bluuebunny/crossref_metadata_2025_split huggingface dataset:
TKT-PARP1 axis induces radioresistance by promoting DNA double-strand break repair in hepatocellular carcinoma
Authors: Geng Longpo , Zhu Mingming , Luo Dongjun , Chen Huihui , Li Binghua , Lao Yuanxiang , An Hongda , Wu Yue , Li Yunzheng , Xia Anliang , Shi Yi , Tong Zhuting , Lu Shanshan , Xu Dengqiu , Wang Xu , Zhang Wenjun , Sun Beicheng , Xu Zhu 
Published: January 2024

AbstractHepatocellular carcinoma (HCC) stands as the fifth most prevalent malignant tumor on a global scale and presents as the second leading cause of cancer-related mortality. DNA damage-based radiotherapy (RT) plays a pivotal role in the treatment of HCC. Nevertheless, radioresistance remains a primary factor contributing to the failure of radiation therapy in HCC patients. In this study, we investigated the functional role of transketolase (TKT) in the repair of DNA double-strand breaks (DSBs) in HCC. Our research unveiled that TKT is involved in DSB repair, and its depletion significantly reduces both non-homologous end joining (NHEJ) and homologous recombination (HR)-mediated DSB repair. Mechanistically, TKT interacts with PARP1 in a DNA damage-dependent manner. Furthermore, TKT undergoes PARylation by PARP1, resulting in the inhibition of its enzymatic activity, and TKT can enhance the auto-PARylation of PARP1 in response to DSBs in HCC. The depletion of TKT effectively mitigates the radioresistance of HCC, both in vitro and in mouse xenograft models. Moreover, high TKT expression confers resistance of RT in clinical HCC patients, establishing TKT as a marker for assessing the response of HCC patients who received cancer RT. In summary, our findings reveal a novel mechanism by which TKT contributes to the radioresistance of HCC. Overall, we identify the TKT-PARP1 axis as a promising potential therapeutic target for improving RT outcomes in HCC.
Integrating rare genetic variants into DPYD pharmacogenetic testing may help preventing fluoropyrimidine-induced toxicity
Authors: Larrue Romain , Fellah Sandy , Hennart Benjamin , Sabaouni Naoual , Boukrout Nihad , Van der Hauwaert Cynthia , Delage Clément , Cheok Meyling , Perrais Michaël , Cauffiez Christelle , Allorge Delphine , Pottier Nicolas 
Published: January 2024

AbstractVariability in genes involved in drug pharmacokinetics or drug response can be responsible for suboptimal treatment efficacy or predispose to adverse drug reactions. In addition to common genetic variations, large-scale sequencing studies have uncovered multiple rare genetic variants predicted to cause functional alterations in genes encoding proteins implicated in drug metabolism, transport and response. To understand the functional importance of rare genetic variants in DPYD, a pharmacogene whose alterations can cause severe toxicity in patients exposed to fluoropyrimidine-based regimens, massively parallel sequencing of the exonic regions and flanking splice junctions of the DPYD gene was performed in a series of nearly 3000 patients categorized according to pre-emptive DPD enzyme activity using the dihydrouracil/uracil ([UH2]/[U]) plasma ratio as a surrogate marker of DPD activity. Our results underscore the importance of integrating next-generation sequencing-based pharmacogenomic interpretation into clinical decision making to minimize fluoropyrimidine-based chemotherapy toxicity without altering treatment efficacy.
Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer
Authors: Mah Chui Yan , Nguyen An Dieu Trang , Niijima Takuto , Helm Madison , Dehairs Jonas , Ryan Feargal J. , Ryan Natalie , Quek Lake-Ee , Hoy Andrew J. , Don Anthony S. , Mills Ian G. , Swinnen Johannes V. , Lynn David J. , Nassar Zeyad D. , Butler Lisa M. 
Published: January 2024

Abstract
Background
Peroxisomes are central metabolic organelles that have key roles in fatty acid homoeostasis. As prostate cancer (PCa) is particularly reliant on fatty acid metabolism, we explored the contribution of peroxisomal β-oxidation (perFAO) to PCa viability and therapy response.

