bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-mitochondrion sequencing uncovers distinct mutational patterns and heteroplasmy landscape in mouse astrocytes and neurons
Authors: Kadam Parnika S. , Yang Zijian , Lu Youtao , Zhu Hua , Atiyas Yasemin , Shah Nishal , Fisher Stephen , Nordgren Erik , Kim Junhyong , Issadore David , Eberwine James 
Published: July 2024

Abstract
Background
Mitochondrial (mt) heteroplasmy can cause adverse biological consequences when deleterious mtDNA mutations accumulate disrupting “normal” mt-driven processes and cellular functions. To investigate the heteroplasmy of such mtDNA changes, we developed a moderate throughput mt isolation procedure to quantify the mt single-nucleotide variant (SNV) landscape in individual mouse neurons and astrocytes. In this study, we amplified mt-genomes from 1645 single mitochondria isolated from mouse single astrocytes and neurons to (1) determine the distribution and proportion of mt-SNVs as well as mutation pattern in specific target regions across the mt-genome, (2) assess differences in mtDNA SNVs between neurons and astrocytes, and (3) study co-segregation of variants in the mouse mtDNA.

Results
(1) The data show that specific sites of the mt-genome are permissive to SNV presentation while others appear to be under stringent purifying selection. Nested hierarchical analysis at the levels of mitochondrion, cell, and mouse reveals distinct patterns of inter- and intra-cellular variation for mt-SNVs at different sites. (2) Further, differences in the SNV incidence were observed between mouse neurons and astrocytes for two mt-SNV 9027:G > A and 9419:C > T showing variation in the mutational propensity between these cell types. Purifying selection was observed in neurons as shown by the Ka/Ks statistic, suggesting that neurons are under stronger evolutionary constraint as compared to astrocytes. (3) Intriguingly, these data show strong linkage between the SNV sites at nucleotide positions 9027 and 9461.

Conclusions
This study suggests that segregation as well as clonal expansion of mt-SNVs is specific to individual genomic loci, which is important foundational data in understanding of heteroplasmy and disease thresholds for mutation of pathogenic variants.
Diversely evolved xibalbin variants from remipede venom inhibit potassium channels and activate PKA-II and Erk1/2 signaling
Authors: Pinheiro-Junior Ernesto Lopes , Alirahimi Ehsan , Peigneur Steve , Isensee Jörg , Schiffmann Susanne , Erkoc Pelin , Fürst Robert , Vilcinskas Andreas , Sennoner Tobias , Koludarov Ivan , Hempel Benjamin-Florian , Tytgat Jan , Hucho Tim , von Reumont Björn M. 
Published: July 2024

Abstract
Background
The identification of novel toxins from overlooked and taxonomically exceptional species bears potential for various pharmacological applications. The remipede Xibalbanus tulumensis, an underwater cave-dwelling crustacean, is the only crustacean for which a venom system has been described. Its venom contains several xibalbin peptides that have an inhibitor cysteine knot (ICK) scaffold.

Results
Our screenings revealed that all tested xibalbin variants particularly inhibit potassium channels. Xib1 and xib13 with their eight-cysteine domain similar to spider knottins also inhibit voltage-gated sodium channels. No activity was noted on calcium channels. Expanding the functional testing, we demonstrate that xib1 and xib13 increase PKA-II and Erk1/2 sensitization signaling in nociceptive neurons, which may initiate pain sensitization. Our phylogenetic analysis suggests that xib13 either originates from the common ancestor of pancrustaceans or earlier while xib1 is more restricted to remipedes. The ten-cysteine scaffolded xib2 emerged from xib1, a result that is supported by our phylogenetic and machine learning-based analyses.

