bluuebunny/crossref_metadata_2025_split huggingface dataset:
The experience of family carers for people with moderate to advanced dementia within a domestic home setting: a systematically constructed narrative synthesis
Authors: James Charles , Walshe Catherine , Swarbrick Caroline 
Published: August 2023

AbstractBackgroundCaring for someone with moderate to advanced dementia within a domestic home setting can be burdensome and time-consuming. To ensure the effectiveness of care planning and delivery, especially towards the end of life, understanding the nature and impact of such caregiving on the family carer is important. Synthesising existing research will allow greater insight into this experience.Review question‘How do family carers describe their experience of providing home-based care for people with moderate to advanced dementia?’DesignA narrative synthesis of qualitative research exploring the experiences of people with moderate to advanced dementia and their family carers was conducted. Databases (MEDLINE, CINAHL, EMBASE, PsychINFO, Web of Science and Academic Search Complete) were searched from 1984 to 2020. Similarities and differences between papers were grouped using textual narrative synthesis.FindingsThis paper reports findings from a PhD thesis (James, 2021). Included papers (n=17) incorporated those focused on caring for people with advanced dementia (n=8), and those with moderate dementia (n=9). Family carers reported an experience of loss, burden, and grief. Experiences of internal conflict also led to psychological distress. These experiences had a negative impact on the general health of the family carer. Improvement in the family carer’s inter-relationships and the feeling of being useful or having a sense of meaning were reported as positive aspects of caregiving.ConclusionA complete description of family carers’ experiences may be inadequate in conveying an acknowledgement of dementia as an illness within the domestic home. Their justifications and determinants for balancing family carers’ challenges and distress to morals also remain unclear. Further research is required to ascertain how family carers may proportionally balance their personified loss with their personified value earlier in the disease trajectory.
In vivo time-lapse imaging and analysis of mitochondria in neural progenitor cells in the developing brain
Authors: Feng Martin S. , Kettelberger Maggie R. , Bestman Jennifer E. 
Published: August 2023

ABSTRACTNeural progenitor cells (NPCs) are the highly polarized dividing stem cells of the developing brain that give rise to all neurons and glia. Early on, NPCs divide symmetrically and expand the pool of progenitor cells, but as development continues the NPCs begin to asymmetrically divide to produce neurons. The mechanisms that govern this irreversible commitment to neurogenesis are not fully understood, but in other stem cell populations the regulation of mitochondria and cell metabolism is key to controlling stem cell fate. Here we use timelapse 3D confocal microscopy to observe NPCs, their cellular progeny, and their mitochondria in the developingXenopustectum. Our results track individual NPCs over days and show that they contain abundant mitochondria that form complicated networks distributed throughout the cells. We find that NPCs preparing to divide shift mitochondria toward the cell body where they become asymmetrically distributed, suggesting that the cells control which progeny inherit mitochondria. This uneven distribution of mitochondria in cell preparing to divide led us to test the role that mitochondria play in cell division. We overexpressed the mitochondrial biogenesis master regulator, PGC-1a, which induced the NPCs to asymmetrically divide and produce neurons, while PGC-1a knockdown limited neurogenesis. Together these data suggest that the regulation of mitochondria by NPCs prior to cell division and their unequal inheritance during cell division, contributes to the fate of the newborn cells in the developing brain.
EZH2 inhibition sensitizes IDH1R132H mutant gliomas to histone deacetylase inhibitor
Authors: Sprinzen Houghton Lisa , Garcia Franklin Godinez , Mela Angeliki , Lei Liang , Upadhyayula Pavan , Mahajan Aayushi , Humala Nelson , Manier Lisa , Caprioli Richard , Quiñones-Hinojosa Alfredo , Casaccia Patrizia , Canoll Peter 
Published: August 2023

AbstractIsocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis, however its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H mutated glioma that shows elevated production of 2-Hydroxyglutarate (2-HG) and increased tri-methylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wildtype cells, combination treatment with Tazemetostat is synergistic in both mutant and wildtype models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.Main PointsMurine gliomas initiated by the IDH1R132H mutation (in the presence of additional genetic alterations, such as p53 loss and PDGF overexpression) recapitulate the metabolic and transcriptional features of the proneural subtype, as they are characterized by increased 2HG levels, and are enriched for OPC lineage-restricted genes compared to IDH-wildtype murine gliomas. In murine IDH1-R132H glioma cells, EZH2 inhibition is not cytotoxic as a monotherapy but reduces levels of H3K27me3 and increases levels of H3K27ac. IDH1R132H cells are relatively resistant to Panobinostat cytotoxicity compared to IDH-wildtype cells, but combining treatment with EZH2 inhibition synergistically kills glioma cells and increases H3K27ac.
SR2: Sparse Representation Learning for Scalable Single-cell RNA Sequencing Data Analysis
Authors: Zhao Kai , So Hon-Cheong , Lin Zhixiang 
Published: August 2023

AbstractSingle-cell RNA-sequencing (scRNA-seq) technology has been widely used to measure the transcriptome of cells in complex and heterogeneous systems. Integrative analysis of multiple scRNA-seq data can transform our understanding of various aspects of biology at the single-cell level. Many computational methods are proposed for data integration. However, few methods for scRNA-seq data integration explicitly model variation from heterogeneous biological conditions for interpretation. Modeling the variation helps understand the effect of biological conditions on complex biological systems.Our study proposes SR2 to capture gene expression patterns from heterogeneous biological conditions and discover cell identity simultaneously. Therefore, it can uncover the effect of biological conditions on the gene expression of cells and simultaneously achieve state-of-the-performance in cell identity discovery in our comprehensive comparison. Notably, SR2 is extended to model the effects of biological conditions on gene expression for cell populations, thus uncovering the effect of biological conditions on gene expression for cell populations and identifying putative condition-associated cell populations. To improve its scalability, we incorporate a batch-fitting strategy to ensure it is scalable to scRNA-seq data with arbitrary sample sizes. Moreover, the broad applicability of SR2 in biomedical studies has been demonstrated via applications. The complete package of SR2 is available athttps://github.com/kai0511/SR2.
Quantitative description of the phase separation behavior of the multivalent SLP65-CIN85 complex
Authors: Maier Joachim , Sieme Daniel , Wong Leo E. , Dar Furqan , Wienands Jürgen , Becker Stefan , Griesinger Christian 
Published: August 2023

AbstractBiomolecular condensates play a major role in cell compartmentalization, besides membrane-enclosed organelles. The multivalent SLP65 and CIN85 proteins are downstream B cell receptor (BCR)-signaling effectors, required for a proper immune response. Both proteins phase separate together with vesicles to form pre-signaling clusters. Within this tripartite system, six PRMs of SLP65 interact promiscuously with three SH3 domains of the CIN85 monomer, establishing 18 individual SH3-PRM interactions whose individual dissociation constants we determined. Based on these 18 dissociation constants, we measured the phase separation properties of the natural SLP65/CIN85 system as well as designer constructs that emphasize the strongest SH3/PRM interactions. By modelling these various SLP65/CIN85 constructs with the program LASSI (LAttice simulation engine for Sticker and Spacer Interactions) we reproduced the observed phase separation properties. In addition, LASSI revealed a deviation in the experimental measurement, which was independently identified as a previously unknown intramolecular interaction. Thus, thermodynamic properties of the individual PRM/SH3 interactions allow to model the phase separation behavior of the SLP65/CIN85 system faithfully.
ddRAD-seq-derived SNPs reveal novel association signatures for fruit-related traits in peach
Authors: Ksouri Najla , Sánchez Gerardo , Forcada Carolina Font i , Contreras-Moreira Bruno , Gogorcena Yolanda 
Published: August 2023

