bluuebunny/crossref_metadata_2025_split huggingface dataset:
Split intein-mediated protein trans-splicing to express large dystrophins
Authors: Tasfaout Hichem , Halbert Christine , Allen James , Reyes Theodore , Grimm Dirk , Hauschka Stephen , Chamberlain Jeffrey 
Published: June 2023

Abstract

Gene replacement using Adeno-associated viral (AAV) vectors represents a promising approach for many diseases. However, this therapeutic modality is challenged by the modest packaging capacity of AAVs (~4.7 kb), limiting its application for disorders involving large genes, such as Duchenne muscular dystrophy with a coding sequence >11 kb. Here we developed a novel method for expressing large dystrophins by utilizing the protein trans-splicing mechanism mediated by split inteins. We identified several split intein pairs that can efficiently join two or three fragments and generate, respectively, a large midi-dystrophin or the entire full-length dystrophin. We show that the delivery of two or three AAVs into dystrophic mice results in robust expression of large dystrophins with significant functional improvements compared with current micro-dystrophins. Moreover, using the potent myotropic AAVMYO, we demonstrate that low doses (2x1013 vg/kg) are sufficient to express large dystrophins in striated muscles bodywide with significant physiological corrections in young or very old dystrophic mice. Our data support the feasibility of this approach in vivo and show a clear superiority of large dystrophins over micro-dystrophins that are being tested in clinical trials. This novel method could benefit any patient with Duchenne or Becker muscular dystrophy regardless of genotype and could be adapted to numerous other disorders caused by mutations in large genes exceeding the carrying capacity of AAV.
Common risk alleles for schizophrenia within the Major Histocompatibility Complex predict white matter microstructure
Authors: Simmonds Emily , Pardinas Antonio , Anney Richard , Legge Sophie , Walters James , Harrison Neil , O'Donovan Michael , Escott-Price Valentina , Caseras Xavier 
Published: June 2023

Abstract
Recent research has highlighted the role of complement genes in shaping the microstructure of the brain during early development, and in contributing to common allele risk for Schizophrenia. We hypothesised that common risk variants for schizophrenia within complement genes will associate with structural changes in white matter microstructure within tracts innervating the frontal lobe. Our results show that risk alleles within the complement gene set, but also intergenic alleles, significantly predict axonal density in these white matter tracts. More specifically, risk alleles within the Major Histocompatibility Complex (MHC) region in chromosome 6 appeared to drive these association, although intergenic alleles mostly within chromosome 19 also show to play part. No significant associations were found for the orientation dispersion index. Our results suggest changes in axonal packing - but not in axonal coherence - determined by common risk alleles within the MHC genomic region, as a potential neurobiological mechanism for schizophrenia.
Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression
Authors: Deng Zhi-De , Ousdal Olga Theresa , Oltedal Leif , Angulo Brian , Baradits Mate , Spitzberg Andrew , Kessler Ute , Sartorius Alexander , Dols Annemiek , Narr Katherine , Espinoza Randall , Waarde Jeroen Van , Tendolkar Indira , Eijndhoven Philip van , Wingen Guido van , Takamiya Akihiro , Kishimoto Taishiro , Jorgensen Martin , Jorgensen Anders , Paulson Olaf , Yrondi Antoine , Peran Patrice , Soriano-Mas Carles , Cardoner Narcís , Cano Marta , Diermen Linda van , Schrijvers Didier , Belge Jean-Baptiste , Emsell Louise , Bouckaert Filip , Vandenbulcke Mathieu , Kiebs Maximilian , Hurlemann Rene , Mulders Peter , Redlich Ronny , Dannlowski Udo , Kavakbasi Erhan , Kritzer Michael , Ellard Kristen , Camprodon Joan , Petrides Georgios , Maholtra Anil , Abbott Christopher , Argyelan Miklos 
Published: June 2023

Abstract
Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this common causal network (CCN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis (Principal Component Analysis, PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CCN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CCN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes. This evidence further supports that treatment interventions converge on a CCN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.
Tumor heterogeneity and prognostic impact of the aberrant splicing burden of colorectal cancers
Authors: Eilertsen Ina , Langerud Jonas , Johannessen Bjarne , Nesbakken Arild , Lothe Ragnhild , Sveen Anita 
Published: June 2023