Conclusions
Our functional characterization of synthesized variants of xib1, xib2, and xib13 elucidates their potential as inhibitors of potassium channels in mammalian systems. The specific interaction of xib2 with Kv1.6 channels, which are relevant to treating variants of epilepsy, shows potential for further studies. At higher concentrations, xib1 and xib13 activate the kinases PKA-II and ERK1/2 in mammalian sensory neurons, suggesting pain sensitization and potential applications related to pain research and therapy. While tested insect channels suggest that all probably act as neurotoxins, the biological function of xib1, xib2, and xib13 requires further elucidation. A novel finding on their evolutionary origin is the apparent emergence of X. tulumensis-specific xib2 from xib1. Our study is an important cornerstone for future studies to untangle the origin and function of these enigmatic proteins as important components of remipede but also other pancrustacean and arthropod venoms.
Adults prenatally exposed to the Dutch Famine exhibit a metabolic signature associated with a broad spectrum of common diseases
Authors: Taeubert M. Jazmin , Kuipers Thomas B. , Zhou Jiayi , Li Chihua , Wang Shuang , Wang Tian , Tobi Elmar W. ,   BBMRI-NL Metabolomics consortium, Belsky Daniel W. , Lumey L. H. , Heijmans Bastiaan T. 
Published: July 2024

Abstract
Background
Exposure to famine in the prenatal period is associated with an increased risk of metabolic disease, including obesity and type 2 diabetes. We employed nuclear magnetic resonance (NMR) metabolomic profiling to identify the metabolic changes that are associated with survival of prenatal famine exposure during the Dutch Famine at the end of World War II and subsequently assess their link to disease.

Methods
NMR metabolomics data were generated from serum in 480 individuals prenatally exposed to famine (mean 58.8 years, 0.5 SD) and 464 controls (mean 57.9 years, 5.4 SD). We tested associations of prenatal famine exposure with levels of 168 individual metabolic biomarkers and compared the metabolic biomarker signature of famine exposure with those of 154 common diseases.

Results
Prenatal famine exposure was associated with higher concentrations of branched-chain amino acids ((iso)-leucine), aromatic amino acid (tyrosine), and glucose in later life (0.2–0.3 SD, p < 3 × 10−3). The metabolic biomarker signature of prenatal famine exposure was positively correlated to that of incident type 2 diabetes from the UK Biobank (r = 0.77, p = 3 × 10−27), also when re-estimating the signature of prenatal famine exposure among individuals without diabetes (r = 0.67, p = 1 × 10−18). Remarkably, this association extended to 115 common diseases for which signatures were available (0.3 ≤ r ≤ 0.9, p < 3.2 × 10−4). Correlations among metabolic signatures of famine exposure and disease outcomes were attenuated when the famine signature was adjusted for body mass index.

Conclusions
Prenatal famine exposure is associated with a metabolic biomarker signature that strongly resembles signatures of a diverse set of diseases, an observation that can in part be attributed to a shared involvement of obesity.
The impact of the COVID-19 pandemic on tuberculosis treatment outcomes in 49 high burden countries
Authors: Gunsaru Vester , Henrion Marc Y. R. , McQuaid C. Finn 
Published: July 2024

Abstract
Background
The COVID-19 pandemic disrupted tuberculosis (TB) health services, including treatment support and access to drugs, as patients were not able to access health facilities. While the effect of this disruption on treatment outcomes has been studied in isolated treatment centres, cities and provinces, the impact of the pandemic on TB treatment outcomes at a country and regional level has not been evaluated.

Methods
We used treatment outcomes for new and relapse TB cases reported to the World Health Organization (WHO) from 49 high TB, TB/HIV and drug-resistant TB burden countries from 2012 to 2019. We developed multinomial logistic regression models for trends in TB treatment success, failure, death and loss to follow up. We predicted TB treatment outcomes for 2020 and 2021, comparing these to observations, by computing ratios between observed and predicted probabilities. We aggregated these risk ratios (RR) for six WHO-defined regions using random-effects meta-analysis.

Results
Across 49 countries and four TB treatment outcomes, 17 (out of 196) country-outcome pairs in 2020 and 21 in 2021 had evidence of systematic differences between observed and predicted TB treatment outcome probabilities. Regionally, only four (out of 24) region-outcome pairs had evidence of systematic differences in 2020 and four in 2021, where the European region accounted for four of these in total. Globally, there was evidence of systematic differences in treatment failure in both 2020 (RR: 1.14, 95%CI: 1.01–1.28, p = 0.0381) and 2021 (RR: 1.36, 95%CI: 1.03–1.78, p = 0.0277), deaths in 2020 (RR: 1.08, 95%CI: 1.03–1.13, p = 0.0010) and losses to follow up in 2020 (RR: 0.91, 95%CI: 0.86–0.97, p = 0.0059).

