bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detecting subtle transcriptomic perturbations induced by lncRNAs knock-down in single-cell CRISPRi screening using a new sparse supervised autoencoder neural network
Authors: Truchi Marin , Lacoux Caroline , Gille Cyprien , Fassy Julien , Magnone Virginie , Lopes Goncalves Rafael , Girard-Riboulleau Cédric , Manosalva-Pena Iris , Gautier-Isola Marine , Lebrigand Kevin , Barbry Pascal , Spicuglia Salvatore , Vassaux Georges , Rezzonico Roger , Barlaud Michel , Mari Bernard 
Published: March 2024

Single-cell CRISPR-based transcriptome screens are potent genetic tools for concomitantly assessing the expression profiles of cells targeted by a set of guides RNA (gRNA), and inferring target gene functions from the observed perturbations. However, due to various limitations, this approach lacks sensitivity in detecting weak perturbations and is essentially reliable when studying master regulators such as transcription factors. To overcome the challenge of detecting subtle gRNA induced transcriptomic perturbations and classifying the most responsive cells, we developed a new supervised autoencoder neural network method. Our Sparse supervised autoencoder (SSAE) neural network provides selection of both relevant features (genes) and actual perturbed cells. We applied this method on an in-house single-cell CRISPR-interference-based (CRISPRi) transcriptome screening (CROP-Seq) focusing on a subset of long non-coding RNAs (lncRNAs) regulated by hypoxia, a condition that promote tumor aggressiveness and drug resistance, in the context of lung adenocarcinoma (LUAD). The CROP-seq library of validated gRNA against a subset of lncRNAs and, as positive controls, HIF1A and HIF2A, the 2 main transcription factors of the hypoxic response, was transduced in A549 LUAD cells cultured in normoxia or exposed to hypoxic conditions during 3, 6 or 24 h. We first validated the SSAE approach on HIF1A and HIF2 by confirming the specific effect of their knock-down during the temporal switch of the hypoxic response. Next, the SSAE method was able to detect stable short hypoxia-dependent transcriptomic signatures induced by the knock-down of some lncRNAs candidates, outperforming previously published machine learning approaches. This proof of concept demonstrates the relevance of the SSAE approach for deciphering weak perturbations in single-cell transcriptomic data readout as part of CRISPR-based screening.
MYC: there is more to it than cancer
Authors: Zacarías-Fluck Mariano F. , Soucek Laura , Whitfield Jonathan R. 
Published: March 2024

MYC is a pleiotropic transcription factor involved in multiple cellular processes. While its mechanism of action and targets are not completely elucidated, it has a fundamental role in cellular proliferation, differentiation, metabolism, ribogenesis, and bone and vascular development. Over 4 decades of research and some 10,000 publications linking it to tumorigenesis (by searching PubMed for “MYC oncogene”) have led to MYC becoming a most-wanted target for the treatment of cancer, where many of MYC’s physiological functions become co-opted for tumour initiation and maintenance. In this context, an abundance of reviews describes strategies for potentially targeting MYC in the oncology field. However, its multiple roles in different aspects of cellular biology suggest that it may also play a role in many additional diseases, and other publications are indeed linking MYC to pathologies beyond cancer. Here, we review these physiological functions and the current literature linking MYC to non-oncological diseases. The intense efforts towards developing MYC inhibitors as a cancer therapy will potentially have huge implications for the treatment of other diseases. In addition, with a complementary approach, we discuss some diseases and conditions where MYC appears to play a protective role and hence its increased expression or activation could be therapeutic.
Anti-leishmanial activity of Eleutherine plicata Herb. and predictions of isoeleutherin and its analogues
Authors: Albuquerque Kelly Cristina Oliveira de , Veiga Andreza do Socorro Silva da , Silveira Fernando Tobias , Campos Marliane Batista , Costa Ana Paula Lima da , Brito Ananda Karolyne Martins , Melo Paulo Ricardo de Souza , Percario Sandro , Molfetta Fábio Alberto de , Dolabela Maria Fâni 
Published: March 2024

