bluuebunny/crossref_metadata_2025_split huggingface dataset:
PRIMITI: a computational approach for accurate prediction of miRNA-target mRNA interaction
Authors: Uthayopas Korawich , de Sá Alex G. C. , Alavi Azadeh , Pires Douglas E. V. , Ascher David B. 
Published: April 2024

AbstractCurrent medical research has been demonstrating the roles of miRNAs in a variety of cellular mechanisms, lending credence to the association between miRNA dysregulation and multiple diseases. Understanding the mechanisms of miRNA is critical for developing effective diagnostic and therapeutic strategies. miRNA-mRNA interactions emerge as the most important mechanism to be understood despite their experimental validation constraints. Accordingly, several computational models have been developed to predict miRNA-mRNA interactions, albeit presenting limited predictive capabilities, poor characterisation of miRNA-mRNA interactions and low usability. To address these drawbacks, we developed PRIMITI, a PRedictive model for the Identification of novel MIRNA-Target mRNA Interactions. PRIMITI is a novel machine learning model that utilises CLIP-seq and expression data to characterise functional target sites in 3’-untranslated regions (3’-UTRs) and predict miRNA-target mRNA repression activity. The model was trained using a reliable negative sample selection approach and the robust extreme gradient boosting (XGBoost) model, which was coupled with newly introduced features, including sequence and genetic variation information. PRIMITI achieved an area under the receiver operating characteristic (ROC) curve (AUC) up to 0.96 for a prediction of functional miRNA-target site binding and 0.96 for a prediction of miRNA-target mRNA repression activity on cross-validation and an independent blind test. Additionally, the model outperformed state-of-the-art methods in recovering miRNA-target repressions in an unseen microarray dataset and in a collection of validated miRNA-mRNA interactions, highlighting its utility for preliminary screening. PRIMITI is available on a reliable, scalable and user-friendly web server athttps://biosig.lab.uq.edu.au/primiti.
Investigating Musculoskeletal Pain Among Pregnant Women in Dhaka Division: A Cross-Sectional Study
Authors: Uddin Jalal , Shumi Shahida Sultana 
Published: April 2024

AbstractObjectivesThis study aimed to investigate musculoskeletal pain among pregnant women in Dhaka Division, Bangladesh, considering demographic factors, pain and pregnancy-related experiences.Materials and MethodsData were collected from 300 pregnant women attending outpatient clinical check-ups at two hospitals in Dhaka Division, Bangladesh. A standardized questionnaire covering demographic information, pregnancy-related inquiries, and pain assessment using the Numeric Pain Rating Scale (NPRS) was administered. Data were analyzed using SPSS version 25 software.ResultsThe majority of participants were aged 20-25 years, resided in rural areas, and had completed primary education. Most participants were housewives. A significant proportion reported experiencing musculoskeletal pain, predominantly in the second trimester. Associations were found between musculoskeletal pain and both age (p=0.025) and trimester of pregnancy (p=0.008).ConclusionsThe findings emphasized significant associations between maternal age and musculoskeletal pain, highlighting the importance of considering age-related factors in maternal care. Additionally, a high prevalence of musculoskeletal pain during the second trimester was observed.
Diabetes as risk factor to severity of dengue in naïve patients
Authors: dos Santos Bárbara F. , Gandolfi Flora A. , Milhim Bruno H. G. A. , Dourado Fernanda S. , Silva Gislaine C. D. , Zini Nathalia , Rezende Gratão Victor Hugo , Mariani Matheus Pascoal , Abbas Tamires Nasie , Garcia Pedro H. C. , Rocha Rodrigo S. , Vasilakis Nikos , Nogueira Maurício L. , Estofolete Cássia F. 
Published: April 2024

