bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated combinatorial functional genomics and spatial transcriptomics of tumors decodes genotype to phenotype relationships
Authors: Breinig Marco , Lomakin Artem , Heidari Elyas , Ritter Michael , Rukhovich Gleb , Böse Lio , Butthof Luise , Wendler-Link Lena , Wiethoff Hendrik , Poth Tanja , Sahm Felix , Schirmacher Peter , Stegle Oliver , Gerstung Moritz , Tschaharganeh Darjus F. 
Published: May 2024

ABSTRACTLinking the complex genetic changes underlying cancer to relevant disease-phenotypes poses a challenge. Therefore, we present CHOCOLAT-G2P, a scalable approach that integrates multiplex in vivo functional genomics with spatial transcriptomics. By redeploying RNA-templated ligation probes of commercial spatial transcriptomics technology, we streamline mapping composite genetic alterations and transcriptome-wide phenotyping on the same tissue section on a single readout platform. Using this framework, we studied combinatorial effects of 8 perturbations that induce autochthonous mosaic liver tumors sampled from 256 genotypes. Interrogating 324 tumors across six ∼6×6 mm2sections, we charted phenotypic landscapes of genotypically-defined tumor ecosystems, revealing zonation-associated hepatocellular carcinoma subclasses and associations between tumor subtypes and stromal-as well as immune-cell signatures. Further, we decoded epistasis within compound genotypes uncovering opposing roles ofVegfaand mutantCtnnb1to cholangiocarcinoma development. Thus, CHOCOLAT-G2P lays a foundation to decipher how combinations of alterations interact to reprogram tumor cells and their microenvironment within the holistic context of tissue and whole organisms. (https://chocolat-g2p.dkfz.de/).
Transient evolutionary epidemiology of viral adaptation and lethal mutagenesis
Authors: Guillemet Martin , Hardy Erwan , Roze Denis , Gandon Sylvain 
Published: May 2024

AbstractBeneficial mutations drive the within-host adaptation of viral populations and can prolong the duration of host infection. Yet, most mutations are not adaptive and the increase of the mean fitness of viral populations is hampered by deleterious and lethal mutations. Because of this ambivalent role of mutations, it is unclear if a higher mutation rate boosts or slows down viral adaptation. Here we study the interplay between selection, mutation, genetic drift and within-host dynamics of viral populations. We obtain good approximations for the transient evolutionary epidemiology of viral adaptation under the assumption that the mutation rate is high and the effects of non-lethal mutations remain small. We use this theoretical framework to discuss the feasibility of lethal mutagenesis to treat viral infections in the light of quantitative predictions we obtained for the critical mutation rates of a range of different viruses.
Suppression of miRs-497/195 axis possibly confers endocrine therapy resistance via elevated expression of FLT4 and the noncoding RNA MIR503HG
Authors: Pramanik Saheli , Das Partha , Mukherjee Monalisa , Desai Kartiki V. 
Published: May 2024

ABSTRACTBackgroundEndocrine therapy resistance (ETR) in breast cancer is achieved via multiple pathways including a decrease in ER, dysregulation of cell cycle genes, and/or mutations in ER/co-activators/co-repressors. We have reported earlier that high expression of Jumonji domaining containing protein 6 (JMJD6) induced ETR by depleting ER expression. In this study, 3 cellular models representing distinct ETR pathways; Tamoxifen resistant (TAMR), Long-term Estrogen deprived (LTEDI), JMJD6 overexpressing (JOE) cells, and parental MCF7 were subjected to RNA-sequencing, CNC, and ceRNA network analysis. We hypothesised that post-comparison RNA regulations that are common to all cell lines, will reveal actionable markers and targets. These will be shared by all patients with ET-resistant disease, independent of the initiating event.Results170 differentially expressed genes were found, of these, 73 maintained the same directionality in expression (ETR cassette genes). These genes segregated TCGA ER+ tumors into two groups, one intermixing with ER-tumors. Pathway-based curation of ETR genes identified 21 genes (7 up- and 14 down-regulated) that participated in multiple cancer hallmark pathways. Genes upregulated in ETR cells were less expressed in ER+ tumors at diagnosis when compared to normal breast samples but their higher expression indicated adverse survival outcomes. Next, these genes were used for CNC and ceRNA network construction and a triad FLT4:MIR503HG:miR-497/195/424 was discovered. The expression levels of miRNAs were predicted via network analysis and quantitative RT-PCR was used to validate the down regulation of miR-497/195/424 and upregulation of their targets, FLT4 and MIR503HG in ETR cells.ConclusionsWe show that total RNA-seq data can be successfully used to predict actionable miRNAs that achieve drug resistance. Re-expression of ETR genes such as FLT4 in tumor cells, that are less expressed at diagnosis, may be indicative of ETR onset. Finally, ETR may arise due to suppression of miR-424/497/195 leading to higher expression of FLT4 and MIR503HG. We posit that FLT4 may be a suitable target and RT-PCR analysis of this RNA triad could be developed as a detection strategy for ETR in ER+ breast cancer.
Clinical considerations on antimicrobial resistance potential of complex microbiological samples
Authors: Solymosi Norbert , Tóth Adrienn Gréta , Nagy Sára Ágnes , Csabai István , Feczkó Csongor , Reibling Tamás , Németh Tibor 
Published: May 2024