Abstract
The colorectal cancer (CRC) transcriptome has important clinicopathological associations. Alternative splicing is a major determinant of transcriptomic complexity, but the impact of aberrant splicing on tumor heterogeneity and patient outcome from CRC is not well described. We investigated inter- and intra-tumor splicing heterogeneity among 504 primary tumor samples and 42 non-malignant colonic mucosa samples from 314 patients analyzed on splicing-sensitive microarrays. Most (62%) cancer-specific splicing events were rare across the tumors, and even heterogeneously expressed among multiregional samples, consistent with splicing noise. However, several novel events had high prevalence and a significant impact on the expression level of cancer-critical target genes, such as SFRP4 and RNF43. The tumor splicing burden (TSB) was identified as a main discriminatory feature of the splicing profiles of CRCs. The TSB was not driven by suspected noisy events, but correlated with gene set enrichment scores of splicing-related pathways and cell cycle progression. A high TSB was an independent predictor of a favorable 5-year relapse-free survival (multivariable hazard ratio 0.55, 95% confidence interval 0.32–0.92), and not confounded by immune cell infiltration or intra-tumor heterogeneity. This study highlights the contribution of splicing to tumor heterogeneity in CRC, and we propose the TSB as a prognostically relevant feature.
Differential roles of the medial and lateral orbitofrontal cortex in decision-making
Authors: Qiu Lixin , Qiu Yidan , Liao Jiajun , Li Jinhui , Zhang Xiaoying , Chen Kemeng , Huang Qinda , Huang Ruiwang 
Published: June 2023

Abstract
Inferring potential outcomes and updating behavior are prerequisites for making flexible decisions. These abilities are highly associated with the functions of the orbitofrontal cortex (OFC). Previous studies proposed that the lateral OFC (lOFC) infers the potential outcomes and the medial OFC (mOFC) encodes the general information to guide behavior. However, recent works suggested that both these two subregions responded to the same decision-related variable. Therefore, the exact roles of mOFC and lOFC in decision-making remain unclear. To study this issue, we conducted an inference-based decision-making experiment combining with functional magnetic resonance imaging techniques. Here we found that both the mOFC and lOFC represented the inferred outcomes, but only the lOFC was responsible for the outcome inference. Although the inferred outcomes were decodable in both subregions, the outcome in the mOFC was context-general coding, whereas it was context-specific in lOFC. Moreover, the functional coupling analysis showed that the mOFC may update behavior through sensory mediation and motor execution, whereas the lOFC may update behavior through task rule retrieving, alertness maintaining, and motor planning. We concluded that the OFC subregions may be collectively activated in decision-making, but their exact roles can be dissociable.
Reduction of satellite signature effect in high accuracy satellite laser ranging to Etalon
Authors: An Ning , Guan wen bo , Podesta Ricardo Cesar , Nuñez Natalia Edith , Gao Jian , dong xue , ma lei , liu zhi cheng 
Published: June 2023

Abstract
Etalon satellite is regarded as one of the most promising tools for studying crustal motions, Earth rotation and other scientific applications. Unfortunately, its outsized shape and signature caused an adverse satellite signature effect on its range accuracy. In this study, we use the Retroreflector Uneven Distribution Model to simulate the echo signals sent from Etalon and figure out how the value of the corresponding center of mass corrections changes according to the incident angles. A center mass of correction filter has been proposed and implemented in the standard SLR data processing to eliminate satellite signature effect from the distribution of the post-fit residuals of Etalon. The measurements with minimum variability are selected by modifying the rejection criterion of effective returns. The statistical results of our study reveal that the new algorithm has a significantly better ranging accuracy. The mean RMS of normal points has been reduced from 163.7 ± 41.8ps to 118.2 ± 8.94ps, while the stability of the collected data has been improved by 79%. In addition, the new algorithm is able to improve the range accuracy of Etalon-2 by almost identical proportions. This method seeks to minimize the range bias induced by the variations in satellite signature effect at different incident angles, which provides a theoretical reference for the research on millimetre level satellite laser ranging.
Updating approach for lexicographic optimization-based planning to improve cervical cancer plan quality
Authors: Caricato Paolo , Trivellato Sara , Pellegrini Roberto , Montanari Gianluca , Daniotti Martina Camilla , Bordigoni Bianca , Faccenda Valeria , Panizza Denis , Meregalli Sofia , Bonetto Elisa , Voet Peter , Arcangeli Stefano , Ponti Elena 
Published: June 2023

