bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice
Authors: Kleis Piret , Paschen Enya , Djie-Maletz Andrea , Vlachos Andreas , Haas Carola A. , Häussler Ute 
Published: January 2025

AbstractBackgroundMesial temporal lobe epilepsy (MTLE) is a prevalent form of focal epilepsy characterized by seizures originating from the hippocampus and adjacent regions. Neurostimulation presents an alternative for surgery-ineligible patients with intractable seizures. However, conventional approaches have limited efficacy and require refinement for better seizure control. While hippocampal low-frequency stimulation (LFS) has shown promising seizure reduction in animal studies and small clinical cohorts, its mechanisms, sex-specific outcomes, and long-term effects remain unknown.ObjectivesWe aimed to identify the long-term antiepileptic and cognitive outcomes and potential underlying mechanisms of hippocampal LFS in chronically epileptic male and female mice.MethodsWe used the intrahippocampal kainate mouse model replicating the features of MTLE: spontaneous seizures, hippocampal sclerosis, and memory deficits. We applied 1 Hz electrical LFS in the sclerotic hippocampus 6 hours a day, four times a week for 5 weeks and examined its effects on epileptiform activity, spatial memory, and kainate-induced pathological features at cellular and synaptic levels.ResultsLong-term hippocampal LFS consistently diminished focal seizures in epileptic male and female mice, with seizure reduction extending beyond the stimulation period. Additionally, LFS relieved spatial memory deficits and reversed pathological long-term potentiation-like changes at perforant path-dentate granule cell synapses. LFS had no significant effect on generalized convulsive seizures, anxiety-like behaviour, neurogenesis, hippocampal sclerosis, excitatory synapse marker expression, or presynaptic vesicles in perforant path fibers.ConclusionThese findings provide clinically relevant insights into the seizure type-specific effects of hippocampal LFS, which, alongside synaptic and behavioural improvements, could contribute to enhanced seizure control and quality of life in MTLE patients.
Telomeric SUMO level influences the choices of APB formation pathways and ALT efficiency
Authors: Zhao Rongwei , Wivagg Allison , Lackner Rachel M. , Salsman Jayme , Dellaire Graham , Matunis Michael J , Chenoweth David M. , Zhao Xiaolan , Zhang Huaiying 
Published: January 2025

AbstractMany cancers use an alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT telomeric DNA synthesis occurs in ALT telomere-associated PML bodies (APBs). However, the mechanisms by which APBs form are not well understood. Here, we monitored the formation of APBs with time-lapse imaging employing CRISPR knock-in to track the promyelocytic leukemia (PML) protein at endogenous levels. We found APBs form via two pathways: telomeres recruit PML proteins to nucleate PML bodies de novo, or telomeres fuse with preformed PML bodies. Both nucleation and fusion of APBs require interactions between SUMO and SUMO interaction motifs (SIMs). Moreover, APB nucleation is associated with higher levels of SUMOs and SUMO-mediated recruitment of DNA helicase BLM, resulting in more robust telomeric DNA synthesis. Finally, further boosting SUMO levels at telomeres enhances APB nucleation, BLM enrichment, and telomeric DNA synthesis. Thus, high SUMO levels at telomeres promote APB formation via nucleation, resulting in stronger ALT activity.
SPARC is a new driver of early breast tumor progression via TGF-β -dependent mechanism
Authors: Sciacca Marianela , del Pilar Carballo María , Lacunza Ezequiel , Marino Lina , Cardozo Paola Noelia , Padilla Naira Rodríguez , López-López Tamara , Abba Martin , Courtois Laura , Bieche Ivan , Vincent-Salomon Anne , Bilbao Érica Rojas , Podsypanina Katrina , Boissan Mathieu , Chavrier Philippe , Eiján Ana María , Sáez Pablo J , Lodillinsky Catalina 
Published: January 2025