AbstractBackgroundDengue cases can progress to severe ant life-threating forms particularly in subsequent heterologous infections. However, recent studies had explored additional risk factors, including underlying health conditions, even in individuals without prior exposure to dengue, notably, in patients with endothelial dysfunction and chronic inflammation. This study examines the link between diabetes and the development of severe dengue disease in dengue-naive patients during the 2019 dengue outbreak in São Jose do Rio Preto, Brazil.MethodologyWe enrolled 529 laboratory-confirmed dengue cases, identified through DENV RT-PCR or NS1 antigen assays in a hospital cohort of acute febrile illness. Subsequently, we investigated the presence of anti-dengue and anti-Zika IgG antibodies. Samples testing positive for Zika were excluded from the analyses. Two groups were analyzed: naïve (DV-), and dengue history (DV+).ResultsInitially, presence of diabetes and kidney disease, as well as being dengue-naive, were associated with a higher frequency of severe and potentially severe clinical outcomes. Multivariate analysis identified diabetes as a risk factor, while the presence of anti-dengue antibodies was considered protective. Analysis of dengue naïve samples, highlighted diabetes as an independent risk factor to severe forms of dengue disease. In DV+ patients, no condition was highlighted as a risk factor by univariate analysis or multivariate analysis.ConclusionsWe investigated and confirmed diabetes as a risk factor for severe dengue disease in individuals without prior dengue or Zika exposure. Our conclusions raise significant concerns given diabetes’ ever increasing global prevalence and its potential impact on patients with or previous dengue exposure.SummaryThe simultaneous escalation of diabetes and dengue worldwide is striking. Notably, diabetes presents as a significant risk factor for severe dengue. This accentuates the necessity of diabetes control in dengue prevention, considering its widespread prevalence and influence on disease severity.
Triggering and modulation of a complex behavior by a single peptidergic command neuron inDrosophila
Authors: Fernandez-Acosta Magdalena , Zanini Rebeca , Heredia Fabiana , Volonté Yanel , Menezes Juliane , Prüger Katja , Ibarra Julieta , Arana Maite , Perez María Sol , Veenstra Jan A , Wegener Christian , Gontijo Alisson , Garelli Andrés 
Published: April 2024

ABSTRACTAt the end of their growth phase,Drosophilalarvae remodel their bodies, firmly glue themselves to a substrate, and harden their cuticle in preparation for metamorphosis. This process is termed pupariation and it is triggered by a surge in the steroid hormone ecdysone. Substrate attachment is achieved by a recently-described pupariation subprogram called glue expulsion and spreading behavior (GSB). An epidermis-to-CNS Dilp8-Lgr3 relaxin signaling event that occurs downstream of ecdysone after pupariation initiation is critical for unlocking progression of the pupariation motor program towards GSB, but the factors and circuits acting downstream of Lgr3 signaling remain unknown. Here, we screened for such factors using cell type-specific RNA interference (RNAi) and behavioral monitoring. We identify Myoinhibiting peptide (Mip) and its highly conserved neuronal receptor, Sex peptide receptor (SPR), as a critical neuropeptidergic signaling pathway required to trigger and modulate multiple action components of GSB. In addition, we find that Mip is specifically required in a pair of descending neurons, whose optogenetic activation at a specific competence window triggers GSB-like behavior and whose neurogenetic silencing completely abrogates GSB without overtly affecting other pupariation components. This strongly suggests that these descending Mip neurons are developmentally-regulated GSB command neurons. Dissection of the GSB action components via muscle calcium-level monitoring coupled with cell-type specific RNAi indicates that Mip acts on multiple SPR-positive neuronal populations, which collectively define and pattern the sequence and timing of GSB actions. Hence, we have identified a pair of descending command neurons that utilize both synaptic transmission and neuropeptidergic signaling to trigger and modulate a complex innate behavior inDrosophila. Our results advance our molecular and cellular understanding of pupariation control, reveal the complexity of glue expulsion and spreading behavior control, provide insight into conserved aspects of Mip-SPR signaling in animals, and contribute to the understanding of how multi-step innate behaviors are coordinated in time and with other developmental processes through command neurons and neuropeptidergic signaling.
High-throughput crystallographic fragment screening of Zika virus NS3 Helicase
Authors: Godoy Andre S , Mesquita Nathalya C. M. R. , Noske Gabriela Dias , Gawriljuk Victor Oliveira , Lithgo Ryan M , Balcomb Blake H , Aschenbrenner Jasmin Cara , Tomlinson Charles W.E. , Winokan Max , Scheen Jenke , Marples Peter George , Chandran Anu V. , Ni Xiaomin , Thompson Warren , Fairhead Michael , Fearon Daren , Koekemoer Lizbé , Xavier Mary-Ann Elvina , Walsh Martin , Oliva Glaucius , von Delft Frank 
Published: April 2024