ABSTRACTAntimicrobial resistance (AMR) is one of our greatest public health challenges. Targeted use of antibiotics (AB) can reduce the occurrence and spread of AMR and boost the effectiveness of treatment. This requires knowledge of the antibiotic susceptibility (AS) of the pathogens involved in the disease. Therapeutic recommendations based on classical antibiotic susceptibility testing (AST) are based on the analysis of only a fraction of the bacteria present in the disease process. Next and third generation sequencing technologies allow the identification of antimicrobial resistance genes (ARGs) present in a bacterial community. Using this genomic approach, we can map the antimicrobial resistance potential (AMRP) of a complex, multi-bacterial microbial sample. The same approach can be used to identify antibiotics without any ARGs in the sample that interfere with their activity. Our paper summarises the clinical interpretation opportunities of genomic analysis results from 574Escherichia colistrains and a complex microbiological sample from canine external otitis. In clinical metagenomics, AMRP may be an important approach to make AB therapy more targeted and effective.Graphical abstract
Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming
Authors: Hofvander Jakob , Qiu Alvin , Lee Kiera , Bilenky Misha , Carles Annaïck , Cao Qi , Moksa Michelle , Steif Jonathan , Su Edmund , Sotiriou Afroditi , Goytain Angela , Hill Lesley A. , Singer Sam , Andrulis Irene L. , Wunder Jay S. , Mertens Fredrik , Banito Ana , Jones Kevin B. , Underhill T. Michael , Nielsen Torsten O. , Hirst Martin 
Published: May 2024

SummarySynovial sarcoma (SyS) is an aggressive soft-tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the formation of the SS18::SSX fusion oncoprotein. SS18::SSX associates with mammalian BAF complexes suggesting deregulation of chromatin architecture as the oncogenic driver in this tumour type. To examine the epigenomic state of SyS we performed comprehensive multi-omics analysis on 52 primary pre-treatment human SyS tumours. Our analysis revealed a continuum of epigenomic states across the cohort at fusion target genes independent of rare somatic genetic lesions. We identify cell-of-origin signatures defined by enhancer states and reveal unexpected relationships between H2AK119Ub1 and active marks. The number of bivalent promoters, dually marked by the repressive H3K27me3 and activating H3K4me3 marks, has strong prognostic value and outperforms tumor grade in predicting patient outcome. Finally, we identify SyS defining epigenomic features including H3K4me3 expansion associated with striking promoter DNA hypomethylation in which SyS displays the lowest mean methylation level of any sarcoma subtype. We explore these distinctive features as potential vulnerabilities in SyS and identify H3K4me3 inhibition as a promising therapeutic strategy.
Identifying the practice patterns of optometrists in providing falls prevention management: A mixed-methods systematic review protocol
Authors: Lee Si Ye , Alam Khyber , Charng Jason , Niyazmand Hamed , Chen Jingyi , Hill Anne-Marie 
Published: May 2024

