bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remodeling of dermal adipose tissue alleviates cutaneous toxicity induced by anti-EGFR therapy
Authors: Chen Leying , You Qing , Liu Min , Li Shuaihu , Wu Zhaoyu , Hu Jiajun , Xia Liangyong , Zhang Shiyi 
Published: November 2021

AbstractAnti-epidermal growth factor receptor (EGFR) therapy–associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.Graphical abstract
Mapping morphological malformation to genetic dysfunction in blood vessel organoids with 22q11.2 Deletion Syndrome
Authors: He Siyu , Xu Cong , Lao Yeh-Hsing , Chauhan Shradha , Xiao Yang , Willner Moshe J. , Jin Yinuo , McElroy Shannon , Rao Sneha B. , Gogos Joseph A. , Tomer Raju , Azizi Elham , Xu Bin , Leong Kam W. 
Published: November 2021

AbstractDiGeorge Syndrome, or 22q11.2 deletion syndrome (22q11.2 DS), is a genetic disorder caused by microdeletions in chromosome 22, impairing the function of endothelial cells (EC) and/or mural cells and leading to deficits in blood vessel development such as abnormal aortic arch morphology, tortuous retinal vessels, and tetralogy of Fallot. The mechanism by which dysfunctional endothelial cells and pericytes contribute to the vasculopathy, however, remains unknown. In this study, we used human blood vessel organoids (VOs) generated from iPSC of 22q11.2 DS patients to model the vascular malformations and genetic dysfunctions. We combined high-resolution lightsheet imaging and single-cell transcriptome analysis to link the genetic profile and vascular phenotype at the single-cell level. We developed a comprehensive analytical methodology by integrating deep learning-mediated blood vessel segmentation, network graph construction, and tessellation analysis for automated morphology characterization. We report that 22q11.2DS VOs demonstrate a smaller size with increased angiogenesis/sprouting, suggesting a less stable vascular network. Overall, clinical presentations of smaller vascular diameter, less connected vasculature, and increased branch points were recapitulated in 22q11.2DS VOs. Single-cell transcriptome profiling showed heterogeneity in both 22q11.2DS and control VOs, but the former demonstrated alterations in endothelial characteristics that are organ-specific and suggest a perturbation in the vascular developmental process. Intercellular communication analysis indicated that the vascular dysfunctions in 22q11.2 deletion were due to a lower cell-cell contact and upregulated extracellular matrix organization involving collagen and fibronectin. Voronoi diagram-based tessellation analysis also indicated that the colocalization of endothelial tubes and mural cells was different between control and 22q11.2 VOs, indicating that alterations in EC and mural interactions might contribute to the deficits in vascular network formation. This study illustrates the utility of VO in revealing the pathogenesis of 22q11.2DS vasculopathy.
Morpholino-mediated knockdown of the brain mineralocorticoid receptor affects glucocorticoid signaling and neuroplasticity in wild ocellated wrasse (Symphodus ocellatus)
Authors: Nugent Bridget M. , Stiver Kelly A. , Han Jiawei , Kindsvater Holly K. , Marsh-Rollo Susan E. , Hofmann Hans A. , Alonzo Suzanne H. 
Published: November 2021

ABSTRACTUncovering the genetic, physiological, and developmental mechanisms underlying phenotypic variation is necessary for understanding how genetic and genomic variation shape phenotypic variation and for discovering possible targets of selection. Although the neural and endocrine mechanisms underlying social behavior are evolutionarily ancient, we lack an understanding of the proximate causes and evolutionary consequences of variation in these mechanisms. Here, we examine in the natural environment the behavioral, neuromolecular, and fitness consequences of a morpholino-mediated knockdown of the mineralocorticoid receptor (MR) in the brain of nesting males of the ocellated wrasse, Symphodus ocellatus, a species with male alternative reproductive tactics. Even though MR knockdown did not significantly change male behavior directly, this experimental manipulation strongly altered glucocorticoid signaling and neuroplasticity in the preoptic area, the putative hippocampus homolog, and the putative basolateral amygdala homolog. We also found that individual variation in stress axis gene expression and neuroplasticity is strongly associated with variation in male behavior and fitness-related traits. The brain region-specific effects of MR knockdown on phenotypic integration in the wild reported here suggest specific neuroendocrine and neuroplasticity pathways that may be targets of selection.
2-photon-fabricated nano-fluidic traps for extended detection of single macromolecules and colloids in solution
Authors: Vanderpoorten Oliver , Babar Ali Nawaz , Krainer Georg , Jacquat Raphaёl P.B. , Challa Pavan K. , Peter Quentin , Toprakcioglu Zenon , Xu Catherine K. , Keyser Ulrich F. , Baumberg Jeremy , Kaminski Clemens F. , Knowles Tuomas P. J. 
Published: November 2021