Conclusions
While for some countries and regions there were significant differences between observed and predicted treatment outcomes probabilities, there was insufficient evidence globally to identify systematic differences between observed and expected TB treatment outcome probabilities because of COVID-19-associated disruptions in general. However, larger numbers of treatment failures and deaths on treatment than expected were observed globally, suggesting a need for further investigation.
Ultrasound parameters of arteries and heart in normal fetuses
Authors: Chen Guihong , Wang Pin , Zhang Yanhong , Li Na , Fu Liman , Chen Yu , Geng Xuna , Han Yongfeng , Qin Lu , Gao Bulang , Yu Tianxiao , Mi Jie 
Published: July 2024

Abstract
Background
Currently, no normal ultrasound data of the fetuses during the 20–40 gestation have been obtained for references of fetal growth and development. If such ultrasound data existed for prenatal diagnosis of possible diseases and abnormalities, neonates would be able to get timely treatment immediately after birth. This study was thus performed to obtain ultrasound parameters of normal fetuses during the 20–40 week gestation and the distribution of ultrasound parameters with the gestational age for references of detecting potential fetal diseases and abnormalities.

Methods
Normal fetuses without any abnormalities were enrolled, and the ultrasound parameters of the general biology, arteries, and aorta were measured and analyzed.

Results
417 normal fetuses were enrolled. A significant (P < 0.05) negative correlation with the gestational age was detected in the peak systolic velocity/peak diastolic velocity (S/D), pulsatility index (PI) and resistance index (RI) of the umbilical artery (UA). A relatively stable relationship with the gestational age was detected in the fetal weight%, S/D, PI and RI of the middle cerebral artery (MCA), peak systolic velocity (PSV) and velocity time integral (VTI) of the intra-abdominal UA, fetal heart to chest ratio, mitral valve (MV)- and tricuspid valve (TV)-E/A peak flow velocity, aortic isthmic Z-score and displacement, distance between the brachiocephalic artery-left common carotid artery (BA-LCCA) and LCCA-left subclavian artery (LSA), Z-score of aorta, ascending aorta (AAO), pulmonary artery (PA), main pulmonary artery (MPA), and descending aorta (DAO). A significant (P < 0.05) positive correlation with the gestational age was detected in the fetal biological data, MCA PSV and VTI, free-UA PSV and VTI and cardio-thoracic ratio, cardiac parameters, ductus arteriosus (DA) and isthmus diameter, aortic parameters, PA and MPA diameter, MPA PSV and VTI, isthmus flow volume and velocity and PA flow volume, DA and BA parameters, and LCCA and LSA parameters (flow volume, PSV, and VTI).

Conclusion
A certain correlation and distribution trend is detected in the ultrasound parameters of normal fetuses, and the ratios among different parameters remain relative stable. These findings can be used for determination of abnormal growth of the fetuses in prenatal ultrasound scan.

Graphic Abstract
Therapeutic effect of small extracellular vesicles from cytokine-induced memory-like natural killer cells on solid tumors
Authors: Shi Yinghong , Chen Yanxia , Wang Yi , Mo Dan , Ai Huisheng , Zhang Jianguo , Guo Mei , Qian Hui 
Published: July 2024

Abstract
Small extracellular vesicles (sEV) derived from diverse natural killer (NK) cell lines have proven their exceptional antitumor activities. However, sEV from human primary NK cells, especially memory-like NK cells, are rarely utilized for cancer treatment. In this study, we obtained sEV from IL-12, IL-15 and IL-18 cultured human memory-like NK cells (mNK-sEV) that showed strong cytokine-secretory ability. It was uncovered that mNK-sEV entered cancer cells via macropinocytosis and induced cell apoptosis via caspase-dependent pathway. Compared to sEV from conventionally cultured NK cells (conNK-sEV), mNK-sEV inhibited tumor growth to a greater extent. Concomitantly, pharmacokinetics and biodistribution results validated a higher accumulation of mNK-sEV than conNK-sEV in tumors of xenografted murine models. Notably, elevated containment of granulysin (GNLY) within mNK-sEV, at least in part, may contribute to the enhanced therapeutic effect. Herein our results present that mNK-sEV can be a novel class of therapeutic reagent for effective cancer treatment.

