistically, reduced Slc25a21 in AKI disrupts mitochondrial 2-oxoadipate transport, affecting related metabolites influx and the tricarboxylic acid cycle. These findings demonstrate a previously unappreciated metabolic function of Slc25a21 in tubular cells, and suggest that targeting mitochondrial metabolic homeostasis by sustaining Slc25a21 expression could be a potential novel therapeutic strategy for AKI.
PGRN protects against serum deprivation-induced cell death by promoting the ROS scavenger system in cervical cancer
Authors: Feng Tingting , Xu Xiaoying , Wang Xiao , Tang Wei , Lu Yi
Published: December 2024

Progranulin (PGRN), an autocrine growth factor with tumorigenic roles in a variety of tumors, is a putative survival factor for normal and cancer cells in vitro. However, the fundamental mechanism of PGRN-mediated survival of cancer cells suffering from various types of microenvironmental stresses, such as serum deprivation, remains unknown. We show here that serum deprivation decreases intracellular PGRN protein levels in cervical cancer cells. PGRN protects cervical cancer cells against serum deprivation-induced apoptosis, limits reactive oxygen species (ROS) levels, maintains mitochondria integrity, and reduces oxidative damage of protein, lipid and DNA. PGRN enhances the ROS scavenger system, as evidenced by increased superoxide dismutase (SOD), catalase protein expression and activity, elevated GSH and NADPH levels and increased phase II detoxification enzyme expression in cervical cancer cells after serum withdrawal. The role of PGRN in ROS clearance is mediated by the PGRN-stimulated nuclear factor erythroid-derived 2-like 2 (NFE2L2)-antioxidant response element (ARE) pathway. Our study reveals an antioxidant role of PGRN in supporting the survival of cervical cancer cells under oxidative stress. This insight provides a new perspective on the how cervical cancer cells adapt to microenvironmental stress, contributing to cell viability and other malignant characteristics.
Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer
Authors: Sampson Josephina , Ju Hyun-min , Zhang Nan , Yeoh Sharon , Choi Jene , Bayliss Richard
Published: December 2024

The fusion event between EML4 and ALK drives a significant oncogenic activity in 5% of non-small cell lung cancer (NSCLC). Even though potent ALK-tyrosine kinase inhibitors (ALK-TKIs) are successfully used for the treatment of EML4-ALK-positive NSCLC patients, a subset of those patients eventually acquire resistance during their therapy. Here, we investigate the kinase responses in EML4-ALK V1 and V3-harbouring NSCLC cancer cells after acute inhibition with ALK TKI, lorlatinib (LOR). Using phosphopeptide chip array and upstream kinase prediction analysis, we identified a group of phosphorylated tyrosine peptides including ERBB and AKT proteins that are upregulated upon ALK-TKI treatment in EML4-ALK-positive NSCLC cell lines. Dual inhibition of ALK and ERBB receptors or AKT disrupts RAS/MAPK and AKT/PI3K signalling pathways, and enhances apoptosis in EML4-ALK + NSCLC cancer cells. Heregulin, an ERBB3 ligand, differentially modulates the sensitivity of EML4-ALK cell lines to ALK inhibitors. We found that EML4-ALK cells made resistant to LOR are sensitive to inhibition of ERBB and AKT. These findings emphasize the important roles of AKT and ERBB3 to regulate signalling after acute LOR treatment, identifying them as potential targets that may be beneficial to prevent adaptive resistance to EML4-ALK-targeted therapies in NSCLC.
Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis
Authors: Yuan Zengzhuang , Han Xinyan , Xiao Manyu , Zhu Taoyu , Xu Yaping , Tang Qian , Lian Chen , Wang Zijin , Li Junming , Wang Boyu , Li Changhui , Xiang Xiaochen , Jin Ruobai , Liu Yufei , Yu Xinyu , Zhang Kehang , Li Songsong , Ray Madhumita , Li Rong , Gruzdev Artiom , Shao Shiqun , Shao Fangwei , Wang Hua , Lian Wang , Tang Yong , Chen Di , Lei Ying , Jin Xuru , Li Qinglin , Long Weiwen , Huang Huaqiong , DeMayo Francesco J. , Liu Jian
Published: December 2024