AbstractThe analysis of nanoscopic species, such as proteins and colloidal assemblies, at the single-molecule level has become vital in many areas of fundamental and applied research. Approaches to increase the detection timescales for single molecules in solution without immobilising them onto a substrate surface and applying external fields are much sought after. Here we present an easy-to-implement and versatile nanofluidics-based approach that enables increased observational-timescale analysis of single biomacromolecules and nanoscale colloids in solution. We use two-photon-based hybrid lithography in conjunction with soft lithography to fabricate nanofluidic devices with nano-trapping geometries down to 100 nm in height. We provide a rigorous description and characterisation of the fabrication route that enables the writing of nanoscopic 3D structures directly in photoresist and allows for the integration of nano-trapping and nano-channel geometries within micro-channel devices. Using confocal fluorescence burst detection, we validated the functionality of particle confinement in our nano-trap geometries through measurement of particle residence times. All species under study, including nanoscale colloids, α-synuclein oligomers, and double-stranded DNA, showed a three to five-fold increase in average residence time in the detection volume of nano-traps, due to the additional local steric confinement, in comparison to free space diffusion in a nearby micro-channel. Our approach thus opens-up the possibility for single-molecule studies at prolonged observational timescales to analyse and detect nanoparticles and protein assemblies in solution without the need for surface immobilisation.
Characterizing and explaining impact of disease-associated mutations in proteins without known structures or structural homologues
Authors: Sen Neeladri , Anishchenko Ivan , Bordin Nicola , Sillitoe Ian , Velankar Sameer , Baker David , Orengo Christine 
Published: November 2021

AbstractMutations in human proteins lead to diseases. The structure of these proteins can help understand the mechanism of such diseases and develop therapeutics against them. With improved deep learning techniques such as RoseTTAFold and AlphaFold, we can predict the structure of proteins even in the absence of structural homologues. We modeled and extracted the domains from 553 disease-associated human proteins without known protein structures or close homologues in the Protein Databank (PDB). We noticed that the model quality was higher and the RMSD lower between AlphaFold and RoseTTAFold models for domains that could be assigned to CATH families as compared to those which could only be assigned to Pfam families of unknown structure or could not be assigned to either. We predicted ligand-binding sites, protein-protein interfaces, conserved residues in these predicted structures. We then explored whether the disease-associated missense mutations were in the proximity of these predicted functional sites, if they destabilized the protein structure based on ddG calculations or if they were predicted to be pathogenic. We could explain 80% of these disease-associated mutations based on proximity to functional sites, structural destabilization or pathogenicity. When compared to polymorphisms a larger percentage of disease associated missense mutations were buried, closer to predicted functional sites, predicted as destabilising and/or pathogenic. Usage of models from the two state-of-the-art techniques provide better confidence in our predictions, and we explain 93 additional mutations based on RoseTTAFold models which could not be explained based solely on AlphaFold models.
FDJD: RNA-Seq Based Fusion Transcript Detection Using Jaccard Distance
Authors: Mohebbi Hamidreza , Haspel Nurit 
Published: November 2021