AbstractBreeding for new peach cultivars with enhanced traits is a prime target in breeding programs. In this study, we used a discovery panel of 90 peach accessions in order to dissect the genetic architecture of 16 fruit-related traits. ddRAD-seq genotyping and the intersection between three variant callers yielded 13,045 high-confidence SNPs. These markers were subjected to an exhaustive association analysis by testing up to seven GWAS models. Blink was selected as the most adjusted, simultaneously balancing false positive and negative associations. Totally, we identified 16 association signals for six traits showing high broad-sense heritability: harvest date, fruit weight, flesh firmness, contents of flavonoids, anthocyanins and sorbitol. By assessing the allelic effect of significant markers on phenotypic attributes, nine SNP alleles were denoted favorable. A promising marker (SNC_034014.1_7012470) was found to be simultaneously associated with harvest date and fruit firmness conferring a positive allelic effect on both traits. We anticipate that this marker could be used to improve firmness in late harvested cultivars. Candidate causal genes were shortlisted when fulfilling the following criteria: i) position within the linkage disequilibrium block, ii) functional annotation and iii) expression pattern. A bibliographic review of previously reported QTLs mapping nearby the associated markers allowed us to benchmark the accuracy of our approach. Despite the moderate germplasm size, ddRAD-seq allowed us to produce an accurate representation of peach’s genome resulting in SNP markers suitable for empirical association studies. Together with candidate genes, they lay the foundation for further genetic dissection of peach key traits.
Uridine as a potentiator of aminoglycosides through activation of carbohydrate transporters
Authors: Lang Manon , Renard Stéphane , El-Meouche Imane , Amoura Ariane , Denamur Erick , Brosschot Tara , Ingersoll Molly , Bacqué Eric , Mazel Didier , Baharoglu Zeynep 
Published: August 2023

AbstractAminoglycosides (AGs) are broad-spectrum antibiotics effective against Gram-negative bacteria. AG uptake depends on membrane potential, but the precise mechanisms are incompletely understood. We report here a new mechanism of active AG uptake in Gram-negative bacteria. InE. coli, overexpression of various carbohydrate transporters increases susceptibility to AGs. Conversely, deletion of a single transporter has little impact. We propose a new uptake model where AGs act as substrates for redundant carbohydrate transporters. This mechanism appears to be shared among Gram-negative ESKAPE pathogens. We screened for molecules that induce transporters’ expression and identified uridine. When uridine is co-administered with AGs under conditions mimicking urinary tract infections, the efficacy of AG therapies is significantly improved againstE. coli, including resistant strains, due to enhanced bacterial uptake. Based on previous knowledge on the use of uridine in humans, we propose that uridine can be a potentiating adjuvant to AG treatment of infectious diseases in the hospital.
Disordered C-terminal domain drives spatiotemporal confinement of RNAPII to enhance search for chromatin targets
Authors: Ling Yick Hin , Ye Ziyang , Liang Chloe , Yu Chuofan , Park Giho , Corden Jeffry L. , Wu Carl 
Published: August 2023

AbstractEfficient gene expression requires RNA Polymerase II (RNAPII) to find chromatin targets precisely in space and time. How RNAPII manages this complex diffusive search in 3D nuclear space remains largely unknown. The disordered carboxy-terminal domain (CTD) of RNAPII, which is essential for recruiting transcription-associated proteins, forms phase-separated dropletsin vitro, hinting at a potential role in modulating RNAPII dynamics. Here, we use single-molecule tracking and spatiotemporal mapping in living yeast to show that the CTD is required for confining RNAPII diffusion within a subnuclear region enriched for active genes, but without apparent phase separation into condensates. Both Mediator and global chromatin organization are required for sustaining RNAPII confinement. Remarkably, truncating the CTD disrupts RNAPII spatial confinement, prolongs target search, diminishes chromatin binding, impairs pre-initiation complex formation, and reduces transcription bursting. This study illuminates the pivotal role of the CTD in driving spatiotemporal confinement of RNAPII for efficient gene expression.
SUPERVISED WHITE MATTER BUNDLE SEGMENTATION IN GLIOMA PATIENTS WITH TRANSFER LEARNING
Authors: Riccardi Chiara , Ghezzi Sofia , Amorosino Gabriele , Zigiotto Luca , Sarubbo Silvio , Jovicich Jorge , Avesani Paolo 
Published: August 2023