Ferroptosis has been shown to play a crucial role in preventing cancer development, but the underlying mechanisms of dysregulated genes and genetic alternations driving cancer development by regulating ferroptosis remain unclear. Here, we showed that the synergistic role of ELF3 overexpression and PTEN deficiency in driving lung cancer development was highly dependent on the regulation of ferroptosis. Human ELF3 (hELF3) overexpression in murine lung epithelial cells only caused hyperplasia with increased proliferation and ferroptosis. hELF3 overexpression and Pten genetic disruption significantly induced lung tumor development with increased proliferation and inhibited ferroptosis. Mechanistically, we found it was due to the induction of SLC7A11, a typical ferroptosis inhibitor, and ELF3 directly and positively regulated SLC7A11 in the PTEN-deficient background. Erastin-mediated inhibition of SLC7A11 induced ferroptosis in cells with ELF3 overexpression and PTEN deficiency and thus inhibited cell colony formation and tumor development. Clinically, human lung tumors showed a negative correlation between ELF3 and PTEN expression and a positive correlation between ELF3 and SLC7A11 in a subset of human lung tumors with PTEN-low expression. ELF3 and SLC7A11 expression levels were negatively associated with lung cancer patients’ survival rates. In summary, ferroptosis induction can effectively attenuate lung tumor development induced by ELF3 overexpression and PTEN downregulation or loss-of-function mutations.
Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader
Authors: Chen Li , Zou Yahui , Sun Renhong , Huang Mei , Zhu Xiaotong , Tang Xiao , Yang Xiaobao , Li Dake , Fan Gaofeng , Wang Yu
Published: December 2024

Poly (ADP-ribose) polymerase 1 (PARP1) catalyzes poly (ADP) ribosylation reaction, one of the essential post-translational modifications of proteins in eukaryotic cells. Given that PARP1 inhibition can lead to synthetic lethality in cells with compromised homologous recombination, this enzyme has been identified as a potent target for anti-cancer therapeutics. However, the clinical application of existing PARP1 inhibitors is restrained by side effects associated with DNA trapping and off-target effects, highlighting the need for improved therapeutic strategies. By integrating protein degradation technology, we synthesized a PROTAC molecule 180055 based on the Rucaparib junction and VHL ligand, which efficiently and selectively degraded PARP1 and inhibited PARP1 enzyme activity without a noticeable DNA trapping effect. Furthermore, 180055 kills tumor cells carrying BRCA mutations with a minor impact on the growth of normal cells both in vitro and in vivo. This suggests that 180055 is a PARP1-degrading compound with excellent pharmacological efficacy and extremely high biological safety that deserves further exploration and validation in clinical trials.
Marcks overexpression in retinal ganglion cells promotes optic nerve regeneration
Authors: Peng Xue-Qi , Li Yan-Zhong , Gu Chen , He Xuan-Cheng , Li Chang-Ping , Sun Yong-Quan , Du Hong-Zhen , Teng Zhao-Qian , Liu Chang-Mei
Published: December 2024

Regeneration of injured central nervous system (CNS) axons is highly restricted, leading to permanent neurological deficits. The myristoylated alanine-rich C-kinase substrate (MARCKS) is a membrane-associated protein kinase C (PKC) substrate ubiquitously expressed in eukaryotic cells, plays critical roles in development, brain plasticity, and tissues regeneration. However, little is known about the role of Marcks in CNS axon regeneration. Here we show that Marcks overexpression promotes robust axon regeneration either before or after optic nerve crush, but insignificantly impacts neuronal survival. Notably, immunostaining and RNA sequencing demonstrate that Marcks overexpression does not affect known regeneration-associated genes and pathways. Furthermore, combining CNTF which activates the JAK-STAT3 pathway and Marcks overexpression further enhances axon regeneration. Finally, we demonstrate functionally essential effector domain (ED) of MARCKS has similar effects on inducing axon regeneration in RGCs. These results suggest that manipulating Marcks and its ED may become a therapeutic approach to promote axon regeneration after CNS injury.
SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation
Authors: Gao Tingwen , Guo Zhenyang , Weng Xinyu , Cui Yikai , Li Peng , Hu Tao , Luo Wei , Dong Zheng , Wei Peng , Cai Yun , Lu Yijing , Gao Rifeng , Li Hua , Zhong Xin , Ge Junbo
Published: December 2024