ABSTRACTThe Zika virus (ZIKV), discovered in Africa in 1947, swiftly spread across continents, causing significant concern due to its recent association with microcephaly in newborns and Guillain-Barré syndrome in adults. Despite a decrease in prevalence, the potential for a resurgence remains, necessitating urgent therapeutic interventions. Like other flaviviruses, ZIKV presents promising drug targets within its replication machinery, notably the NS3 helicase (NS3Hel) protein, which plays critical roles in viral replication. However, a lack of structural information impedes the development of specific inhibitors targeting NS3Hel. Here we applied high-throughput crystallographic fragment screening on ZIKV NS3Hel, which yielded structures that reveal 3D binding poses of 46 fragments at multiple sites of the protein, including 11 unique fragments in the RNA-cleft site. These fragment structures provide templates for direct design of hit compounds and should thus assist the development of novel direct-acting antivirals against ZIKV and related flaviviruses, thus opening a promising avenue for combating future outbreaks.
MT-125 Inhibits Non-Muscle Myosin IIA and IIB, Synergizes with Oncogenic Kinase Inhibitors, and Prolongs Survival in Glioblastoma
Authors: Kenchappa Rajappa , Radnai Laszlo , Young Erica J. , Zarco Natanael , Lin Li , Dovas Athanassios , Meyer Christian T. , Haddock Ashley , Hall Alice , Canoll Peter , Cameron Michael D. , Nagaiah Naveen KH , Rumbaugh Gavin , Griffin Patrick R. , Kamenecka Theodore M. , Miller Courtney A. , Rosenfeld Steven S. 
Published: April 2024

SUMMARYWe have identified a NMIIA and IIB-specific small molecule inhibitor, MT-125, and have studied its effects in GBM. MT-125 has high brain penetrance and retention and an excellent safety profile; blocks GBM invasion and cytokinesis, consistent with the known roles of NMII; and prolongs survival as a single agent in murine GBM models. MT-125 increases signaling along both the PDGFR- and MAPK-driven pathways through a mechanism that involves the upregulation of reactive oxygen species, and it synergizes with FDA-approved PDGFR and mTOR inhibitorsin vitro. Combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined PI3 Kinase/mTOR inhibitor significantly improves survival in orthotopic GBM models over either drug alone, and in the case of sunitinib, markedly prolongs survival in ∼40% of mice. Our results provide a powerful rationale for developing NMII targeting strategies to treat cancer and demonstrate that MT-125 has strong clinical potential for the treatment of GBM.HighlightsMT-125 is a highly specific small molecule inhibitor of non-muscle myosin IIA and IIB, is well-tolerated, and achieves therapeutic concentrations in the brain with systemic dosing.Treating preclinical models of glioblastoma with MT-125 produces durable improvements in survival.MT-125 stimulates PDGFR- and MAPK-driven signaling in glioblastoma and increases dependency on these pathways.Combining MT-125 with an FDA-approved PDGFR inhibitor in a mouse GBM model synergizes to improve median survival over either drug alone, and produces tumor free, prolonged survival in over 40% of mice.
TheWnt/β-catenin/TCF/Sp5/Zic4gene network that regulates head organizer activity inHydrais differentially regulated in epidermis and gastrodermis
Authors: Iglesias Ollé Laura , Perruchoud Chrystelle , Sanchez Paul Gerald Layague , Vogg Matthias Christian , Galliot Brigitte 
Published: April 2024

AbstractInHydra, head formation depends on Wnt/β-catenin signaling, which positively regulatesSp5andZic4, with Sp5 limitingWnt3/β-cateninexpression and Zic4 triggering tentacle formation. Using transgenic lines in which theHySp5promoter drives eGFP expression in the epidermis or gastrodermis, we show that in intact animals, epidermalHySp5:GFP is expressed strongly apically and weakly along the body column, while gastrodermalHySp5:GFP is also maximally expressed apically but absent from the oral region, and remains high along the upper body column. During apical regeneration, gastrodermalHySp5:GFP appears early and diffusely, epidermalHySp5:GFP later. Upon alsterpaullone treatment, apicalHySp5:GFPexpression is shifted to the body column where epidermalHySp5:GFP transiently forms ectopic circular figures. Afterβ-catenin(RNAi), only epidermalHySp5:GFP is down-regulated, while pseudo-bud structures expressing gastrodermalHySp5:GFP develop.Sp5(RNAi) highlights the negative autoregulation ofSp5in epidermis, involving direct binding of Sp5 to its own promoter as observed in human HEK293T cells. In these cells, HyZic4, which can interact with huTCF1, regulatesWnt3negatively andSp5positively. This differential regulation of theWnt/β-catenin/TCF/Sp5/Zic4network in epidermis and gastrodermis highlights distinct architectures and patterning roles in the hypostome, tentacle and body column, as well as distinct regulations in homeostatic and developmental organizers.
Microenvironment Drives Reentrant Condensation of Aβ40
Authors: Sarkar Susmita , Mondal Jagannath 
Published: April 2024