AbstractObjectiveThe objective of this systematic review is to synthesise the best available evidence for optometrists’ practice patterns in providing falls prevention management.IntroductionFalls remain the main cause of injury-related hospitalisation and mortality in Australia and worldwide, significantly affecting older adults. The increased risk of comorbidities, including visual impairment in this cohort is linked to a higher incidence of falls. Despite being primary eye care practitioners, community optometrists may not consistently integrate falls prevention strategies into their practice. Furthermore, the extent to which they adhere to evidence-based recommendations for falls management remains unclear.Inclusion criteriaThe review will include optometrists, in regions where optometry is a regulated profession, and report their understanding and practice patterns in delivering falls prevention management to older community-dwelling adults. Qualitative, quantitative, and mixed methods studies will be eligible for inclusion. It is envisioned that most studies will be qualitative. Studies published in English and those published from 1980 onwards will be eligible for inclusion since published evidence for falls prevention began to increase sharply around this time.MethodsThe review will follow the JBI guidelines for mixed methods systematic reviews and will be developed and reported in accordance with PRISMA-P guidelines. Databases that will be searched are Excerpta Medica Database (Embase), Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Complete, and OVID MEDLINE. Grey literature will be searched through Conference Proceedings Citation Index (Web of Science), Google Scholar, and ProQuest Dissertations databases. Two reviewers will independently conduct all screening and critical appraisal. The reviewers will screen all articles’ titles and abstracts retrieved from the searches to determine potential eligibility. All full-text articles considered relevant will then be assessed for final eligibility for inclusion. The final included articles will be assessed for methodological rigour using the JBI SUMARI critical appraisal tools, subsequently, all relevant data will be extracted. Discrepancies at any stage of the procedures will be resolved through discussion and consensus with a third senior researcher. A convergent integrated approach to synthesising and integrating the quantitative and qualitative data will be followed.Review registration CRD42024539668
The clinical and molecular landscape of breast cancer in women of African and South Asian ancestry
Authors: Thorn GJ , Gadaleta E , Dayem Ullah AZM , James LGE , Abdollahyan M , Barrow-McGee R , Jones JL , Chelala C 
Published: May 2024

ABSTRACTOur study evaluates the molecular and clinical effects of genetic ancestry in African and South Asian women compared to European using a combined cohort of 7,253 breast cancer patients available from four data sources: the 100,000 Genomes Project (UK), The Cancer Genome Atlas (US), the Breast Cancer Now Biobank (UK) and Genes & Health (UK).We find that non-European breast cancer patients present significantly earlier and die at a younger age. The African ancestry group has an increased prevalence of higher grade and hormone receptor negative disease. The South Asian group shows tendency towards lower stage at diagnosis and lower tumour mutational burden. We observe significant differences and similarities in the somatic mutational landscape. We identify differences in germline mutation rates in genes used in genetic testing and others implicated in breast cancer predisposition. Potential therapeutic targets are differentially mutated. We report a higher propensity for homologous recombination deficiency serving as a potential therapy response indicator.Although precision oncology holds the promise of revolutionising healthcare, it could exacerbate the disparities it seeks to eradicate unless research biases are addressed. We harness multimodal data to improve our understanding of ancestry-associated differences in breast cancer and highlight opportunities to advance health equity.
Insights into Hypertension: Microbial Load, Salivary Cytokine Levels and Salivary Flow in Edentulous Patients With Complete Dentures: a Case-Control Study
Authors: Gonçalves Pizziolo Pillar , Clemente Lorena Mosconi , Ribeiro Aline Barbosa , Oliveira Viviane de Cássia , Macedo Ana Paula , Salgado Helio Cesar , Fazan Rubens , Watanabe Evandro , Lovato da Silva Cláudia Helena , Ribeiro Adriana Barbosa 
Published: May 2024

BACKGROUNDTooth loss has been established as a correlate with an increased risk of cardiovascular disease (CVD) and hypertension. However, the influence of complete denture usage on hypertension remains inadequately explored in scientific literature.METHODSThis case-control study evaluated the microbial load of the biofilm of dentures and the palate, salivary levels of cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17) and Salivary Flow (SF) of healthy (CG), controlled hypertensives (G1), underreported hypertensives (G2) and uncontrolled hypertensives (G3). The sample was characterized by sociodemographic data, clinical information, systolic (SBP), and Diastolic Blood Pressure (DBP). The microbial load ofCandidaspp.,Staphylococcusspp., enterobacteria, and mutans group streptococci was evaluated by quantifying colony-forming unit (CFU), SF of unstimulated saliva by mL per minute, and salivary cytokines by flow cytometry.RESULTS80 patients were evaluated (66±7.2 years). The time of edentulism was longer in G3 and positively associated with SBP. The CFU of mutans group streptococci on the denture was higher in G3 and showed a negative association with smoking habit, and this had a positive association with salivary cytokines (IL-4, IL-2, IL-17, IFN-γ), diabetes, and CVD. Patients in group G3, who only use upper dentures, had significantly higher SBP (p=0.024) and levels of IL-2 (p=0.024).CONCLUSIONSTime of edentulism may play a role in hypertension. Smoking habits modulated microbiota and interleukins, especially in diabetic and CVD patients. Furthermore, non-functional dentures had an association with hypertensive patients not controlled by medication, reflected in an increase in SBP and IL-2.
Association between enterotypes of the gut microbiota and features of stroke
Authors: Ogata Toshiyasu , Arima Hisatomi , Kawazoe Miki , Baba Yasuhiko 
Published: May 2024