AbstractDuctal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor of invasive ductal carcinoma (IDC). The challenge lies in discriminating between DCIS progressors and DCIS non-progressors, often resulting in over- or under-treatment in many cases. Membrane type 1 (MT1)-matrix metalloproteinase (MMP) has been previously identified as an essential gene involved in DCIS progression. Here, RNA-sequencing analysis of MT1-MMPhighsubpopulation derived from invasive breast tumors in the intraductal xenograft model was compared against a dataset of human high-grade DCIS, and Secreted Protein Acidic and Cysteine Rich (SPARC) has emerged as a master candidate involved in early breast tumor progression.We report that SPARC is up-regulated in DCIS as compared to normal breast epithelial tissues, and further increased in IDC relative to synchronous DCIS foci. We found a positive correlation between SPARC and MT1-MMP expression in DCIS lesions. At the mechanistic level, depletion of SPARC reduced MT1-MMP expression, the degradative capacity of the cells and the activation of the TGF-β signalling canonical pathway. Pharmacological inhibition of the TGF-β signalling pathway decreased SPARC and MT1-MMP at the mRNA and protein level, and concomitantly the cell degradative capacity and 3D cell migration. Strikingly, inhibition of the TGF-β signalling pathway limits the invasive transition of breast tumors in a new triple-negative mouse intraductal syngeneic xenograft model. Moreover, high SPARC expression was positively correlated with both, TGF-β and its receptor, TGFBRI, in a basal type of breast cancer collection supporting our findings. This study identifies SPARC as a new driver of early breast tumor progression via a TGF-β-dependent mechanism, suggesting TGF-β signaling pathway as a potential target for patients with high SPARC expression.
Nuclear disruption as a mechanism of the chemotherapeutic drug paclitaxel in interphase
Authors: Hale Thomas , Hale Victoria L , Kolata Piotr , Santos Ália dos , Allegretti Matteo 
Published: January 2025

AbstractPaclitaxel is a microtubule stabilising drug used to treat breast, ovarian, and lung cancers. Its anticancer mechanism is thought to rely on mitotic arrest of fast-dividing cells and subsequent apoptosis following mitotic spindle disruption. However, paclitaxel reduces tumour size even in slow-dividing tumours, indicating an alternative, poorly characterised mechanism in interphase. Understanding paclitaxel’s less characterised effects is important for more effective cancer treatments, reducing tumour resistance and drug toxicity in healthy cells.Here, we found that paclitaxel-induced microtubule reorganisation in interphase also affects the perinuclear distribution of actin and vimentin filaments. The formation of large microtubule-vimentin bundles coincided with nuclear shape deformation, nuclear envelope invaginations, loss of control of nuclear membrane spacing, and changes to nuclear lamina organisation. Concurrently, Lamin A/C protein levels were decreased, and this depended on nuclear-cytoskeletal connectivity through LINC complex component SUN2. Finally, we show that Lamin A/C expression levels, which are often aberrant in cancer cells, are important in determining cell sensitivity to paclitaxel and recovery from treatment. Overall, our data supports nuclear architecture disruption as an additional mechanism for paclitaxel during interphase and independent of mitotic arrest.
Chameau (HBO1) regulates starvation in a temperature-dependent manner inDrosophila melanogaster
Authors: Venkatasubramani Anuroop Venkateswaran , Ichinose Toshiharu , Forne Ignasi , Tanimoto Hiromu , Peleg Shahaf , Imhof Axel 
Published: January 2025

AbstractThe body temperature ofDrosophila melanogasterdepends on the extrinsic temperature. Numerous studies in fruit flies have shown that environmental temperature has an effect on metabolism, lifespan and starvation resilience. We have previously shown that Chameau (Chm), a MYST-domain acetyltransferase, promotes aging but also increases starvation resilience. As starvation resilience is highly temperature dependent, we explored the effect of temperature on starvation resilience in fruit flies with reducedchmexpression. Strikingly, we found that an increase of 2°C was sufficient to restore starvation resilience inchmmutants. The increase in temperature rescued the dampened expression of genes involved in insulin, hormone and starvation response as well as a reduced rate of weight loss and misregulation of trehalose, which we observed inchmmutants at 23°C. Our data show that whereas Chm has an important role in regulating starvation at 23°C and below, it becomes obsolete at higher temperatures. Our finding that a gene plays an important role only under specific environmental conditions has important implications in light of the recent global change of climate conditions.
Engineering a highly selective, hemoprotein-based scavenger as a carbon monoxide poisoning antidote with no hypertensive effect
Authors: Dent Matthew R. , DeMartino Anthony W. , Xu Qinzi , Chen Xiukai , Ghandi Alay , Hwang John , Bocian Kaitlin A. , Alipour Elmira , Burak Ucer K. , Baker Stephen R. , Srimath Kandada Ajay Ram , Bulbul Angka , Kim-Shapiro Daniel B. , Rose Jason J. , Tejero Jesus , Gladwin Mark T. 
Published: January 2025