Abstract
Background
To investigate the capability of mCycle (Elekta AB, Stockholm, Sweden), a fully automated lexicographic-optimization planning algorithm, to enhance plan quality of an already-validated Wish-List (WL) pushing on the organs-at-risk (OAR) sparing.
Material and Methods
Twenty-four mono-institutional cervical cancer VMAT plans were retrospectively selected. Two WLs have been defined to reproduce manual plans (WL01), and to improve the OAR sparing without affecting minimum target coverage and plan delivery accuracy (WL02). These WLs were used to automatically re-plan the selected cases. Manual plans (MP) and mCycle plans (mCP01 and mCP02) were compared in terms of dose distributions, complexity, delivery accuracy, and clinical acceptability. Two senior physicians independently performed a blind clinical evaluation, and a global quality index was used for overall assessment.
Results
WL tweaking requests 5 and 3 working days for the WL01 and the WL02, respectively. The re-planning took 3 working days in both cases. mCP01 best performed in terms of target coverage (PTV V95% (%): MP 98.0 [95.6–99.3], mCP01 99.2 [89.7–99.9], mCP02 96.9 [89.4–99.5]), while mCP02 showed an OAR sparing improvement (e.g., Rectum D50% (Gy): MP 41.7 [30.2–47.0], mCP01 40.3 [31.4–45.8], mCP02 32.6 [26.9–42.6]). The complexity of mCPs increased without affecting plan delivery accuracy. In blinded comparisons, all mCPs were considered clinically acceptable, and were preferred over MP in 90% of cases. Globally, mCPs registered plan quality scores at least comparable to MP.
Conclusions
This study showed the flexibility of the lexicographic approach in creating more demanding WL that can potentially minimize toxicities in RT plans.
Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy
Authors: Kim Il-Kyu , Diamond Mark , Yuan Salina , Kemp Samantha , Li Qinglan , Lin Jeffrey , Li Jinyang , Norgard Robert , Thomas Stacy , Merolle Maria , Katsuda Takeshi , Tobias John , Politi Katerina , Vonderheide Robert , Stanger Ben 
Published: June 2023

Abstract
Acquired resistance to immune checkpoint immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we found that tumors underwent an epithelial-to-mesenchymal transition (EMT) that resulted in reduced sensitivity to T cell-mediated killing. EMT-transcription factors (EMT-TFs) ZEB1 and SNAIL function as master genetic and epigenetic regulators of this tumor-intrinsic effect. Acquired resistance was not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, EMT was associated with epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), which renders tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings show how resistance to immunotherapy in PDAC can be acquired through plasticity programs that render tumor cells impervious to T cell killing.
Dissecting transcription of the 8q24-MYC locus in prostate cancer recognizes the equilibration between androgen receptor direct and indirect dual-functions
Authors: Guo Ju , Wei Zhao , Jia Tianwei , Wang Liyang , Nama Nuosu , Liang Jiaqian , Liao Xinghua , Liu Xiaming , Gao Yanfei , Liu Xiaoqiang , Wang Keshan , Fu Bin , Chen Shaoyong Shawn 
Published: June 2023

Abstract
Background：Androgen receptor (AR) activation and repression dual-functionality only becomes known recently and still remains intriguing in prostate cancer (PCa). MYC is a prominent oncogene functionally entangled with AR signaling in PCa. However, AR regulatory mechanisms on MYC gene transcription remains unclear.
Methods：Bioinformatics analysis of androgen-mediated RNA-Seq and MYC ChIP-Seq datasets are used for AR and MYC transcriptional networks. AR ChIP-qPCR analysis are programed to find AR binding sites (ABSs) which regulate MYC transcription. 3C-qPCR and 3C-ddPCR analyses affirmed androgen-dependent MYC-Pro-P10 interaction. CRISPR/Cas9-mediated double genomic knock-out (KO) strategy is used to show that P10-KO slightly lessened androgen-elicited MYC transrepression.
Results：Here we recognize AR bi-directional transcription mechanisms by exploiting the prominent 8q24-MYC locus conferring androgen hyper-sensitivity. At ~25Kb downstream of the MYC gene, we identified an undefined ABS, P10. By chromatin analyses, we validated androgen-dependent spatial interaction between P10 and MYC-Promoter (MYC-Pro) and temporal epigenetic repression of these MYC-proximal elements. We next designed a CRISPR/Cas9-mediated double genomic knock-out (KO) strategy to show that P10-KO slightly lessened androgen-elicited MYC transrepression in LNCaP-AR cells. In similar genomic editing assays, androgen-mediated MYC repression became slightly deepened upon KO of P11, an ABS in the PVT1 gene locus highly enriched in AR-binding motifs and peaks. We also investigated multiple ABSs in the established PCAT1 super-enhancer that distally interacts with MYC-Pro for transactivation, with each KO pool consistently shown to relieve androgen-elicited MYC repression. In the end, we systemically assessed androgen effects in the 8q24-MYC locus and along PCa genome to generalize H3K27ac and BRD4 re-distribution from pioneer factors (FoxA1 and HoxB13) to AR sites.
Conclusion：Together, we reconciled these observations by unifying AR dual-functions that are mechanistically coupled to and equilibrated by co-factor redistribution.
Evaluation of case-based combined with team-based learning guided blended learning on standardized residency training
Authors: Ling Xin , Zuyi Chen , Jin Yunxiu , Min Nie 
Published: June 2023