Introduction: Leishmaniasis is caused by protozoa of the genus Leishmania, classified as tegumentary and visceral. The disease treatment is still a serious problem, due to the toxic effects of available drugs, the costly treatment and reports of parasitic resistance, making the search for therapeutic alternatives urgent. This study assessed the in vitro anti-leishmanial potential of the extract, fractions, and isoeleutherin from Eleutherine plicata, as well as the in silico interactions of isoeleutherin and its analogs with Trypanothione Reductase (TR), in addition to predicting pharmacokinetic parameters.Methods: From the ethanolic extract of E. plicata (EEEp) the dichloromethane fraction (FDEp) was obtained, and isoeleutherin isolated. All samples were tested against promastigotes, and parasite viability was evaluated. Isoeleutherin analogues were selected based on similarity in databases (ZINK and eMolecules) to verify the impact on structural change.Results and Discussion: The extract and its fractions were not active against the promastigote form (IC50 &gt; 200 μg/mL), while isoeleutherin was active (IC50 = 25 μg/mL). All analogues have high intestinal absorption (HIA), cell permeability was moderate in Caco2 and low to moderate in MDCK. Structural changes interfered with plasma protein binding and blood-brain barrier permeability. Regarding metabolism, all molecules appear to be CYP3A4 metabolized and inhibited 2–3 CYPs. Molecular docking and molecular dynamics assessed the interactions between the most stable configurations of isoeleutherin, analogue compound 17, and quinacrine (control drug). Molecular dynamics simulations demonstrated stability and favorable interactions with TR. In summary, fractionation contributed to antileishmanial activity and isoleutherin seems to be promising. Structural alterations did not contribute to improve pharmacokinetic aspects and analogue 17 proved to be more promising than isoeleutherin, presenting better stabilization in TR.
Prenatal transposition of great arteries diagnosis and management: a Chinese single-center study
Authors: Guo Jie , Ling Wen , Dang Tingting , Guo Shan , Ma Hong , Huang Qiong , Zeng Liqin , Weng Zongjie , Wu Qiumei 
Published: March 2024

ObjectiveThis study aimed to assess the diagnostic value of prenatal echocardiography for identifying transposition of the great arteries (TGA) during pregnancy and evaluating the associated outcomes.MethodsWe conducted a retrospective analysis of 121 prenatally diagnosed patients with TGA at our hospital between January 2012 and September 2022. This analysis included prenatal ultrasound, prenatal screening, clinical management and follow-up procedures.ResultsAmong the 103 fetuses considered in the study, 90 (87.4%) were diagnosed with complete transposition of the great arteries (D-TGA), while 13 (12.6%) exhibited corrected transposition of the great arteries (CC-TGA). Diagnoses were distributed across the trimester, with 8 D-TGA and 2 CC-TGA patients identified in the first trimester, 68 D-TGA patients and 9 CC-TGA patients in the second trimester, and 14 D-TGA and 2 CC-TGA patients referred for diagnosis in the third trimester. Induction of labour was pursued for 76 D-TGA patients (84.4%) and 11 CC-TGA patients (84.6%), and 14 D-TGA patients (15.6%) and 2 CC-TGA patients (15.4%) continued pregnancy until delivery. Among the D-TGA patients, 9 fetuses (10.0%) underwent surgery, two of which were inadvertent fatality, while the remaining seven experienced positive outcomes. Additionally, seven TGA patients received palliative care, leading to four fatalities among D-TGA patients (5.2%), whereas 1 D-TGA patients and 2 CC-TGA patients survived.ConclusionThis study underscores the feasibility of achieving an accurate prenatal diagnosis of TGA during early pregnancy. The utility of prenatal ultrasound in the development of personalized perinatal plans and the application of multidisciplinary treatment during delivery are conducive.
Multi-omics subgroups associated with glycaemic deterioration in type 2 diabetes: an IMI-RHAPSODY Study
Authors: Li Shiying , Dragan Iulian , Tran Van Du T. , Fung Chun Ho , Kuznetsov Dmitry , Hansen Michael K. , Beulens Joline W. J. , Hart Leen M. ‘t , Slieker Roderick C. , Donnelly Louise A. , Gerl Mathias J. , Klose Christian , Mehl Florence , Simons Kai , Elders Petra J. M. , Pearson Ewan R. , Rutter Guy A. , Ibberson Mark 
Published: March 2024