ABSTRACTCarbon monoxide (CO) poisoning causes 50,000-100,000 emergency department visits and ∼1,500 deaths in the United States annually. Current treatments are limited to supplemental and/or hyperbaric oxygen to accelerate CO elimination. Even with oxygen therapy, nearly half of CO poisoning survivors suffer long-term cardiac and neurocognitive deficits related to slow CO clearance, highlighting a need for point of care antidotal therapies. Given the natural interaction between CO and ferrous heme, we hypothesized that the hemoprotein RcoM, a transcriptional regulator of microbial CO metabolism, would make an ideal platform for CO-selective scavenging from endogenous hemoproteins. We engineered an RcoM truncate (RcoM-HBD-CCC) that exhibits high CO affinity (Ka,CO= 2.8×1010M-1), remarkable selectivity for CO over oxygen (Ka,O2= 1.4×105M-1;Ka,CO/Ka,O2= 1.9×105), thermal stability (Tm= 72°C), slow autoxidation rate (kox= 1.1 h-1). In a murine model of acute CO poisoning, infused RcoM-HBD-CCC accelerated CO clearance from hemoglobin in red blood cells and was rapidly excreted in urine. Moreover, infused RcoM-HBD-CCC elicited minimal hypertension in mice compared to infused hemoglobin, attributed to a comparatively limited reactivity toward nitric oxide (NO) via dioxygenation (kNOD(RcoM) = 6-8×106M-1s-1vskNOD(Hb) = 6-8×107M-1s-1). These data suggest that RcoM-HBD-CCC is a safe, selective, and efficacious CO scavenger. Additionally, by limiting hypertension RcoM-HBD-CCC improves end-organ adverse effects compared with hemoglobin-based therapeutics.
Target-basedde novodesign of cyclic peptide binders
Authors: Wang Fanhao , Zhang Tiantian , Zhu Jintao , Zhang Xiaoling , Zhang Changsheng , Lai Luhua 
Published: January 2025

AbstractCyclic peptides have become a new focus in drug discovery due to their ability to bind challenging targets, including “undruggable” protein-protein interactions, with low toxicity. Despite their potential, general methods forde novodesign of cyclic peptide ligands based on target protein structures remain limited. Here, we developed CYC_BUILDER, a reinforcement learning based fragment growing method for efficient assembly of peptide fragments and cyclization to generate diverse cyclic peptide binders for target proteins. CYC_BUILDER employs a Monte Carlo Tree Search (MCTS) framework to integrate seed fragment exploration, fragment fusion based peptide growth, structure optimization, evaluation and peptide cyclization. It supports peptide cyclization through both head-to-tail amide bond and disulfide bond formation. We first validated CYC_BUILDER on known protein-cyclic peptide complexes, demonstrating its ability to accurately re-generate cyclic peptide binders in terms of both sequences and binding poses. We then applied it to design cyclic peptide inhibitors for TNFα, a key mediator in inflammation-related diseases. Among the nine experimentally tested designed peptides, four showed potent binding to TNFαand inhibited its cellular activity. CYC_BUILDER provides an efficient tool for cyclic peptide drug design, offering significant potential for addressing challenging therapeutical targets.
5’UTR-mediated retention of eIF3 on 80S ribosomes promotes co-translational folding of ER membrane proteins
Authors: Han Baochun , Zhang Siqiong , Duan Haoran , Zhang Yurui , Yu Binbin , Lin Weimin , Cheng Yabin , Wolf Dieter A. 
Published: January 2025

AbstractCo-translational folding of nascent polypeptides is essential for protein function and cellular homeostasis. Ribosome-associated chaperones assist in this process, but coordination between their recruitment and translation initiation remains poorly understood. We report here that specific binding sites for eukaryotic translation initiation factor eIF3 within the 5’ untranslated regions (5’UTRs) of mRNAs promote its retention on 80S ribosomes during the synthesis of select endoplasmic reticulum (ER) membrane proteins. Disruption of these eIF3 binding sites leads to misfolding and sequestration of newly synthesized membrane proteins into ER whorls. Sequestration into ER whorls is exacerbated by HSP70 inhibition but can be rescued by overexpressing HSPA8 and HSPA1. Cross-linking assays reveal that 5’UTR binding sites stabilize eIF3–80S interactions during early elongation, facilitating recruitment of HSPA8 to ribosomes. These findings indicate that genetic instructions within 5’UTRs direct eIF3-mediated chaperone recruitment, ensuring proper co-translational folding of ER membrane proteins.
Mechanistic Elucidation of CLIC1 Membrane Insertion via Structural and Dynamic Modulation
Authors: Cassar Joseph , Serrano-Sanchez Angela , Bragg Jack , Medina-Carmona Encarnacion , Ossa Felipe , Thompson Gary , Abdul-Salam Vahitha , Varela Alvarez Lorena , Ortega-Roldan Jose L. 
Published: January 2025