AbstractBackgroundAn enterotype (e.g., generaBacteroidesandPrevotella) is a classification of patients’ gut microbes into three types, and these types differ in their features of cardiovascular disease. We hypothesized that patients have different enterotypes depending on their arteriosclerosis risk factors, stroke subtype, and severity of stroke.MethodsStool specimens were collected from 100 patients (age: 73.4 ± 11.3 years, 62 men, 38 women) with ischemic stroke after consent was obtained. Data on age, sex, risk of arteriosclerosis, stroke subtype, history of stroke, neurological severity at admission, and prognosis were obtained from the patients’ medical records. Phylogenetic analyses of the 16S rRNA gene (V3–V4 region) extracted from each stool sample were performed. Quantitative analyses of the presence of each bacterial genus in the intestines were performed using a next-generation sequencer. After the number of each genus of gut microbes was extracted, ≥ 30% of the patients with the genusBacteroideswere classified as type I, ≥ 15% with the genusPrevotellawere classified as type II, and the rest were classified as type III. We analyzed the association between the patients’ enterotypes and their characteristics (i.e., arteriosclerosis risk factors such as stroke subtype, and severity of stroke).ResultsThirty-three patients had type I, 10 had type II, and 57 had type III, with no overlap. Patients with types I and II had a lower prevalence of dyslipidemia than those with type III (types I vs II vs III: 36% vs 20% vs 58%, P = 0.028), a lower National Institute of Health and Stroke Scale score at admission (1 vs 1 vs 4 [median], P = 0.025), and the modified Rankin Scale score at discharge tended to be lower (1 vs 1 vs 2 [median], P = 0.094).ConclusionsThe enterotype may affect the risk factors and severity of ischemic stroke.
Intermittent theta burst stimulation (iTBS)-induced changes of resting-state brain entropy (BEN)
Authors: Liu Pan-Shi , Song Dong-Hui , Deng Xin-Ping , Shang Yuan-Qi , Ge Qiu , Wang Ze , Zhang Hui 
Published: May 2024

AbstractIntermittent theta burst stimulation (iTBS) is a novel protocol of repetitive transcranial magnetic stimulation (rTMS). While iTBS has shown better therapeutic effects for depression than conventional high-frequency rTMS (HF-rTMS), its underlying neuronal mechanism remains elusive. Brain entropy (BEN), a measure of irregularity of brain activity, has recently emerged as a novel marker of regional brain activity. Our previous studies have shown the sensitivity of BEN to depression and HF-rTMS, suggesting BEN as a sensitive tool for understanding the brain mechanism of iTBS. To assess this possibility, we calculated BEN using resting state fMRI data provided by an open dataset in OpenNeuro. Sixteen healthy participants underwent 600 pulses of iTBS applied over the left dorsolateral prefrontal cortex (L-DLPFC) at two intensities (90% and 120% of individual resting motor threshold (rMT)) on separate days. We assessed the pre-post stimulation BEN difference and its associations with neurotransmitter receptor and transporter binding maps. Our results showed that subthreshold iTBS (90% rMT) decreased striatal BEN, while suprathreshold iTBS (120% rMT) increased striatal BEN. We also found significant differences in the spatial correlation between BEN changes induced by different stimulation intensities and various neurotransmitters. These results suggest that differences in BEN caused by iTBS stimulation intensity may be related to the release of other neurotransmitters. The study underscores the significance of iTBS stimulation intensity and provides a basis for future clinical investigations to identify stimulation intensities with good therapeutic benefits.
Tissue growth associated transition of podoplanin-expressing stromal cells in the postnatal mouse femur
Authors: Notoh Hinako , Nara Rikuto , Suzuki Nobuaki , Suzuki Atsuo , Okamoto Shuichi , Tsukiji Nagaharu , Kanematsu Takeshi , Suzuki Naruko , Katsumi Akira , Kojima Tetsuhito , Suzuki-Inoue Katsue , Matsushita Tadashi , Tamura Shogo 
Published: May 2024