IntroductionType 2 diabetes (T2D) onset, progression and outcomes differ substantially between individuals. Multi-omics analyses may allow a deeper understanding of these differences and ultimately facilitate personalised treatments. Here, in an unsupervised “bottom-up” approach, we attempt to group T2D patients based solely on -omics data generated from plasma.MethodsCirculating plasma lipidomic and proteomic data from two independent clinical cohorts, Hoorn Diabetes Care System (DCS) and Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS), were analysed using Similarity Network Fusion. The resulting patient network was analysed with Logistic and Cox regression modelling to explore relationships between plasma -omic profiles and clinical characteristics.ResultsFrom a total of 1,134 subjects in the two cohorts, levels of 180 circulating plasma lipids and 1195 proteins were used to separate patients into two subgroups. These differed in terms of glycaemic deterioration (Hazard Ratio=0.56;0.73), insulin sensitivity and secretion (C-peptide, p=3.7e-11;2.5e-06, DCS and GoDARTS, respectively; Homeostatic model assessment 2 (HOMA2)-B; -IR; -S, p=0.0008;4.2e-11;1.1e-09, only in DCS). The main molecular signatures separating the two groups included triacylglycerols, sphingomyelin, testican-1 and interleukin 18 receptor.ConclusionsUsing an unsupervised network-based fusion method on plasma lipidomics and proteomics data from two independent cohorts, we were able to identify two subgroups of T2D patients differing in terms of disease severity. The molecular signatures identified within these subgroups provide insights into disease mechanisms and possibly new prognostic markers for T2D.
Multi-scenario simulation of land use dynamics and ecological risk: a case study of the liaohe estuary national wetland reserve using PLUS-Markov and PSR models
Authors: Hu Nanlin , Wang Guodong , Ma Zijun , Zhao Meiling , Yuan Yusong , Zhang Tao , Chen Qi , Meng Jingci , Wang Jiaying 
Published: March 2024

Introduction: Wetland has been exposed to tremendous stresses and hazards, leading to many potential ecological risks in the past few decades. There is an urgent need to assess the ecological risk status of the wetland, especially when examining how the intensity of socio-economic growth, policy changes, and other variables affect land use and ecological risk changes.Methods: This study models the LULC pattern in the Liaohe Estuary National Nature Wetland Reserve under various future scenarios in 2000–2040 and develops a long-term Pressure-State-Response ecological risk assessment model based on the characteristics of the northern wetland environment in China, combined with the simulated multi-scenario PLUS model.Results: As the two most distinct vegetation types in the reserve area, Phragmites australis and Suaeda glauca presented decreasing trends of 59.7 ha/year and 9.0 ha/year in the economy development scenario (EDS), higher than 57.3 ha/year, 8.2 ha/year in the natural increase scenario (NIS), and 35.4 ha/year and 5.8 ha/year in the ecological protect scenario (EPS). From the core area to the buffer area to the outer experimental area, the slope rate of vegetation deterioration rises severely. In comparison to the scenario of EDS, the area of aquiculture and oil wells can be lowered by 11.4 ha/year and 1.1 ha/year with the application of ecological protection measures. Besides, under three scenarios, mean ecological risks are all showing an increasing trend from 2000 to 2040, which is generally higher in the EDS scenario than that in the NIS and EPS scenarios. The proportion of the high and very high level of ecological risk area continually increased from 28.8% to 40.4% from 2000 to 2040, which was mainly located in the south estuary and west urban areas. In addition, among the three protected areas, the ecological risk in the core area has a lower growth rate than that in the outer buffer zone and experimental zone.Discussion: Aiming for the development of Liaohe Estuary National Park, these findings provide quantitative guidance for protecting and restoring natural resources.
Elucidating the role of TWIST1 in ulcerative colitis: a comprehensive bioinformatics and machine learning approach
Authors: Ou Wenjie , Qi Zhaoxue , Liu Ning , Zhang Junzi , Mi Xuguang , Song Yuan , Fang Yanqiu , Cui Baiying , Hou Junjie , Yuan Zhixin 
Published: March 2024