Abstract
Background
School and Hospital of Stomatology, Wuhan University has launched a special teaching mode in resident standardized training, called Case-based learning (CBL) combined with team-based learning (TBL) guided “blended learning”. It is adopted to fully stimulate students’ awareness of independent learning and develop personalized diagnosis and treatment plans through clinical department rotation, regular group learning and clinical lectures. Taking the specialty of endodontics as an example, this study introduces the specific content of this special teaching model, and evaluates the satisfaction of residents including postgraduate students and social residents, and its’ effect.
Methods
In the continuing education of standardized residency training, CBL combined with TBL guided online and offline “blended learning” method was used with professional postgraduate students and social residents as the main body, and a training model of“teacher as the guidance and team as the cooperation”was constructed. In addition to the rotation of clinical departments, the teaching methods such as group learning and clinical lecture were proposed. The original theoretical teaching and autonomous learning was supported, too. An anonymous questionnaire survey was conducted to analyze the the satisfaction of residents and teaching effects.
Results
The CBL combined with TBL guided“blended learning”mode was significantly better than the traditional theory teaching and autonomous learning, and gained a high satisfaction among the students. Except for the clinical lecture, clinical departments rotation and group learning gained a higher satisfaction compared with traditional theory teaching and autonomous learning, the differences were statistically significant (P < 0.05). Students generally though that clinical lectures and group learning were beneficial to improve their clinical thinking ability and enrich their knowledge system. 75.73% of the students thought that clinical lectures with the combination of clinical subject discussion and case report were more conducive to the formulation of personalized diagnosis and treatment plans.
Conclusions
In the process of standardized residency training, CBL combined with TBL guided “blended learning” mode is conducive to the cultivation of research doctors with clinical research thinking ability and make up personalized diagnosis and treatment plans for patients.
Hfq C-terminal region forms a β-rich amyloid-like motif without perturbing the N-terminal Sm-like structure
Authors: Berbon Mélanie , Martinez Denis , Morvan Estelle , Grelard Axelle , Kauffmann Brice , Waeytens Jehan , Wien Frank , Arluison Véronique , Habenstein Birgit 
Published: June 2023

Abstract
Hfq is a pleitropic actor, serving as stress response and virulence factor in the bacterial cell. It achieves this function mostly through its binding to small noncoding RNAs, conferring annealing with mRNAs. To execute these functions, Hfq assembles into a symmetric torus-shaped hexamer, called the Sm-core, with two concave structurally distinct surfaces and a convex rim. Extending outward from this core, Hfq presents a C-terminal region, described as intrinsically disordered in solution. Many as-pects of the role and the structure of this elongated C-terminal remain unclear. For instance, this region in its truncated form can promote amyloid-like filament assembly. Here, we show that a minimal 11-residue motif found at the end of the Hfq sequence assembles into filaments with amyloid characteristics, based on x-ray diffraction, infrared spectroscopy, circular dichroism and solid-state Nuclear Magnetic Resonance. Furthermore, our data suggest that the full-length Hfq in its filamentous state contains a similar molecular fingerprint than that of the short β-strand peptide, and that the Sm-core structure is not affected by filament formation. Hfq proteins might thus co-exist in two forms in vivo, either as isolated, soluble hexamers or as self-assembled hex-amers through amyloid-reminiscent interactions. This property may help modulating Hfq cellular functions.
Identification of prognostic neutrophil extracellular traps-related genes subtypes predicts prognostic and immune microenvironment for osteosarcoma patients
Authors: Yang Jibin , Yu Hao , Yang Lidan , Yang Jin , Cheng Piaotao , Gong Shouhang , Ouyang Huayi , Zeng Ni , Jiang Feng , Peng Jiachen , Pan BoChen 
Published: June 2023

Abstract
Background
Neutrophil extracellular traps (NETs) are known to play a crucial role in tumorigenesis. The present study sought to identify a molecular subtype and prognostic signature that is based on NETs-related genes (NRGs). NRGs may provide insight into osteosarcoma molecular mechanisms and predict prognosis.
Methods
We search TARGET and GEO databases to obtain expression levels of NRGs and clinical data of 89 patients with osteosarcoma. Consensus clustering analysis was used to explore the molecular subtypes. The differences (variations) in immune characteristics and biological processes across various molecular subtypes were examined using GSEA, ESTIMATE, and ssGSEA. An NRG signature was constructed using LASSO regression. Kaplan-Meier (K-M) plots, Cox regressions, and nomogram analysis were performed to determine its prognostic significance in osteosarcoma.
Results
Molecular subtypes associated with NETs were discovered. Cluster 2 was linked to a more favorable prognosis, greater immune cell infiltration degree and immunogenicity, and a more favorable immunotherapy response than Cluster 1. Patients in the low-risk group had better survival outcomes than patients in the high-risk group. Additionally, high risk scores were independently correlated with poor prognoses as per the Cox regression analysis. Furthermore, the nomogram, which incorporates clinical characteristics and risk scores, has the potential to improve prediction accuracy.
Conclusion
Patients with osteosarcoma may be divided into two subtypes of NETs. An NRG-related prognostic signature was developed for patients with osteosarcoma.