Methods
Bioinformatic analysis was performed on clinical transcriptomic datasets to identify the perFAO enzyme, 2,4-dienoyl CoA reductase 2 (DECR2) as a target gene of interest. Impact of DECR2 and perFAO inhibition via thioridazine was examined in vitro, in vivo, and in clinical prostate tumours cultured ex vivo. Transcriptomic and lipidomic profiling was used to determine the functional consequences of DECR2 inhibition in PCa.

Results
DECR2 is upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa (CRPC). Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and therapy-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. DECR2 influences cell cycle progression and lipid metabolism to support tumour cell proliferation. Further, co-targeting of perFAO and standard-of-care androgen receptor inhibition enhanced suppression of PCa cell proliferation.

Conclusion
Our findings support a focus on perFAO, specifically DECR2, as a promising therapeutic target for CRPC and as a novel strategy to overcome lethal treatment resistance.
The E3 ubiquitin ligase Itch regulates death receptor and cholesterol trafficking to affect TRAIL-mediated apoptosis
Authors: Holloway James , Seeley Aidan , Cobbe Neville , Turkington Richard C. , Longley Daniel B. , Evergren Emma 
Published: January 2024

AbstractThe activation of apoptosis signalling by TRAIL (TNF-related apoptosis-inducing ligand) through receptor binding is a fundamental mechanism of cell death induction and is often perturbed in cancer cells to enhance their cell survival and treatment resistance. Ubiquitination plays an important role in the regulation of TRAIL-mediated apoptosis, and here we investigate the role of the E3 ubiquitin ligase Itch in TRAIL-mediated apoptosis in oesophageal cancer cells. Knockdown of Itch expression results in resistance to TRAIL-induced apoptosis, caspase-8 activation, Bid cleavage and also promotes cisplatin resistance. Whilst the assembly of the death-inducing signalling complex (DISC) at the plasma membrane is not perturbed relative to the control, TRAIL-R2 is mis-localised in the Itch-knockdown cells. Further, we observe significant changes to mitochondrial morphology alongside an increased cholesterol content. Mitochondrial cholesterol is recognised as an important anti-apoptotic agent in cancer. Cells treated with a drug that increases mitochondrial cholesterol levels, U18666A, shows a protection from TRAIL-induced apoptosis, reduced caspase-8 activation, Bid cleavage and cisplatin resistance. We demonstrate that Itch knockdown cells are less sensitive to a Bcl-2 inhibitor, show impaired activation of Bax, cytochrome c release and an enhanced stability of the cholesterol transfer protein STARD1. We identify a novel protein complex composed of Itch, the mitochondrial protein VDAC2 and STARD1. We propose a mechanism where Itch regulates the stability of STARD1. An increase in STARD1 expression enhances cholesterol import to mitochondria, which inhibits Bax activation and cytochrome c release. Many cancer types display high mitochondrial cholesterol levels, and oesophageal adenocarcinoma tumours show a correlation between chemotherapy resistance and STARD1 expression which is supported by our findings. This establishes an important role for Itch in regulation of extrinsic and intrinsic apoptosis, mitochondrial cholesterol levels and provides insight to mechanisms that contribute to TRAIL, Bcl-2 inhibitor and cisplatin resistance in cancer cells.
The central role of tilted anisotropy for field-free spin–orbit torque switching of perpendicular magnetization
Authors: Hu Chen-Yu , Chen Wei-De , Liu Yan-Ting , Huang Chao-Chung , Pai Chi-Feng 
Published: January 2024