The macrophage-associated inflammation response plays an important role in myocardial ischemia-reperfusion injury (MIRI). SHEP1(SH2 domain-containing Eph receptor-binding protein 1) has been implicated in adhesion and migration of inflammatory cells. However, the role and molecular mechanism of SHEP1 regulating macrophage remains unclear during MIRI. Here, the expression of SHEP1 was increased in macrophages co-cultured with hypoxia-reoxygenated cardiomyocytes and within ischemia-reperfusion injured myocardium at the early stage of injury. Cell migration and inflammation were also enhanced in SHEP1 knock-out macrophages and macrophage-specific deficiency of SHEP1 mice under MIRI, which further led to deteriorated cardiac injury and cardiac function in vivo. Mechanistically, macrophage-derived SHEP1 competitively bound to G3BP1 to suppress inflammation via the MAPK pathway. In addition, administrating inhibitor of G3BP1 could improve cardiac function in macrophage-specific deficiency of SHEP1 mice under MIRI. Our results demonstrate that SHEP1 deficiency in macrophages exacerbates MIRI through G3BP1-dependent signaling pathway. SHEP1-G3BP1 interaction are therefore indispensable for SHEP1 regulated- infiltration and proinflammatory responses of macrophages, which provided a potential and clinically significant therapeutic target for MIRI.
Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells
Authors: Kim Justin , Brunetti Bryce , Kumar Ayanesh , Mangla Ankit , Honda Kord , Yoshida Akihiro
Published: December 2024

The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.
CPNE7 promotes colorectal tumorigenesis by interacting with NONO to initiate ZFP42 transcription
Authors: Zhao Liangbo , Sun Xiao , Hou Chenying , Yang Yanmei , Wang Peiwen , Xu Zhaoyuan , Chen Zhenzhen , Zhang Xiangrui , Wu Guanghua , Chen Hong , Xing Hao , Xie Huimin , He Luyun , Jin Shuiling , Liu Benyu
Published: December 2024

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death globally. Also, there is still a lack of effective therapeutic strategies for CRC patients owing to a poor understanding of its pathogenesis. Here, we analysed differentially expressed genes in CRC and identified CPNE7 as a novel driver of colorectal tumorigenesis. CPNE7 is highly expressed in CRC and negatively correlated with patients’ prognosis. Upregulation of CPNE7 promotes proliferation and metastasis of cancer cells in vitro and in vivo, and vice versa. Mechanistically, CPNE7 interacts with NONO to initiate ZFP42 transcription, thus promoting CRC progression. Moreover, ZFP42 knockdown inhibits tumor cell proliferation and migration while promoting apoptosis. Notably, delivery of CPNE7 shRNA or the small molecule gramicidin, which blocks the interaction between CPNE7 and NONO, hinders tumor growth in vivo. In conclusion, our findings demonstrate that the CPNE7-NONO-ZFP42 axis promotes colorectal tumorigenesis and may be a new potential therapeutic target.
GPx1 deficiency confers increased susceptibility to ferroptosis in macrophages from individuals with active Crohn’s disease
Authors: Sousa James A. , Callejas Blanca E. , Wang Arthur , Higgins Eve , Herik Aydin , Andonian Natalie , Yousuf Munazza , Colarusso Pina , Raman Maitreyi , McKay Derek M.
Published: December 2024

Intestinal cell death is a defining feature of Crohn’s disease (CD), a major form of inflammatory bowel disease. The focus on this aspect of enteric inflammation has mainly been on epithelial cells, while other cell types such as stromal and myeloid cells have received less attention. Hypothesising that decreased macrophage viability in an oxidative environment could be a contributing factor to the pathophysiology of CD, we found that monocyte-derived macrophages from individuals with active CD (but not those in clinical disease remission) have increased sensitivity to cell death induced by H2O2. Molecular biology and pharmacological studies ruled out apoptosis and necroptosis, while increased lipid peroxidation and surface expression of the transferrin receptor implicated ferroptosis as the mechanism of the H2O2-induced cell death: this was supported by suppression of H2O2-cytotoxicity by liproxstatin-1, a pharmacological inhibitor of ferroptosis. Selenoproteins are important antioxidants, and selenium deficiency can be a feature of CD. Despite normal dietary intake of selenium, monocyte-derived macrophages and intestinal macrophages in individuals with CD had decreased protein and/or mRNA expression of the selenoprotein, glutathione peroxidase (GPx)-1. Knockdown of GPx1 in macrophages from healthy volunteers resulted in increased H2O2-induced cell death reminiscent of that observed with macrophages from CD. In summary, monocyte-derived macrophages from individuals with CD have increased susceptibility to H2O2-induced ferroptosis cell death, that may be facilitated, at least in part, by reduced expression of the antioxidant GPx1. We suggest that reduced GPx1 in monocytes recruited to the gut and intestinal macrophages renders these cells vulnerable to reactive oxygen species-evoked ferroptosis cell death and that unraveling the participation of this pathway in Crohn’s disease may reveal novel therapeutic approaches to this chronic condition.
Targeting PPARγ via SIAH1/2-mediated ubiquitin-proteasomal degradation as a new therapeutic approach in luminal-type bladder cancer
Authors: Tu Chih-Chieh , Hsieh Tsung-Han , Chu Cheng-Ying , Lin Yu-Chen , Lin Bo-Jyun , Chen Chun-Han
Published: December 2024