AbstractGene fusions events, which are the result of two genes fused together to create a hybrid gene, were first described in cancer cells in the early 1980s. These events are relatively common in many cancers including prostate, lymphoid, soft tissue, and breast. Recent advances in next-generation sequencing (NGS) provide a high volume of genomic data, including cancer genomes. The detection of possible gene fusions requires fast and accurate methods. However, current methods suffer from inefficiency, lack of sufficient accuracy, and a high false-positive rate. We present an RNA-Seq fusion detection method that uses dimensionality reduction and parallel computing to speed up the computation. We convert the RNA categorical space into a compact binary array calledbinary fingerprints, which enables us to reduce the memory usage and increase efficiency. The search and detection of fusion candidates are done using the Jaccard distance. The detection of candidates is followed by refinement. We benchmarked our fusion prediction accuracy using both simulated and genuine RNA-Seq datasets. Paired-end Illumina RNA-Seq genuine data were obtained from 60 publicly available cancer cell line data sets. The results are compared against the state-of-the-art-methods such as STAR-Fusion, InFusion, and TopHat-Fusion. Our results show that FDJD exhibits superior accuracy compared to popular alternative fusion detection methods. We achieved 90% accuracy on simulated fusion transcript inputs, which is the highest among the compared methods while maintaining comparable run time.
Systems medicine dissection of chromosome 1q amplification reveals oncogenic regulatory circuits and informs targeted therapy in cancer
Authors: Trasanidis Nikolaos , Katsarou Alexia , Ponnusamy Kanagaraju , Shen Yao-An , Kostopoulos Ioannis V , Bergonia Bien , Keren Keren , Reema Paudel , Xiao Xiaolin , Szydlo Richard M , Sabbattini Pierangela MR , Roberts Irene AG , Auner Holger W , Naresh Kikkeri N , Chaidos Aristeidis , Wang Tian-Li , Magnani Luca , Caputo Valentina S , Karadimitris Anastasios 
Published: November 2021

AbstractUnderstanding the biological and clinical impact of copy number aberrations (CNA) in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several cancers, including the blood cancer, multiple myeloma (MM). Although several chr1q genes portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here we integrate patient multi-omics datasets with genetic variables to identify 103 adverse prognosis genes in chr1q-amp MM. Amongst these, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways, whilst in co-operation with FOXM1, activates a proliferative gene signature which predicts adverse prognosis across multiple cancers. Notably, pharmacological disruption of the PBX1-FOXM1 axis, including with a novel PBX1 inhibitor is selectively toxic against chr1q-amp cancer cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in cancer.SignificanceWe provide a comprehensive systems medicine strategy to unveil oncogenic circuitries and inform novel precision therapy decisions against CNA in cancer. This first clinical multi-omic analysis of chr1q-amp in MM identifies a central PBX1-FOXM1 regulatory axis driving high-risk prognosis, as a novel therapeutic target against chr1q-amp in cancer.
Genome manipulation by guide-directed Argonaute cleavage
Authors: Huang Shan , Wang Kaihang , Mayo Stephen L. 
Published: November 2021

ABSTRACTMany prokaryotic argonautes (pAgos) mediate DNA interference by using small DNA guides to cleave target DNA. A recent study shows that CbAgo, a pAgo from Clostridium butyricum, induces DNA interference between homologous sequences and generates double-stranded breaks (DSBs) in target DNAs. This mechanism enables the host to defend against invading DNAs such as plasmids and viruses. However, whether such a CbAgo-mediated DNA cleavage is mutagenic remains unexplored. Here we demonstrate that CbAgo, directed by plasmid-encoded guide sequences, can cleave genome target sites and induce chromosome recombination between downstream homologous sequences in Escherichia coli. The recombination rate correlates well with pAgo DNA cleavage activity and the mechanistic study suggests the recombination involves DSBs and RecBCD processing. In RecA-deficient E. coli strain, guide-directed CbAgo cleavage on chromosomes severely impairs cell growth, which can be utilized as counter-selection to assist Lambda-Red recombineering. These findings demonstrate the guide-directed cleavage of pAgo on the host genome is mutagenic and can lead to different outcomes according to the function of the host DNA repair machinery. We anticipate this novel DNA-guided interference to be useful in broader genetic manipulation. Our study also provides an in vivo assay to characterize or engineer pAgo DNA cleavage activity.
Interventions in sexual and reproductive health services addressing violence against women in low- and middle- income countries: a mixed-methods systematic review
Authors: Lewis Natalia V , Munas Muzrif , Colombini Manuela , d’Oliveira Ana Flavia , Pereira Stephanie , Shrestha Satya , Rajapakse Thilini , Shaheen Amira , Rishal Poonam , Alkaiyat Abdulsalam , Richards Alison , García-Moreno Claudia M , Feder Gene S , Bacchus Loraine J 
Published: November 2021