Graphical Abstract
Extracellular vesicles at the crossroad between cancer progression and immunotherapy: focus on dendritic cells
Authors: Schioppa Tiziana , Gaudenzi Carolina , Zucchi Giovanni , Piserà Arianna , Vahidi Yasmin , Tiberio Laura , Sozzani Silvano , Del Prete Annalisa , Bosisio Daniela , Salvi Valentina 
Published: July 2024

AbstractExtracellular vesicles (EVs) are nanosized heat-stable vesicles released by virtually all cells in the body, including tumor cells and tumor-infiltrating dendritic cells (DCs). By carrying molecules from originating cells, EVs work as cell-to-cell communicators in both homeostasis and cancer but may also represent valuable therapeutic and diagnostic tools. This review focuses on the role of tumor-derived EVs (TEVs) in the modulation of DC functions and on the therapeutic potential of both tumor- and DC-derived EVs in the context of immunotherapy and DC-based vaccine design. TEVs were originally characterized for their capability to transfer tumor antigens to DCs but are currently regarded as mainly immunosuppressive because of the expression of DC-inhibiting molecules such as PD-L1, HLA-G, PGE2 and others. However, TEVs may still represent a privileged system to deliver antigenic material to DCs upon appropriate engineering to reduce their immunosuppressive cargo or increase immunogenicity. DC-derived EVs are more promising than tumor-derived EVs since they expose antigen-loaded MHC, costimulatory molecules and NK cell-activating ligands in the absence of an immunosuppressive cargo. Moreover, DC-derived EVs possess several advantages as compared to cell-based drugs such as a higher antigen/MHC concentration and ease of manipulation and a lower sensitivity to immunosuppressive microenvironments. Preclinical models showed that DC-derived EVs efficiently activate tumor-specific NK and T cell responses either directly or indirectly by transferring antigens to tumor-infiltrating DCs. By contrast, however, phase I and II trials showed a limited clinical efficacy of EV-based anticancer vaccines. We discuss that the future of EV-based therapy depends on our capability to overcome major challenges such as a still incomplete understanding of their biology and pharmacokinetic and the lack of standardized methods for high-throughput isolation and purification. Despite this, EVs remain in the limelight as candidates for cancer immunotherapy which may outmatch cell-based strategies in the fullness of their time.
Radiogenomic analysis for predicting lymph node metastasis and molecular annotation of radiomic features in pancreatic cancer
Authors: Tang Yi , Su Yi-xi , Zheng Jin-mei , Zhuo Min-ling , Qian Qing-fu , Shen Qing-ling , Lin Peng , Chen Zhi-kui 
Published: July 2024

Abstract
Background
To provide a preoperative prediction model for lymph node metastasis in pancreatic cancer patients and provide molecular information of key radiomic features.

Methods
Two cohorts comprising 151 and 54 pancreatic cancer patients were included in the analysis. Radiomic features from the tumor region of interests were extracted by using PyRadiomics software. We used a framework that incorporated 10 machine learning algorithms and generated 77 combinations to construct radiomics-based models for lymph node metastasis prediction. Weighted gene coexpression network analysis (WGCNA) was subsequently performed to determine the relationships between gene expression levels and radiomic features. Molecular pathways enrichment analysis was performed to uncover the underlying molecular features.

Results
Patients in the in-house cohort (mean age, 61.3 years ± 9.6 [SD]; 91 men [60%]) were separated into training (n = 105, 70%) and validation (n = 46, 30%) cohorts. A total of 1,239 features were extracted and subjected to machine learning algorithms. The 77 radiomic models showed moderate performance for predicting lymph node metastasis, and the combination of the StepGBM and Enet algorithms had the best performance in the training (AUC = 0.84, 95% CI = 0.77–0.91) and validation (AUC = 0.85, 95% CI = 0.73–0.98) cohorts. We determined that 15 features were core variables for lymph node metastasis. Proliferation-related processes may respond to the main molecular alterations underlying these features.

Conclusions
Machine learning-based radiomics could predict the status of lymph node metastasis in pancreatic cancer, which is associated with proliferation-related alterations.
Identification of TEFM as a potential therapeutic target for LUAD treatment
Authors: Hu Wenxuan , Yang Jian , Hu Kang , Luo Gaomeng , Chen Zhike , Lu Zihao , Li Yongsen , Lv Xin , zhao Jun , Xu Chun 
Published: July 2024

Abstract
Background
Molecularly targeted therapies have recently become a hotspot in the treatment of LUAD, with ongoing efforts to identify new effective targets due to individual variability. Among these potential targets, the mitochondrial transcription elongation factor (TEFM) stands out as a crucial molecule involved in mitochondrial synthetic transcriptional processing. Dysregulation of TEFM has been implicated in the development of various diseases; however, its specific role in LUAD remains unclear.