Background: Ulcerative colitis (UC) is a common and progressive inflammatory bowel disease primarily affecting the colon and rectum. Prolonged inflammation can lead to colitis-associated colorectal cancer (CAC). While the exact cause of UC remains unknown, this study aims to investigate the role of the TWIST1 gene in UC.Methods: Second-generation sequencing data from adult UC patients were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified, and characteristic genes were selected using machine learning and Lasso regression. The Receiver Operating Characteristic (ROC) curve assessed TWIST1’s potential as a diagnostic factor (AUC score). Enriched pathways were analyzed, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Variation Analysis (GSVA). Functional mechanisms of marker genes were predicted, considering immune cell infiltration and the competing endogenous RNA (ceRNA) network.Results: We found 530 DEGs, with 341 upregulated and 189 downregulated genes. TWIST1 emerged as one of four potential UC biomarkers via machine learning. TWIST1 expression significantly differed in two datasets, GSE193677 and GSE83687, suggesting its diagnostic potential (AUC = 0.717 in GSE193677, AUC = 0.897 in GSE83687). Enrichment analysis indicated DEGs associated with TWIST1 were involved in processes like leukocyte migration, humoral immune response, and cell chemotaxis. Immune cell infiltration analysis revealed higher rates of M0 macrophages and resting NK cells in the high TWIST1 expression group, while TWIST1 expression correlated positively with M2 macrophages and resting NK cell infiltration. We constructed a ceRNA regulatory network involving 1 mRNA, 7 miRNAs, and 32 long non-coding RNAs (lncRNAs) to explore TWIST1’s regulatory mechanism.Conclusion: TWIST1 plays a significant role in UC and has potential as a diagnostic marker. This study sheds light on UC’s molecular mechanisms and underscores TWIST1’s importance in its progression. Further research is needed to validate these findings in diverse populations and investigate TWIST1 as a therapeutic target in UC.
Antigen-specific chemokine profiles as biomarkers for detecting Mycobacterium tuberculosis infection
Authors: Ren Weicong , Ma Zichun , Li Qiang , Liu Rongmei , Ma Liping , Yao Cong , Shang Yuanyuan , Zhang Xuxia , Gao Mengqiu , Li Shanshan , Pang Yu 
Published: March 2024

BackgroundLatent tuberculosis (TB) infection can progress to active TB, which perpetuates community transmission that undermines global TB control efforts. Clinically, interferon-γ release assays (IGRAs) are commonly used for active TB case detection. However, low IGRA sensitivity rates lead to false-negative results for a high proportion of active TB cases, thus highlighting IGRA ineffectiveness in differentiating MTB-infected individuals from healthy individuals.MethodsParticipants enrolled at Beijing Chest Hospital from May 2020-April 2022 were assigned to healthy control (HC), LTBI, IGRA-positive TB, and IGRA-negative TB groups. Screening cohort MTB antigen-specific blood plasma chemokine concentrations were measured using Luminex xMAP assays then were verified via testing of validation cohort samples.ResultsA total of 302 individuals meeting study inclusion criteria were assigned to screening and validation cohorts. Testing revealed significant differences in blood plasma levels of CXCL9, CXCL10, CXCL16, CXCL21, CCL1, CCL19, CCL27, TNF-α, and IL-4 between IGRA-negative TB and HC groups. Levels of CXCL9, CXCL10, IL-2, and CCL8 biomarkers were predictive for active TB, as reflected by AUC values of ≥0.9. CXCL9-based enzyme-linked immunosorbent assay sensitivity and specificity rates were 95.9% (95%CI: 91.7-98.3) and 100.0% (92.7-100.0), respectively. Statistically similar AUC values were obtained for CXCL9 and CXCL9-CXCL10 assays, thus demonstrating that combined analysis of CXCL10 and CXCL9 levels did not improve active TB diagnostic performance.ConclusionThe MTB antigen stimulation-based CXCL9 assay may compensate for low IGRA diagnostic accuracy when used to diagnose IGRA-negative active TB cases and thus is an accurate and sensitive alternative to IGRAs for detecting MTB infection.
High hypoxia status in pancreatic cancer is associated with multiple hallmarks of an immunosuppressive tumor microenvironment
Authors: Sadozai Hassan , Acharjee Animesh , Kayani Hateem Z. , Gruber Thomas , Gorczynski Reginald M. , Burke Bernard 
Published: March 2024

IntroductionPancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is a particularly lethal disease that is often diagnosed late and is refractory to most forms of treatment. Tumour hypoxia is a key hallmark of PDAC and is purported to contribute to multiple facets of disease progression such as treatment resistance, increased invasiveness, metabolic reprogramming, and immunosuppression.MethodsWe used the Buffa gene signature as a hypoxia score to profile transcriptomics datasets from PDAC cases. We performed cell-type deconvolution and gene expression profiling approaches to compare the immunological phenotypes of cases with low and high hypoxia scores. We further supported our findings by qPCR analyses in PDAC cell lines cultured in hypoxic conditions.ResultsFirst, we demonstrated that this hypoxia score is associated with increased tumour grade and reduced survival suggesting that this score is correlated to disease progression. Subsequently, we compared the immune phenotypes of cases with high versus low hypoxia score expression (HypoxiaHI vs. HypoxiaLOW) to show that high hypoxia is associated with reduced levels of T cells, NK cells and dendritic cells (DC), including the crucial cDC1 subset. Concomitantly, immune-related gene expression profiling revealed that compared to HypoxiaLOW tumours, mRNA levels for multiple immunosuppressive molecules were notably elevated in HypoxiaHI cases. Using a Random Forest machine learning approach for variable selection, we identified LGALS3 (Galectin-3) as the top gene associated with high hypoxia status and confirmed its expression in hypoxic PDAC cell lines.DiscussionIn summary, we demonstrated novel associations between hypoxia and multiple immunosuppressive mediators in PDAC, highlighting avenues for improving PDAC immunotherapy by targeting these immune molecules in combination with hypoxia-targeted drugs.
Plasma metabolite profiling for S. haematobium biomarkers of infection in pre-school aged children in Shamva District, Zimbabwe
Authors: Midzi Herald , Naicker Thajasvarie , Vengesai Arthur , Choto Emilia T. , Muchesa Petros , Kasambala Maritha , Mduluza-Jokonya Tariro L. , Muleya Victor , Nyagumbo Elliot , Kapanga Donald Tafirenyika , Mabaya Lucy , Mutapi Francisca , Mduluza Takafira 
Published: March 2024

BackgroundMetabolomics approaches are indispensable tools in infection biomarker discovery efforts as they shed light on the underlying pathophysiological mechanisms of disease. In this study, we analysed plasma metabolites that can be used as biomarkers of urogenital schistosomiasis in pre-school aged children below the age of five.MethodsA case-control study was conducted involving 82 pre-school aged children that were age- and sex-matched. Urine samples were collected for three consecutive days to detect S. haematobium infection using urine filtration. Blood samples were also collected and processed to obtain plasma. Beckman Coulter AU480 chemistry analyser and commercial metabolite kits were used for profiling biomarkers in plasma samples. Descriptive statistics and MetaboAnalyst tool, were used for metabolite analysis. For the determination of diagnostic efficiency of plasma biomarkers, the area under the curve (AUC) was calculated from receiver operating characteristic curves at 95% CI.ResultsSuccinic acid, glucose-6-phosphate, phosphatidylcholine, alanine and creatinine levels in plasma were significantly associated with urogenital schistosomiasis (p&lt;0.005) at the population level. Significant increase in concentration at 1.5-fold change (FC) threshold was highest for glucose-6-phosphate with FC value of 2.02 followed by creatinine, albumin and phosphatidylcholine. Creatinine was significantly downregulated with a FC value of 1.98. Of the six dysregulated metabolic pathways, glucose and sucrose metabolism were predominantly affected. Glucose-6-phosphate had the highest AUC (0.81), sensitivity (88.85%) and specificity (90.37%). Phosphatidylcholine and succinic acid also had AUC values greater than 0.7.ConclusionUrogenital schistosomiasis affects the energy-related metabolic pathways in pre-school aged children. Glucose-6-phosphate was identified as a potential indicator of infection at the population level. Furthermore, we recommend intensive validation of schistosome metabolite biomarkers.
Exploring the divergence in perspectives on clinical trial operations in South Korea during the COVID-19 pandemic: a comparison of a trial site and sponsors
Authors: Kim Young-Sang , Kim Anhye , Lee Yil-Seob 
Published: March 2024

IntroductionDuring the COVID-19 pandemic, novel clinical trial methods known as decentralized clinical trials (DCTs) were rapidly introduced. The attitude toward operating clinical trials and perspectives on DCTs may differ between clinical trial sites and sponsors. The impact of the COVID-19 pandemic on clinical trials was investigated for a society of sponsors and a trial site in South Korea.MethodsThe current difficulties and future perspectives on clinical trials were assessed and compared between the site and sponsors.ResultsBoth the site and sponsors reported on their experiences with the challenges of conducting clinical trials during the pandemic era. While 64% of personnel from the site judged that the difficulties were solved by their own solutions, 67.6% of personnel from sponsors considered cooperation with trial sites as a key solution to overcome the difficulties. While half of the personnel from the site were skeptical of the changes in trial operation methods, the sponsors expected the institutionalization of DCT elements.ConclusionIn conclusion, with varying attitudes, sponsors and sites attempted to overcome the challenges of conducting clinical trials during the pandemic era. To conduct clinical trials effectively, both sponsors and sites must work closely together to find solutions with efficient communication. For the successful implementation of new tools such as DCTs, the government needs to solicit support from sponsors and sites and change regulations.