Abstract
The discovery of efficient magnetization switching upon device activation by spin Hall effect (SHE)-induced spin–orbit torque (SOT) changed the course of magnetic random-access memory (MRAM) research and development. However, for electronic systems with perpendicular magnetic anisotropy (PMA), the use of SOT is still hampered by the necessity of a longitudinal magnetic field to break magnetic symmetry and achieve deterministic switching. In this work, we demonstrate that robust and tunable field-free current-driven SOT switching of perpendicular magnetization can be controlled by the growth protocol in Pt-based magnetic heterostructures. We further elucidate that such growth-dependent symmetry breaking originates from the laterally tilted magnetic anisotropy of the ferromagnetic layer with PMA, a phenomenon that has been largely neglected in previous studies. We show experimentally and in simulation that in a PMA system with tilted anisotropy, the deterministic field-free switching exhibits a conventional SHE-induced damping-like torque feature, and the resulting current-induced effective field shows a nonlinear dependence on the applied current density. This relationship could be potentially misattributed to an unconventional SOT origin.
Epigenetic reprogramming shapes the cellular landscape of schwannoma
Authors: Liu S. John , Casey-Clyde Tim , Cho Nam Woo , Swinderman Jason , Pekmezci Melike , Dougherty Mark C. , Foster Kyla , Chen William C. , Villanueva-Meyer Javier E. , Swaney Danielle L. , Vasudevan Harish N. , Choudhury Abrar , Pak Joanna , Breshears Jonathan D. , Lang Ursula E. , Eaton Charlotte D. , Hiam-Galvez Kamir J. , Stevenson Erica , Chen Kuei-Ho , Lien Brian V. , Wu David , Braunstein Steve E. , Sneed Penny K. , Magill Stephen T. , Lim Daniel , McDermott Michael W. , Berger Mitchel S. , Perry Arie , Krogan Nevan J. , Hansen Marlan R. , Spitzer Matthew H. , Gilbert Luke , Theodosopoulos Philip V. , Raleigh David R. 
Published: January 2024

AbstractMechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy.
Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
Authors: Chandramohan Arun , Josien Hubert , Yuen Tsz Ying , Duggal Ruchia , Spiegelberg Diana , Yan Lin , Juang Yu-Chi Angela , Ge Lan , Aronica Pietro G. , Kaan Hung Yi Kristal , Lim Yee Hwee , Peier Andrea , Sherborne Brad , Hochman Jerome , Lin Songnian , Biswas Kaustav , Nestor Marika , Verma Chandra S. , Lane David P. , Sawyer Tomi K. , Garbaccio Robert , Henry Brian , Kannan Srinivasaraghavan , Brown Christopher J. , Johannes Charles W. , Partridge Anthony W. 
Published: January 2024

Abstract
Although stapled α-helical peptides can address challenging targets, their advancement is impeded by poor understandings for making them cell permeable while avoiding off-target toxicities. By synthesizing >350 molecules, we present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects. Key insights include a clear correlation between lipophilicity and permeability, removal of positive charge to avoid off-target toxicities, judicious anionic residue placement to enhance solubility/behavior, optimization of C-terminal length/helicity to enhance potency, and optimization of staple type/number to avoid polypharmacology. Workflow application gives peptides with >292x improved cell proliferation potencies and no off-target cell proliferation effects ( > 3800x on-target index). Application of these ‘design rules’ to a distinct Mdm2(X) peptide series improves ( > 150x) cellular potencies and removes off-target toxicities. The outlined workflow should facilitate therapeutic impacts, especially for those targets such as Mdm2(X) that have hydrophobic interfaces and are targetable with a helical motif.
Towards provably efficient quantum algorithms for large-scale machine-learning models
Authors: Liu Junyu , Liu Minzhao , Liu Jin-Peng , Ye Ziyu , Wang Yunfei , Alexeev Yuri , Eisert Jens , Jiang Liang 
Published: January 2024

AbstractLarge machine learning models are revolutionary technologies of artificial intelligence whose bottlenecks include huge computational expenses, power, and time used both in the pre-training and fine-tuning process. In this work, we show that fault-tolerant quantum computing could possibly provide provably efficient resolutions for generic (stochastic) gradient descent algorithms, scaling as $${{{{{{{\mathcal{O}}}}}}}}({T}^{2}\times {{{{{{{\rm{polylog}}}}}}}}(n))$$
O

(

T

2

×
polylog

(

n

)

)