ABSTRACTIn clinical neuroscience, the segmentation of the main white matter bundles is propaedeutic for many tasks such as pre-operative neurosurgical planning and monitoring of neuro-related diseases. Automating bundle segmentation with data-driven approaches and deep learning models has shown promising accuracy in the context of healthy individuals. The lack of large clinical datasets is preventing the translation of these results to patients. Inference on patients’ data with models trained on healthy population is not effective because of domain shift. This study aims to carry out an empirical analysis to investigate how transfer learning might be beneficial to overcome these limitations. For our analysis, we consider a public dataset with hundreds of individuals and a clinical dataset with several tens of glioma patients. We focus our preliminary investigation on the corticospinal tract. The results show that transfer learning might be effective in partially overcoming the domain shift.
CCT and Cullin1 regulate the TORC1 pathway to promote dendritic arborization in health and disease
Authors: Lottes Erin N. , Ciger Feyza H. , Bhattacharjee Shatabdi , Timmins-Wilde Emily A. , Tete Benoit , Tran Tommy , Matta Jais , Patel Atit A. , Cox Daniel N. 
Published: August 2023

ABSTRACTThe development of cell-type-specific dendritic arbors is integral to the proper functioning of neurons within their circuit networks. In this study, we examine the regulatory relationship between the cytosolic chaperonin CCT, key insulin pathway genes, and an E3 ubiquitin ligase (Cullin1) in homeostatic dendritic development. CCT loss of function (LOF) results in dendritic hypotrophy inDrosophilaClass IV (CIV) multidendritic larval sensory neurons, and CCT has recently been shown to fold components of the TOR (Target of Rapamycin) complex 1 (TORC1),in vitro.Through targeted genetic manipulations, we have confirmed that LOF of CCT and the TORC1 pathway reduces dendritic complexity, while overexpression of key TORC1 pathway genes increases dendritic complexity in CIV neurons. Both CCT and TORC1 LOF significantly reduce microtubule (MT) stability. CCT has been previously implicated in regulating proteinopathic aggregation, thus we examined CIV dendritic development in disease conditions as well. Expression of mutant Huntingtin leads to dendritic hypotrophy in a repeat-length-dependent manner, which can be rescued by TORC1 disinhibition via Cullin1 LOF. Together, our data suggest that Cullin1 and CCT influence dendritic arborization through regulation of TORC1 in both health and disease.SIGNIFICANCEThe insulin pathway has become an increasingly attractive target for researchers interested in understanding the intersection of metabolism and brain health. We have found connections between the insulin pathway and cytosolic protein maintenance in the development of neuronal dendrites. These pathways converge on the dendritic cytoskeleton, particularly microtubules. Neurons expressing mutant Huntingtin also show defects in dendritic development and the underlying cytoskeleton, and we find that disinhibition of the insulin pathway can rescue dendritic hypotrophy in these neurons. This work advances our understanding of the molecular interactions between the insulin pathway and neuronal development in both health and Huntington’s Disease conditions.
The G2phase controls binary division ofToxoplasma gondii
Authors: Hawkins Lauren M. , Wang Chengqi , Chaput Dale , Batra Mrinalini , Marsilia Clem , Awshah Danya , Suvorova Elena S. 
Published: August 2023

ABSTRACTDivision of apicomplexan parasites differs drastically from the division of their host cells. A fraction of apicomplexans divides in the traditional binary mode, such asToxoplasma gondiiin asexual stages, whereas the vast majority instead divide in a multinuclear fashion. Such variety of replication modes and a dearth of conserved conventional regulators have hindered the progress of apicomplexan cell cycle studies. We previously identified five Cdk-related kinases (Crk) involved in endodyogenic division ofT. gondiitachyzoites. The current study investigates the roles of a novel essential cell cycle kinase TgCrk4. We identified this kinase cyclin partner and demonstrated that TgCrk4 regulates processes carried out during conventional G2phase, such as repression of chromosome rereplication and centrosome re-duplication. Accumulation of TgCyc4 in the nucleus and on the centrosomes supported the role of TgCrk4-TgCyc4 complex as a coordinator of chromosome and centrosome cycles inT. gondii. Examination of the TgCrk4-deficient tachyzoites confirmed a cell cycle stop prior to the TgCrk6-regulated spindle assembly checkpoint. Furthermore, we identified an ortholog of the DNA replication licensing factor Cdt1 that was a dominant interactor of the TgCrk4-TgCyc4 complex.T. gondiiCdt1 is highly divergent but preserved critical signature domains and appeared to play a minimal or no role in licensing DNA replication in G1phase. Functional analyses indicated the primary role of TgCdt1 is in controlling chromosome rereplication and centrosome reduplication. Global phosphoproteome analyses identified immediate TgCrk4 substrates, such as DNA replication licensing factor TgORC4, component of the anaphase-promoting complex TgCdc20, γ-tubulin nucleation factor TgGCP2, and the catalytic subunit of cell cycle phosphatase TgPP2ACA. Importantly, our phylogenetic and structural analyses revealed that the functional TgCrk4-TgCyc4 complex was encoded in the limited group of apicomplexans dividing in a binary fashion. Together with the minimal representation of binary division in Apicomplexa phylum, our findings support the novel view of apicomplexans acquiring binary division to repress ancestral multinuclear mechanisms.
Myogenetic Oligodeoxynucleotide Induces Myocardial Differentiation of Murine Pluripotent Stem Cells
Authors: Ishioka Mina , Nihashi Yuma , Sunagawa Yoichi , Umezawa Koji , Shimosato Takeshi , Kagami Hiroshi , Morimoto Tatsuya , Takaya Tomohide 
Published: August 2023