Methods
We conducted a comprehensive analysis of TEFM expression in LUAD, leveraging data from the TCGA database. Subsequently, we validated these findings using clinical specimens obtained from the First Affiliated Hospital of Soochow University, employing western blotting and qRT-PCR techniques. Further experimental validation was performed through the transfection of cells with TEFM overexpression, knockdown, and knockout lentiviruses. The effects of TEFM on LUAD were evaluated both in vitro and in vivo using a range of assays, including CCK-8, colony formation, EdU incorporation, Transwell migration, Tunel assay, flow cytometry, JC-1 staining, and xenograft tumour models.

Results
Our investigation uncovered that TEFM exhibited elevated expression levels in LUAD and exhibited co-localization with mitochondria. Overexpression of TEFM facilitated malignant processes in LUAD cells, whereas its silencing notably curbed these behaviors and induced mitochondrial depolarization, along with ROS production, culminating in apoptosis. Moreover, the absence of TEFM substantially influenced the expression of mitochondrial transcripts and respiratory chain complexes. Results from nude mouse xenograft tumors further validated that inhibiting TEFM expression markedly hindered tumor growth.

Conclusion
TEFM promotes LUAD malignant progression through the EMT pathway and determines apoptosis by affecting the expression of mitochondrial transcripts and respiratory chain complexes, providing a new therapeutic direction for LUAD-targeted therapy.

Graphical Abstract
Spatial transcriptome and single-cell reveal the role of nucleotide metabolism in colorectal cancer progression and tumor microenvironment
Authors: Liu Junzhi , Li Huimin , Wang Lantian , Wang Shurui , Tang Qiang 
Published: July 2024

Abstract
Background
The intricacies of nucleotide metabolism within tumor cells specific to colorectal cancer (CRC) remain insufficiently characterized. A nuanced examination of particular tumor clusters and their dynamic interplay with the tumor microenvironment (TME) may yield profound insights into these therapeutically auspicious communicative networks.

Methods
By integrating ten types of single-cell enrichment scoring methods, we carried out enrichment analysis on CRC cell types, which was validated through four additional single-cell cohorts. Groups of tumor cells were determined using the average values of the scores. Using cellphonedb, monocle, inferCNV, SCENIC, and Cytotrace, functional analyses were performed. Utilizing the RCTD approach, single-cell groupings were mapped onto spatial transcriptomics, analyzing cell dependency and pathway activity to distinguish between tumor cell subtypes. Differential expression analysis identified core genes in nucleotide metabolism, with single-cell and spatial transcriptomics analyses elucidating the function of these genes in tumor cells and the immune microenvironment. Prognostic models were developed from bulk transcriptome cohorts to forecast responses to immune therapy. Laboratory experiments were conducted to verify the biological function of the core gene.

Results
Nucleotide metabolism is significantly elevated in tumor cells, dividing them into two groups: NUhighepi and NUlowepi. The phenotype NUhighepi was discerned to exhibit pronounced malignant attributes. Utilizing the analytical tool stlearn for cell-to-cell communication assessment, it was ascertained that NUhighepi engages in intimate interactions with fibroblasts. Corroborating this observation, spatial transcriptome cell interaction assessment through MISTy unveiled a particular reliance of NUhighepi on fibroblasts. Subsequently, we pinpointed NME1, a key gene in nucleotide metabolism, affirming its role in thwarting metastasis via in vitro examination. Utilizing multiple machine learning algorithms, a stable prognostic model (NRS) has been developed, capable of predicting survival and responses to immune therapy. In addition, targeted drugs have been identified for both high and low scoring groups. Laboratory experiments have revealed that NME1 can inhibit the proliferation and invasion of CRC tumor cells.

Conclusion
Our study elucidates the potential pro-tumor mechanism of NUhighepi and the role of NME1 in inhibiting metastasis, further deepening the understanding of the role of nucleotide metabolism in colorectal cancer, and providing valuable targets for disrupting its properties.