AbstractWithin the framework of liquid-liquid phase separation (LLPS), biomolecular condensation orchestrates vital cellular processes and its dysregulation is implicated in severe pathological conditions. Recent studies highlight the role of intrinsically disordered proteins (IDPs) in LLPS, yet the influence of microenvironmental factors has remained a puzzling factor. Here, via computationally simulating the impact of solution conditions on LLPS behavior of neurologically pathogenic IDP Aβ40, we chanced upon a salt-driven reentrant condensation phenomenon, wherein Aβ40 aggregation increases with low salt concentrations (25-50 mM), followed by a decline with further salt increments.. An exploration into the thermodynamic and kinetic signatures of reentrant condensation unveils a nuanced interplay between protein electrostatics and ionic strength as potential drivers. Notably, the charged residues of the N-terminus exhibit a non-monotonic response to salt screening, intricately linked to the recurrence of reentrant behavior in hydrophobic core-induced condensation. Intriguingly, our findings also unveil the reappearance of similar reentrant condensation phenomena under varying temperature conditions. Collectively, our study illuminates the profoundly context-dependent nature of Aβ40’s liquid-liquid phase separation behavior, extending beyond its intrinsic molecular framework, where microenvironmental cues wield significant influence over its aberrant functionality.
Origin of the far-red absorbance in eustigmatophyte algae red-shifted Violaxanthin-ChlorophyllaProtein
Authors: Agostini Alessandro , Bína David , Barcytė Dovilė , Bortolus Marco , Eliáš Marek , Carbonera Donatella , Litvín Radek 
Published: April 2024

AbstractPhotosynthetic organisms harvest light for energy. Some eukaryotic algae have specialized in harvesting far-red light by tuning chlorophyllaabsorption through a mechanism still to be elucidated. Here, we combined optically detected magnetic resonance and pulsed electron paramagnetic resonance measurements on red-adapted light-harvesting complexes, rVCP, isolated from the freshwater eustigmatophyte algaTrachydiscus minutusto identify the location of the pigments responsible for this remarkable adaptation. The pigments have been found to belong to an excitonic cluster of chlorophyllsaat the core of the complex, close to the central carotenoids in L1/L2 sites. A pair of structural features of the Chla403/a603 binding site, namely the histidine-to-asparagine substitution in the magnesium-ligation residue and the small size of the amino acid at thei-4 position, are proposed to be the origin of this trait. Phylogenetic analysis of various eukaryotic red antennae identified several potential LHCs that could share this tuning mechanism.
Novel sulfatase cancer therapeutics negatively impact Bacteroidota of the colonic microbiota in a non-sulfatase dependent manner
Authors: Crawford Conor J. , Gunawan Christian , Chen Zongjia , Byrne Dominic P , Darby Cosette , Luis Ana S , Elli Stefano , Yates Edwin A , Bolam David N , van der Post Sjoerd , Williams Spencer J , Cartmell Alan 
Published: April 2024