, where n is the size of the models and T is the number of iterations in the training, as long as the models are both sufficiently dissipative and sparse, with small learning rates. Based on earlier efficient quantum algorithms for dissipative differential equations, we find and prove that similar algorithms work for (stochastic) gradient descent, the primary algorithm for machine learning. In practice, we benchmark instances of large machine learning models from 7 million to 103 million parameters. We find that, in the context of sparse training, a quantum enhancement is possible at the early stage of learning after model pruning, motivating a sparse parameter download and re-upload scheme. Our work shows solidly that fault-tolerant quantum algorithms could potentially contribute to most state-of-the-art, large-scale machine-learning problems.
Improving rechargeable magnesium batteries through dual cation co-intercalation strategy
Authors: Roy Ananyo , Sotoudeh Mohsen , Dinda Sirshendu , Tang Yushu , Kübel Christian , Groß Axel , Zhao-Karger Zhirong , Fichtner Maximilian , Li Zhenyou 
Published: January 2024

AbstractThe development of competitive rechargeable Mg batteries is hindered by the poor mobility of divalent Mg ions in cathode host materials. In this work, we explore the dual cation co-intercalation strategy to mitigate the sluggishness of Mg2+ in model TiS2 material. The strategy involves pairing Mg2+ with Li+ or Na+ in dual-salt electrolytes in order to exploit the faster mobility of the latter with the aim to reach better electrochemical performance. A combination of experiments and theoretical calculations details the charge storage and redox mechanism of co-intercalating cationic charge carriers. Comparative evaluation reveals that the redox activity of Mg2+ can be improved significantly with the help of the dual cation co-intercalation strategy, although the ionic radius of the accompanying monovalent ion plays a critical role on the viability of the strategy. More specifically, a significantly higher Mg2+ quantity intercalates with Li+ than with Na+ in TiS2. The reason being the absence of phase transition in the former case, which enables improved Mg2+ storage. Our results highlight dual cation co-intercalation strategy as an alternative approach to improve the electrochemical performance of rechargeable Mg batteries by opening the pathway to a rich playground of advanced cathode materials for multivalent battery applications.
Nb3Cl8: a prototypical layered Mott-Hubbard insulator
Authors: Grytsiuk Sergii , Katsnelson Mikhail I. , Loon Erik G.C.P. van , Rösner Malte 
Published: January 2024

AbstractDespite its simplicity and relevance for the description of electronic correlations in solids, the Hubbard model is seldom inarguably realized in real materials. Here, we show that monolayer Nb3Cl8 is an ideal candidate to be described within a single-orbital Hubbard model, constructed within a “molecular” rather than atomic basis set using ab initio constrained random phase approximation calculations. We provide the necessary ingredients to connect experimental reality with ab initio material descriptions and correlated electron theory, which clarifies that monolayer Nb3Cl8 is a Mott insulator with a gap of about 1.4 to 2.0 eV depending on its dielectric environment. Comparisons to an atomistic three-orbital model show that the single-molecular-orbital description is adequate and reliable. We further comment on the electronic and magnetic structure of the compound and show that the Mott insulating state survives in the low-temperature bulk phases of the material featuring distinct experimentally verifiable characteristics.
Dopamine-independent effect of rewards on choices through hidden-state inference
Authors: Blanco-Pozo Marta , Akam Thomas , Walton Mark E. 
Published: January 2024

AbstractDopamine is implicated in adaptive behavior through reward prediction error (RPE) signals that update value estimates. There is also accumulating evidence that animals in structured environments can use inference processes to facilitate behavioral flexibility. However, it is unclear how these two accounts of reward-guided decision-making should be integrated. Using a two-step task for mice, we show that dopamine reports RPEs using value information inferred from task structure knowledge, alongside information about reward rate and movement. Nonetheless, although rewards strongly influenced choices and dopamine activity, neither activating nor inhibiting dopamine neurons at trial outcome affected future choice. These data were recapitulated by a neural network model where cortex learned to track hidden task states by predicting observations, while basal ganglia learned values and actions via RPEs. This shows that the influence of rewards on choices can stem from dopamine-independent information they convey about the world’s state, not the dopaminergic RPEs they produce.
Production and characterization of human hair keratin bioplastic films with novel plasticizers
Authors: Shubha Anand , Sharmita Gupta , Anita Lakhani 
Published: January 2024