ABSTRACTChloride Intracellular Channel 1 (CLIC1) is a metamorphic protein capable of transitioning from a soluble cytoplasmic state to a membrane-bound chloride channel. This conformational shift, crucial for physiological processes such as cell volume regulation, electrical excitability, and angiogenesis, is linked to pathological conditions including malignancies and cardiovascular diseases. Despite its significance, the molecular mechanism driving CLIC1’s membrane insertion has remained elusive.Using an integrated structural biology approach combining NMR spectroscopy, SAXS, biophysical methods, and mutagenesis, we uncover the dynamic landscape underpinning CLIC1 function. Solution NMR and SAXS reveal that CLIC1 adopts a conformational ensemble in equilibrium, characterized by a compact ground state and a partially extended state exposing key membrane-interacting regions. Zn2+binding acts as a critical trigger, inducing structural rearrangements, increasing protein flexibility, and promoting oligomerization essential for membrane insertion.Our findings demonstrate that structural flexibility, particularly within dynamic loop regions and interdomain linkers, is intrinsic to CLIC1’s ability to adapt to membrane interactions. Zn2+-induced dimerization and tetramerization were identified as key steps preceding insertion, with mutations in the transmembrane (TM) region revealing pivotal roles for residues R29 and W35 in modulating protein dynamics, oligomerization and insertion eXiciency.This study provides a mechanistic framework for CLIC1’s transition to its membrane-bound state, oXering insights into the interplay between conformational dynamics, oligomerization, and metal ion modulation. These findings pave the way for targeted strategies to regulate CLIC1 activity in pathological conditions, underscoring its potential as a therapeutic target.
The current status and future prospects of the Synchrotron Radiation Protein Crystallography Core Facility at NSRRC: a focus on the TPS 05A, TPS 07A and TLS 15A1 beamlines
Authors: Chou Chung-Kuang , Tseng Chien-Chang , Chiang Cheng-Hung , Chen Yi-Hui , Liu Yi-Chun , Huang Chen-Ying , Chao Chun-Hsiung , Huang Chun-Hsiang 
Published: January 2025

The Synchrotron Radiation Protein Crystallography Core Facility (SPXF) at the National Synchrotron Radiation Research Center has been pivotal in advancing structural biology research in Taiwan. Since the 1990s, Taiwan has invested in the development of synchrotron light sources, including the Taiwan Light Source and the Taiwan Photon Source, which have profoundly enhanced protein structure analysis capability. Through the high-performance beamlines, SPXF has enabled significant scientific achievements, contributing to disease research and drug development. The facility's move towards automation and its integration of advanced techniques, such as in situ serial synchrotron crystallography, underscore its commitment to meeting the evolving needs of the research community. The SPXF continues to foster innovation and collaboration, providing world-class resources for both domestic and international users.
Disruptive and incremental innovation as mediators in the CSR-financial performance link: evidence from Vietnam
Authors: Phan Thi Thuc Anh , Nguyen Ngoc Lan , Casanova Lourdes , Nguyen Dai Van , Dao Hoang Minh 
Published: January 2025

Purpose
This study aims to examine how disruptive and incremental innovations mediate the link between corporate social responsibility (CSR) and financial performance from a dynamic capability perspective. Moreover, this study uncovers the moderating effect of business type on the CSR–innovation relationship.

Design/methodology/approach
The authors conduct a quantitative research design through surveying 536 managers of enterprises in Vietnam.

Findings
The findings show the crucial mediating effect of disruptive innovation on the CSR–financial performance link. The authors observe that the influence of CSR on incremental innovation is stronger for state-owned businesses.