AbstractThe S1 family of sulfatases is the sole family of enzymes that desulfate carbohydrates, linking them to inflammatory bowel diseases and various cancers. There is an unmet need for therapeutics against carbohydrate sulfatases, and while effective, orally available inhibitors of S1 steroid sulfatases exist, their efficacy against S1 carbohydrate sulfatases remains largely unexplored. In this study we assess a library of aryl- and carbohydrate sulfamates/sulfonates for their ability to inhibit carbohydrate sulfatases from human colonic bacteria. Surprisingly, these compounds prove ineffective. We show that arylsulfamate inhibitors inhibit the growth of anti-cancer human gut microbiota species independent of sulfatase activity. Leveraging thermal proteome profiling, we identify the non-sulfatase targets responsible for these effects. This work highlights the imperative for developing specific inhibitors targeting carbohydrate sulfatases and unveils the adverse effects of arylsulfamates, a class of drugs designed for hormone cancer treatment, on the human gut microbiota, potentially influencing their therapeutic efficacy.
Structure-Function Relationship in Electrical and Hemodynamic Brain Networks: Insights from EEG and fNIRS during Rest and Task States
Authors: Blanco Rosmary , Preti Maria Giulia , Koba Cemal , Van De Ville Dimitri , Crimi Alessandro 
Published: April 2024

ABSTRACTIdentifying relationships between structural and functional networks is crucial for understanding the large-scale organization of the human brain. The potential contribution of emerging techniques like functional near-infrared spectroscopy to investigate the structure-functional relationship has yet to be explored. In our study, we characterize global and local structure-function coupling using source-reconstructed Electroencephalography (EEG) and Functional near-infrared spectroscopy (fNIRS) signals in both resting state and motor imagery tasks, as this relationship during task periods remains underexplored. Employing the mathematical framework of graph signal processing, we investigate how this relationship varies across electrical and hemodynamic networks and different brain states. Results show that fNIRS structure-function coupling resembles slower-frequency EEG coupling at rest, with variations across brain states and oscillations. Locally, the relationship is heterogeneous, with greater coupling in the sensory cortex and increased decoupling in the association cortex, following the unimodal to transmodal gradient. Discrepancies between EEG and fNIRS are noted, particularly in the frontoparietal network. Cross-band representations of neural activity revealed lower correspondence between electrical and hemodynamic activity in the transmodal cortex, irrespective of brain state while showing specificity for the somatomotor network during a motor imagery task. Overall, these findings initiate a multimodal comprehension of structure-function relationship and brain organization when using affordable functional brain imaging.
Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells
Authors: Zhang Nan , Gao Shuaixin , Peng Haidong , Wu Jinghua , Li Huapeng , Gibson Connor , Wu Sophia , Zhu Jiangjiang , Zheng Qingfei 
Published: April 2024

ABSTRACTHistone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid residue of H3 (i.e., glutamine) and dopamine. In our previous studies, we discovered that the dynamics of this post-translational modification (including installation, removal, and replacement) were regulated by a single enzyme, transglutaminase 2 (TGM2), through reversible transamination. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of TGM2 in colon cancer cells. Due to the enzyme promiscuity of TGM2, non-histone proteins have also been identified as targets of dopaminylation on glutamine residues, however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of modification sites of these dopaminylated proteins were identified, attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that to block the installation of protein dopaminylation may become a promising anti-cancer strategy.TOC
Rare germline structural variants increase risk for pediatric solid tumors
Authors: Gillani Riaz , Collins Ryan L. , Crowdis Jett , Garza Amanda , Jones Jill K. , Walker Mark , Sanchis-Juan Alba , Whelan Chris , Pierce-Hoffman Emma , Talkowski Michael , Brand Harrison , Haigis Kevin , LoPiccolo Jaclyn , AlDubayan Saud H. , Gusev Alexander , Crompton Brian D. , Janeway Katie A. , Van Allen Eliezer M. 
Published: April 2024

AbstractPediatric solid tumors are rare malignancies that represent a leading cause of death by disease among children in developed countries. The early age-of-onset of these tumors suggests that germline genetic factors are involved, yet conventional germline testing for short coding variants in established predisposition genes only identifies pathogenic events in 10-15% of patients. Here, we examined the role of germline structural variants (SVs)—an underexplored form of germline variation—in pediatric extracranial solid tumors using germline genome sequencing of 1,766 affected children, their 943 unaffected relatives, and 6,665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and a four-fold increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we revealed burdens of ultra-rare SVs that cause loss-of-function of highly expressed, mutationally intolerant, neurodevelopmental genes, as well as noncoding SVs predicted to disrupt three-dimensional chromatin domains in neural crest-derived tissues. Collectively, our results implicate rare germline SVs as a predisposing factor to pediatric solid tumors that may guide future studies and clinical practice.