AbstractSkeletal stem/progenitor cells are tissue-resident stem/progenitor cells involved in the formation of the skeletal tissue, bone marrow, and hematopoietic microenvironment. Podoplanin-expressing stromal cells (PDPN-SCs) are skeletal stem/progenitor cell-lineage stromal cells. In the adult mouse bone marrow, PDPN-SCs are present on the diaphyseal arterioles and promote megakaryo/erythropoiesis. However, the localized distribution of PDPN-SCs in neonatal and postnatal femurs remains unclear. In this study, we histologically examined the transition of PDPN-SCs during postnatal femoral growth. In the diaphyseal marrow, PDPN-SCs were present in the neonatal marrow space but disappeared with femoral growth. In the cortical bone, abundant PDPN-SCs existed in the primitive neonatal bone and transitioned to restricted localization in the periosteum and endosteum with tissue growth. In the metaphysis, PDPN-SCs resided in nascent trabecular bones. We also found a novel subset of PDPN-SCs that expressed osterix, suggesting that osterix-positive PDPN-SCs were involved in bone formation. Furthermore, in the diaphyseal arterioles, periarteriolar PDPN-SCs appeared sporadically between 1–2 weeks of age and populated to surround the arterioles. These histological observations can contribute to the understanding of how stromal cells, including PDPN-SCs, engage in postnatal bone and marrow formation.
Mechanics of knee meniscus results from precise balance between material microstructure and synovial fluid viscosity
Authors: Afanador Camilo A.S. , Urcun Stéphane , Sbalzarini Ivo F. , Bordas Stéphane P.A. , Barrera Olga , Rajabi Mohammad Mahdi , Seil Romain , Obeidat Anas 
Published: May 2024

AbstractThe meniscus plays a crucial role in the biomechanics of the knee, serving as load transmitter, and reducing friction between joints. Understanding the biome-chanics of the meniscus is essential to effective treatments of knee injuries and degenerative conditions. In this study, we used two central meniscus samples extracted from a human knee and acquired high-resolutionµ-CT images. Using an implicit immersed boundary technique, we reconstructed two 3D computational models of the menisci. By eroding the channels of the original meniscus geometry, we created new microstructures with varying porosities (0.53to0.8) whilst preserving the connectivity of the porous structure. We investigate the fluid dynamics of the meniscus using a mesh-free numerical method, considering various inlet pressure conditions and analysing the fluid flow within the microstructures. The results of the original microstructure associated with a physiological dynamic viscosity of synovial fluid are in accordance with biophysical experiments on menisci. Furthermore, the eroded microstructure with a33%increase in porosity exhibited a remarkable120%increase in flow velocity. This emphasises the sensitivity of meniscus physiology to porous microstructure properties, showing that detailed computational models can explore physiological and pathological conditions, advancing further knee biomechanics research.
Efficient DNA base editing via an optimized DYW-like deaminase
Authors: Kweon Jiyeon , Park Soomin , Jeon Mi Yeon , Lim Kayeong , Jang Gayoung , Jang An-Hee , Lee Minyoung , Seok Cheong , Lee Chaeyeon , Park Subin , Ahn Jiseong , Jang JiYoon , Sung Young Hoon , Kim Daesik , Kim Yongsub 
Published: May 2024

AbstractCRISPR-based cytosine base editors enable precise genome editing without inducing double-stranded DNA breaks, yet traditionally depend on a limited selection of deaminases from the APOBEC/AID or TadA families. Here, we introduce SsCBE, a novel CRISPR-based cytosine base editor utilizing SsdAtox, a DYW-like deaminase derived from the toxin ofPseudomonas syringae. Strategic engineering of SsdAtoxhas led to remarkable improvements in the base editing efficiency (by up to 8.4-fold) and specificity for SsCBE, while concurrently reducing cytotoxicity. Exhibiting exceptional versatility, SsCBE was delivered and efficiently applied using diverse delivery methods, including the engineered virus-like particles (eVLPs). Its application has enabled targeted cytosine base editing in mouse zygotes and pioneering edits in mitochondrial DNA. The advent of SsCBE marks a significant advancement in the CRISPR toolkit, providing a versatile tool for advanced research and therapeutic strategies.