Originality/value
These findings offer valuable insights for firms aiming to align their CSR strategies with financial objectives and enhance their dynamic capabilities to drive innovation in rapidly changing business environment.
Always good for innovation? Investigating when and why high-performance work systems promote versus inhibit employees’ innovative behavior
Authors: Farooqi Asaad Salam , Song Dian , Yin Yishuai , Yuan Yongzhi 
Published: January 2025

PurposeThis study employs job demands-resources (JD-R) model and self-determination theory (SDT) to examine the double-edged effect of perceived high-performance work systems (HPWS) on employees’ innovative behavior via harmonious passion and obsessive passion. Additionally, the study investigates the cross-level moderating effect of innovative climate on the relationship between perceived HPWS and innovative behavior through the two types of passion.Design/methodology/approachTime-lagged data were collected at three points (Time 1, 2 and 3) to mitigate common method variance. Data were collected from Pakistan with 451 respondents from 90 firms.FindingsFindings reveal that perceived HPWS positively affect employees’ innovative behavior via harmonious passion and negatively influence employees’ innovative behavior via obsessive passion. Moreover, cross-level innovative climate strengthens both the positive and negative impact of perceived HPWS on employees’ innovative behavior.Originality/valueThis study proposes and tests the double-edged effects of perceived HPWS on employees’ innovative behavior, challenging the previous consensus that perceived HPWS is always beneficial for innovative behavior. Besides, we identify organizational innovative climate as a critical condition that amplifies the dual effects of perceived HPWS on employees’ innovative behavior via passion.
Implementing a customer-centric strategy through service design in financial organisations
Authors: Kaartti Virpi , Ojasalo Jukka , Wait Marius 
Published: January 2025

PurposeThe purpose of this article is to explore how the application of service design can support financial organisations to implement their customer-centric business strategy.Design/methodology/approachThis explorative research leaned on a subjective philosophy of interpretivism and followed an explorative qualitative approach by applying in-depth interviews. An abductive mindset was used for theory development.FindingsThe paper introduces a model that explains how service design can be used to implement customer-centric business strategy in financial organisations. The model explains the link between the business strategy and service design and highlights five principles of service design – namely customer-centred, co-creative, holistic, contextual and systemic – which guide designers and business developers when applying service design. In addition, customer journey represents an essential method of service design when aiming for a superior customer experience.Research limitations/implicationsThe research implications of this study relate to novel knowledge of applying service design to implement a customer-centric strategy. The paper encourages managers of established financial organisations to use service design to implement their strategy for a superior customer experience. Our results recommend the customer journey as a main method of service design for this purpose and highlight the prospect of making customer journeys at various levels across organisations.Originality/valueThis paper contributes to literature by integrating knowledge about business strategy, customer centricity and service design in a novel way.
Rising access and falling outcomes: educational change and the GEQIP reforms in Ethiopia
Authors: Rolleston Caine , Oketch Moses , Tiruneh Dawit Tibebu , Rossiter Jack 
Published: January 2025

PurposeThis paper explores the extent to which the period 2012–2021, when the General Education Quality Improvement Programme (GEQIP) reforms to primary education were implemented in Ethiopia, is one of educational improvement, despite the absence of gains in learning outcomes. It examines trends in access, learning progress in Grade 4 school quality and in equity of access and outcomes across regions and between urban and rural contexts.Design/methodology/approachData from several sources are employed including Ethiopian national education data (Education Management Information Systems (EMIS)) and longitudinal school survey data from the Young Lives (YL) and Research on Improving Systems of Education (RISE) projects. Analysis employs descriptive analysis and regression modelling in a value-added framework. Trends in learning outcomes in mathematics and pupil backgrounds are examined alongside school quality, its measures and predictors.FindingsAccess to primary education in Ethiopia has expanded significantly, with some equity improvements. Learning outcomes have declined in most regions, in Southern Nations, Nationalities and Peoples (SNNP) from a mean score of 515 in 2012 to 436 in 2020. Several school and teacher quality indicators targeted by GEQIP improved modestly, including teacher maths scores which improved from a mean of 462 to 507. Improvements have not been sufficient however to outweigh effects of rapid expansion and rising disadvantage, perhaps worsened by shocks including COVID and conflict.Originality/valueThis research contributes to understanding the role of the GEQIP reforms in improving primary education in Ethiopia. It may inform policy on targeted education quality improvement. It informs wider debate on the “learning crisis” especially in sub-Saharan Africa.