AbstractAn 18-base myogenetic oligodeoxynucleotide (myoDN), iSN04, acts an anti-nucleolin aptamer and induces myogenic differentiation of skeletal muscle myoblasts. This study investigated the effect of iSN04 on murine embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). In the undifferentiated state, iSN04 inhibited the proliferation of ESCs and iPSCs but did not affect the expression of pluripotent markers. In the differentiating condition, iSN04 treatment of ESCs/iPSCs from day 5 onward dramatically induced the differentiation intoNkx2-5+beating cardiomyocytes with upregulation ofGata4, Isl1, andNkx2-5, whereas iSN04 treatment from earlier stages completely inhibited cardiomyogenesis. RNA sequencing revealed that iSN04 treatment from day 5 onward contributes to the generation of cardiac progenitors by modulating the Wnt signaling pathway. Immunostaining showed that iSN04 suppressed the cytoplasmic translocation of nucleolin and restricted it to the nucleoli. These results demonstrate that nucleolin inhibition by iSN04 facilitates the terminal differentiation of cardiac mesoderm into cardiomyocytes, but interferes with the differentiation of early mesoderm into the cardiac lineage. This is the first report on the generation of cardiomyocytes from pluripotent stem cells using a DNA aptamer. Since iSN04 did not induce hypertrophic responses in primary-cultured cardiomyocytes, iSN04 would be useful and safe for the regenerative therapy of heart failure using stem cell-derived cardiomyocytes.
Analytical code sharing practices in biomedical research
Authors: Sharma Nitesh Kumar , Ayyala Ram , Deshpande Dhrithi , Patel Yesha M , Munteanu Viorel , Ciorba Dumitru , Fiscutean Andrada , Vahed Mohammad , Sarkar Aditya , Guo Ruiwei , Moore Andrew , Darci-Maher Nicholas , Nogoy Nicole A , Abedalthagafi Malak S. , Mangul Serghei 
Published: August 2023

AbstractData-driven computational analysis is becoming increasingly important in biomedical research, as the amount of data being generated continues to grow. However, the lack of practices of sharing research outputs, such as data, source code and methods, affects transparency and reproducibility of studies, which are critical to the advancement of science. Many published studies are not reproducible due to insufficient documentation, code, and data being shared. We conducted a comprehensive analysis of 453 manuscripts published between 2016-2021 and found that 50.1% of them fail to share the analytical code. Even among those that did disclose their code, a vast majority failed to offer additional research outputs, such as data. Furthermore, only one in ten papers organized their code in a structured and reproducible manner. We discovered a significant association between the presence of code availability statements and increased code availability (p=2.71×10−9). Additionally, a greater proportion of studies conducting secondary analyses were inclined to share their code compared to those conducting primary analyses (p=1.15*10−07). In light of our findings, we propose raising awareness of code sharing practices and taking immediate steps to enhance code availability to improve reproducibility in biomedical research. By increasing transparency and reproducibility, we can promote scientific rigor, encourage collaboration, and accelerate scientific discoveries. We must prioritize open science practices, including sharing code, data, and other research products, to ensure that biomedical research can be replicated and built upon by others in the scientific community.