Bladder cancer (BC) is the second most prevalent genitourinary malignancy worldwide. Despite recent approvals of immune checkpoint inhibitors and targeted therapy for muscle invasive or recurrent BC, options remain limited for patients with non-muscle invasive BC (NMIBC) refractory to Bacillus Calmette-Guérin (BCG) and chemotherapy. NMIBC is more frequently classified as a luminal subtype, in which increased PPARγ activity is a key feature in promoting tumor growth and evasion of immunosurveillance. Cinobufotalin is one of the major compound of bufadienolides, the primary active components of toad venom that has been utilized in the clinical treatment of cancer. We herein focused on cinobufotalin, examining its anticancer activity and molecular mechanisms in luminal-type NMIBC. Our results newly reveal that cinobufotalin strongly suppresses the viability and proliferation of luminal BC cells with minimal cytotoxic effects on normal uroepithelial cells, and exhibits significant antitumor activity in a RT112 xenograft BC model. Mechanistically, our sub-G1-phase cell accumulation, Annexin V staining, caspase-3/8/9 activation, and PARP activation analyses show that cinobufotalin induces apoptosis in luminal-type BC cells. Cinobufotalin significantly inhibited the levels of PPARγ and its downstream targets, as well as lipid droplet formation and free fatty acid levels in RT112 cells. PPARγ overexpression rescued RT112 cells from cinobufotalin-induced apoptosis and mitigated the downregulation of FASN and PLIN4. Finally, we show seemingly for the first time that cinobufotalin promotes SIAH1/2-mediated proteasomal degradation of PPARγ in luminal BC cells. Together, these findings compellingly support the idea that cinobufotalin could be developed as a promising therapeutic agent for treating luminal-type NMIBC.
Tipping the balance of cell death: alternative splicing as a source of MCL-1S in cancer
Authors: Hartman Mariusz L.
Published: December 2024

Apoptosis-regulating proteins from the B-cell lymphoma-2 (BCL-2) family are of continued interest as they represent promising targets for anti-cancer therapies. Myeloid cell leukemia-1 (MCL-1), which usually refers to the long isoform (MCL-1L) is frequently overexpressed in various types of cancer. However, MCL1 pre-mRNA can also undergo alternative splicing through exon skipping to yield the short isoform, MCL-1S. Regarding its structure and function, MCL-1S corresponds to BCL-2 homology domain 3 (BH3)-only pro-apoptotic proteins in contrast to the pro-survival role of MCL-1L. As cancer cells are usually characterized by the high MCL-1L:MCL-1S ratio, several studies revealed that overexpression of MCL-1S may constitute a new therapeutic approach in cancer and presumably overcome resistance to currently available drugs. Switching the balance towards high levels of MCL-1S is feasible by using inhibitors of alternative splicing-regulating proteins and strategies directly interfering with MCL1 pre-mRNA. Additionally, several compounds were shown to increase MCL-1S levels through unelucidated mechanisms, while diversely affecting the level of MCL-1L isoform. These mechanisms require detailed clarification as the balance between the long and short variants of MCL-1 can also contribute to mitochondrial hyperpolarization. In this respect, the role of MCL-1S in the regulation of apoptosis-unrelated events of the mitochondria physiology, including mitochondria fission and fusion also remains to be determined. In this review, the structure and function of MCL-1S isoform, and MCL-1S-targeting approaches are discussed.
Immune modules to guide diagnosis and personalized treatment of inflammatory skin diseases
Authors: Seremet Teofila , Di Domizio Jeremy , Girardin Antoine , Yatim Ahmad , Jenelten Raphael , Messina Francesco , Saidoune Fanny , Schlapbach Christoph , Bogiatzi Sofia , Minisini Frederic , Garzorz-Stark Natalie , Leuenberger Matthieu , Wüthrich Héloise , Vernez Maxime , Hohl Daniel , Eyerich Stefanie , Eyerich Kilian , Guenova Emmanuella , Paul Carle , Gottardo Raphael , Conrad Curdin , Gilliet Michel
Published: December 2024