ABSTRACTObjectivesTo synthesise evidence on the effectiveness, cost-effectiveness, and barriers to responding to violence against women (VAW) in sexual and reproductive health (SRH) services in low- and middle-income countries (LMICs).DesignMixed-methods systematic review.Data sourcesMedline, Embase, Psycinfo, Cochrane, Cinahl, IMEMR, Web of Science, Popline, Lilacs, WHO RHL,ClinicalTrials.gov, Google, Google Scholar, websites of key organisations through December 2019.Eligibility criteriaStudies of any design that evaluated VAW interventions in SRH services in LMICs.Data extraction and synthesisConcurrent narrative quantitative and thematic qualitative syntheses, integration through line of argument and mapping onto a logic model. Two reviewers extracted data and appraised quality.Results26 studies of varied interventions using heterogeneous outcomes. Of ten interventions that strengthened health systems capacity to respond to VAW during routine SRH consultation, three reported no harm and reduction in some types of violence. Of nine interventions that strengthened health systems and communities’ capacity to respond to VAW, three reported conflicting effects on re-exposure to some types of VAW and mixed effect on SRH. The interventions increased identification of VAW but had no effect on the provision (75-100%) and uptake (0.6-53%) of referrals to VAW services. Of seven psychosocial interventions in addition to SRH consultation that strengthened women’s readiness to address VAW, four reduced re-exposure to some types of VAW and improved health. Factors that disrupted the pathway to better outcomes included accepting attitudes towards VAW, fear of consequences, and limited readiness of the society, health systems, and individuals. No study evaluated cost-effectiveness.ConclusionsSome VAW interventions in SRH services reduced re-exposure to some types of VAW and improved some health outcomes in single studies. Future interventions should strengthen capacity to address VAW across health systems, communities, and individual women. First-line support should be better tailored to women’s needs and expectations.PROSPERO protocol CRD42019137167.
Diagnostic signature for Heart Failure with Preserved Ejection Fraction (HFpEF): A Machine Learning Approach Using Multi-Modality Electronic Health Record Data
Authors: Farajidavar Nazli , O’Gallagher Kevin , Bean Daniel , Nabeebaccus Adam , Zakeri Rosita , Bromage Daniel , Kraljevic Zeljko , Teo James TH , Dobson Richard J , Shah Ajay M 
Published: November 2021

ABSTRACTAimsHeart failure with preserved ejection fraction (HFpEF) is thought to be highly prevalent yet remains underdiagnosed. We sought to develop a data-driven diagnostic model to predict from electronic health records (EHR) the likelihood of HFpEF among patients with unexplained dyspnea and preserved left ventricular EF.Methods & ResultsThe derivation cohort comprised patients with dyspnea and echocardiography results. Structured and unstructured data were extracted using an automated informatics pipeline. Patients were retrospectively diagnosed as HFpEF (cases), non-HF (control cohort I), or HF with reduced EF (HFrEF; control cohort II). The ability of clinical parameters and investigations to discriminate cases from controls was evaluated by extreme gradient boosting. A likelihood scoring system was developed and validated in a separate test cohort.The derivation cohort included 1585 consecutive patients: 133 cases of HFpEF (9%), 194 non-HF cases (Control cohort I) and 1258 HFrEF cases (Control cohort II). Two HFpEF diagnostic signatures were derived, comprising symptoms, diagnoses and investigation results. A final prediction model was generated based on the averaged likelihood scores from these two models. In a validation cohort consisting of 269 consecutive patients (with 66 HFpEF cases (24.5%)), the diagnostic power of detecting HFpEF had an AUROC of 90% (P<0.001) and average precision (AP) of 74%.ConclusionThis diagnostic signature enables discrimination of HFpEF from non-cardiac dyspnea or HFrEF from EHR and can assist in the diagnostic evaluation in patients with unexplained dyspnea.
Impaired oligodendrocyte maturation is an early feature in SCA3 disease pathogenesis
Authors: Schuster Kristen H. , Zalon Annie J. , Zhang Hongjiu , DiFranco Danielle M. , Stec Nicholas R. , Haque Zaid , Blumenstein Kate G. , Pierce Amanda M. , Guan Yuanfang , Paulson Henry L. , McLoughlin Hayley S. 
Published: November 2021

ABSTRACTSpinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia, is a polyglutamine neurodegenerative disease for which there is no disease-modifying therapy. The polyglutamine-encoding CAG repeat expansion in the ATXN3 gene results in expression of a mutant form of the ATXN3 protein, a deubiquitinase that causes selective neurodegeneration despite being widely expressed. The mechanisms driving neurodegeneration in SCA3 are unclear. Research to date, however, has focused almost exclusively on neurons. Here, using equal male and female age-matched transgenic mice expressing full-length human mutant ATXN3, we identified early and robust transcriptional changes in selectively vulnerable brain regions that implicate oligodendrocytes in disease pathogenesis. We mapped transcriptional changes across early, mid, and late stages of disease in two selectively vulnerable brain regions, the cerebellum and brainstem. The most significant disease-associated module through weighted gene co-expression network analysis revealed dysfunction in SCA3 oligodendrocyte maturation. These results reflect a toxic gain of function mechanism, as ATXN3 knockout mice do not exhibit any impairments in oligodendrocyte maturation. Genetic crosses to reporter mice revealed a marked reduction in mature oligodendrocytes in SCA3-disease vulnerable brain regions and ultrastructural microscopy confirmed abnormalities in axonal myelination. Further study of isolated oligodendrocyte precursor cells from SCA3 mice established that this impairment in oligodendrocyte maturation is a cell autonomous process. We conclude that SCA3 is not simply a disease of neurons and the search for therapeutic strategies and disease biomarkers will need to account for non-neuronal involvement in SCA3 pathogenesis.SIGNIFICANCE STATEMENTDespite advances in SCA3 disease understanding, much remains unknown about how the disease gene causes brain dysfunction ultimately leading to cell death. We completed a longitudinal transcriptomic analysis of vulnerable brain regions in SCA3 mice to define the earliest and most robust changes across disease progression. Through gene network analyses followed up with biochemical and histological studies in SCA3 mice, we provide evidence for severe dysfunction in oligodendrocyte maturation early in SCA3 pathogenesis. Our results advance understanding of SCA3 disease mechanisms, identify additional routes for therapeutic intervention, and may provide broader insight into polyglutamine diseases beyond SCA3.
Ubiquitous mRNA decay fragments in E. coli redefine the functional transcriptome
Authors: Herzel Lydia , Stanley Julian A. , Yao Chun-Chen , Li Gene-Wei 
Published: November 2021

AbstractBacterial mRNAs have short life cycles, in which transcription is rapidly followed by translation and degradation within seconds to minutes. The resulting diversity of mRNA molecules across different life-cycle stages impacts their functionality but has remained unresolved. Here we quantitatively map the 3′ status of cellular RNAs in Escherichia coli during steady-state growth and report a large fraction of molecules (median>60%) that are fragments of canonical full-length mRNAs. The majority of RNA fragments are decay intermediates, whereas nascent RNAs contribute to a smaller fraction. Despite the prevalence of decay intermediates in total cellular RNA, these intermediates are underrepresented in the pool of ribosome-associated transcripts and can thus distort quantifications for the abundance of full-length, functional mRNAs. The large heterogeneity within mRNA molecules in vivo highlights the importance in discerning functional transcripts and provides a lens for studying the dynamic life cycle of mRNAs.