AbstractSince their invention, conventional plastics have contributed in the betterment of the society in numerous ways, nevertheless their deleterious impacts on the natural ecosystems and living creatures is irrefutable. The management of plastic waste generated is a concern worldwide and therefore quest for the plastic alternates or bioplastics is imminent. Here, we explore the suitability of keratin from human hair waste as the candidate for the production of bioplastic films. Keratin extracted from hair was used to form the films or ‘kertics’ by solution casting and curing. Ethanediol, di-ethylene glycol and tri-ethylene glycol were used as novel plasticizers along with glycerol in the keratin film formation. The film prepared were of the thickness 190–220 µm with the area of about 4.54 ± 0.2 cm2. Water uptake by G100, ED100, DEG100 and TEG100 films was recorded to be 4.8, 6.2, 4.9 and 6.3% respectively. FESEM analysis revealed that the films with 100 µl of 1% glycerol (G100) had continuous surface morphology except few pits of 0.1 µm, also DEG100 and TEG100 films have the most uniform surface morphology with no evident pits, holes or bulges. X-ray diffractogram showed characteristic peak of keratin at 19.5° and the d-spacing value observed was 0.45 nm. The FTIR studies suggested that the films retained keratin in non degraded form, and possessed the characteristic Amide peaks. The films were also found to be biodegradable in studies involving keratinophilic fungal strain of A. oryzae. These films could found potential applications in packaging industry, disposable items manufacturing and biomaterial generation.
RadioLab project: knowledge of radon gas in Italy
Authors: Ambrosino F. , La Verde G. , Colucci M. , Fanti V. , Barrale D. , Caciolli A. , Hemmer S. , De Giorgi M. L. , Ventura A. , Immè J. , Pagano A. , Budinich M. , Vascotto M. , Montalbano V. , Capua M. , Tucci R. , Chiosso M. , Visca L. , Groppi F. , Pugliese M. 
Published: January 2024

AbstractRadioLab is an Italian project, addressed to school-age people, and designed for the dissemination of scientific culture on the theme of environmental radioactivity, with particular regards to the importance of knowledge of radon gas exposure. The project is a nationwide initiative promoted by the National Institute of Nuclear Physics- INFN. First tool used by the project, and of immediate impact to assess the public awareness on radon, is the administration of the survey “do you know the radon gas?”. In the survey, together with the knowledge of radon and of its sources, information on personal, cultural and territorial details regarding the interviewees are also taken. Reasonably, the survey invests not only young people, but also their relatives, school workers and, gradually, the public. The survey is administrated during exhibitions or outreach events devoted to schools, but also open to the public. The survey is in dual form: printed and online. The online mode clearly leads RadioLab project even outside the school environment. Based on the results of the survey, several statistical analyses have been performed and many conclusions are drawn about the knowledge of the population on the radon risk. The RadioLab benefit and the requirement to carry on the project goals, spreading awareness of environmental radioactivity from radon, emerge. The dataset involves all twenty Italian regions and consists of 28,612 entries covering the 5-year period 2018–2022.
Assessment of safety profile of secukinumab in real-world scenario using United States food and drug administration adverse event reporting system database
Authors: Eshwar Vishnu , Kamath Ashwin 
Published: January 2024

AbstractSecukinumab is an anti-IL-17 monoclonal antibody approved for treating psoriasis and various arthritides. A comprehensive evaluation of its safety, especially in a real-world setting, is necessary. This study aimed to describe the adverse events (AE) associated with secukinumab use using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. FAERS data files containing AE reports from 2015 to 2021 were downloaded for data mining. Primary or secondary suspect medications indicated for psoriasis were identified and analyzed. Medical dictionary for regulatory activities (MedDRA version 24.1) was used to analyze the AE terms. To detect potential safety signals of AE from secukinumab use, disproportionality analysis was used. A total of 365,590 adverse event reports were identified; of these, 44,761 reports involved the use of secukinumab. Safety signals were identified for ocular infections and gastrointestinal adverse events at the standardised MedDRA query level. Safety signals for oral candidiasis, oral herpes, conjunctivitis, eye infections, and ulcerative colitis were identified at the preferred term level. The findings of our study are consistent with those of earlier studies, such as the increased risk of infections and inflammatory bowel disease. However, our study also identified additional safety signals that need to be further evaluated.