Previous advances have identified immune pathways associated with inflammatory skin diseases, leading to the development of targeted therapies. However, there is a lack of molecular approaches that delineate these pathways at the individual patient level for personalized diagnostic and therapeutic guidance. Here, we conduct a cross-comparison of expression profiles from multiple inflammatory skin diseases to identify gene modules defining relevant immune pathways. Seven modules are identified, representing key immune pathways: Th17, Th2, Th1, Type I IFNs, neutrophilic, macrophagic, and eosinophilic. These modules allow the development of a molecular map with high diagnostic efficacy for inflammatory skin diseases and clinico-pathologically undetermined cases. Aligning dominant modules with treatment targets offers a rational framework for treatment selection, improving response rates in both treatment-naïve patients and non-responders to targeted therapies. Overall, our approach offers precision medicine for inflammatory skin diseases, utilizing transcriptional modules to support diagnosis and guide personalized treatment selection.
Low-power scalable multilayer optoelectronic neural networks enabled with incoherent light
Authors: Song Alexander , Murty Kottapalli Sai Nikhilesh , Goyal Rahul , Schölkopf Bernhard , Fischer Peer
Published: December 2024

Optical approaches have made great strides towards the goal of high-speed, energy-efficient computing necessary for modern deep learning and AI applications. Read-in and read-out of data, however, limit the overall performance of existing approaches. This study introduces a multilayer optoelectronic computing framework that alternates between optical and optoelectronic layers to implement matrix-vector multiplications and rectified linear functions, respectively. Our framework is designed for real-time, parallelized operations, leveraging 2D arrays of LEDs and photodetectors connected via independent analog electronics. We experimentally demonstrate this approach using a system with a three-layer network with two hidden layers and operate it to recognize images from the MNIST database with a recognition accuracy of 92% and classify classes from a nonlinear spiral data with 86% accuracy. By implementing multiple layers of a deep neural network simultaneously, our approach significantly reduces the number of read-ins and read-outs required and paves the way for scalable optical accelerators requiring ultra low energy.
Nucleosome fibre topology guides transcription factor binding to enhancers
Authors: O’Dwyer Michael R. , Azagury Meir , Furlong Katharine , Alsheikh Amani , Hall-Ponsele Elisa , Pinto Hugo , Fyodorov Dmitry V. , Jaber Mohammad , Papachristoforou Eleni , Benchetrit Hana , Ashmore James , Makedonski Kirill , Rahamim Moran , Hanzevacki Marta , Yassen Hazar , Skoda Samuel , Levy Adi , Pollard Steven M. , Skoultchi Arthur I. , Buganim Yosef , Soufi Abdenour
Published: December 2024

Cellular identity requires the concerted action of multiple transcription factors (TFs) bound together to enhancers of cell-type-specific genes. Despite TFs recognizing specific DNA motifs within accessible chromatin, this information is insufficient to explain how TFs select enhancers1. Here we compared four different TF combinations that induce different cell states, analysing TF genome occupancy, chromatin accessibility, nucleosome positioning and 3D genome organization at the nucleosome resolution. We show that motif recognition on mononucleosomes can decipher only the individual binding of TFs. When bound together, TFs act cooperatively or competitively to target nucleosome arrays with defined 3D organization, displaying motifs in particular patterns. In one combination, motif directionality funnels TF combinatorial binding along chromatin loops, before infiltrating laterally to adjacent enhancers. In other combinations, TFs assemble on motif-dense and highly interconnected loop junctions, and subsequently translocate to nearby lineage-specific sites. We propose a guided-search model in which motif grammar on nucleosome fibres acts as signpost elements, directing TF combinatorial binding to enhancers.