bluuebunny/crossref_metadata_2025_split huggingface dataset:
NK cell metabolic adaptation to infection promotes survival and viral clearance
Authors: Victorino Francisco , Bigley Tarin , Park Eugene , Yao Cong-Hui , Benoit Jeanne , Yang Li-Ping , Piersma Sytse J , Lauron Elvin J , Davidson Rebecca M , Patti Gary J , Yokoyama Wayne M 
Published: March 2021

AbstractNatural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1α (HIF-1α) is a feature of NK cells during murine cytomegalovirus (MCMV) infectionin vivo. HIF-1α-deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1α KO NK cells however, their numbers were significantly reduced. Loss of HIF-1α did not affect NK cell proliferation duringin vivoinfection andin vitrocytokine stimulation. Instead, we found HIF1α-deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulationin vitro. Similarly, during MCMV infection HIF1α-deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1α-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.
Behaviour-drivenArcexpression is greater in dorsal than ventral CA1 regardless of task or sex differences
Authors: Lee J. Quinn , McHugh Rebecca , Morgan Erik , Sutherland Robert J. , McDonald Robert J. 
Published: March 2021

AbstractEvidence from genetic, behavioural, anatomical, and physiological study suggests that the hippocampus functionally differs across its longitudinal (dorsoventral or septotemporal) axis. Although, how to best characterize functional and representational differences in the hippocampus across its long axis remains unclear. While some suggest that the hippocampus can be divided into dorsal and ventral subregions that support distinct cognitive functions, others posit that these regions vary in their granularity of representation, wherein spatial-temporal resolution decreases in the ventral (temporal) direction. Importantly, the cognitive and granular hypotheses make distinct predictions on cellular recruitment dynamics under conditions when animals perform tasks with qualitatively different cognitive-behavioural demands. The cognitive function account implies that dorsal and ventral cellular recruitment differs depending on relevant behavioural demands, while the granularity account suggests similar recruitment dynamics regardless of the nature of the task performed. Here, we quantified cellular recruitment with the immediate early gene (IEG)Arcacross the entire longitudinal CA1 axis in female and male rats performing spatial- and fear-guided memory tasks. Our results show that recruitment is greater in dorsal than ventral CA1 regardless of task or sex. Thisexperimentum crucisleads to the strong inference that the granularity hypothesis for functional differences across the longitudinal axis in the rodent hippocampus is correct.
Fiber tractography bundle segmentation depends on scanner effects, vendor effects, acquisition resolution, diffusion sampling scheme, diffusion sensitization, and bundle segmentation workflow
Authors: Schilling Kurt G , Tax Chantal MW , Rheault Francois , Hansen Colin B , Yang Qi , Yeh Fang-Cheng , Cai Leon Y , Anderson Adam W , Landman Bennett A 
Published: March 2021

AbstractWhen investigating connectivity and microstructure of white matter pathways of the brain using diffusion tractography bundle segmentation, it is important to understand potential confounds and sources of variation in the process. While cross-scanner and cross-protocol effects on diffusion microstructure measures are well described (in particular fractional anisotropy and mean diffusivity), it is unknown how potential sources of variation effect bundle segmentation results, which features of the bundle are most affected, where variability occurs, nor how these sources of variation depend upon the method used to reconstruct and segment bundles. In this study, we investigate six potential sources of variation, or confounds, for bundle segmentation: variation (1) across scan repeats, (2) across scanners, (3) across vendors (4) across acquisition resolution, (5) across diffusion schemes, and (6) across diffusion sensitization. We employ four different bundle segmentation workflows on two benchmark multi-subject cross-scanner and cross-protocol databases, and investigate reproducibility and biases in volume overlap, shape geometry features of fiber pathways, and microstructure features within the pathways. We find that the effects of acquisition protocol, in particular acquisition resolution, result in the lowest reproducibility of tractography and largest variation of features, followed by vendor-effects, scanner-effects, and finally diffusion scheme and b-value effects which had similar reproducibility as scan-rescan variation. However, confounds varied both across pathways and across segmentation workflows, with some bundle segmentation workflows more (or less) robust to sources of variation. Despite variability, bundle dissection is consistently able to recover the same location of pathways in the deep white matter, with variation at the gray matter/ white matter interface. Next, we show that differences due to the choice of bundle segmentation workflows are larger than any other studied confound, with low-to-moderate overlap of the same intended pathway when segmented using different methods. Finally, quantifying microstructure features within a pathway, we show that tractography adds variability over-and-above that which exists due to noise, scanner effects, and acquisition effects. Overall, these confounds need to be considered when harmonizing diffusion datasets, interpreting or combining data across sites, and when attempting to understand the successes and limitations of different methodologies in the design and development of new tractography or bundle segmentation methods.
Nanoparticle Cellular Internalization is Not Required for RNA Delivery to Mature Plant Leaves
Authors: Zhang Huan , Goh Natalie S. , Wang Jeffrey , Demirer Gozde S. , Butrus Salwan , Park So-Jung , Landry Markita P. 
Published: March 2021

AbstractRapidly growing interest in nanoparticle-mediated delivery of DNA and RNA to plants requires a better understanding of how nanoparticles and their cargoes translocate in plant tissues and into plant cells. However, little is known about how the size and shape of nanoparticles influences transport in plants and use of their cargoes, limiting development and deployment of nanotechnology in plant systems. Here, we employ non-biolistically delivered DNA-modified gold nanoparticles (AuNP) spanning various sizes (5 – 20 nm) and shapes (spheres and rods) to systematically investigate their transport following infiltration intoNicotiana benthamiana (Nb)leaves. Generally, smaller AuNPs demonstrate more rapid, higher, and longer-lasting levels of association with plant cell walls compared to larger AuNPs. We observe internalization of rod-shaped but not spherical AuNPs into plant cells, yet surprisingly, 10 nm spherical AuNP functionalized with small-interfering RNA (siRNA) are most efficient at siRNA delivery and inducing gene silencing in mature plant leaves. These results indicate the importance of nanoparticle size in efficient biomolecule delivery, and, counterintuitively, demonstrate that efficient cargo delivery is possible and potentially optimal in the absence of nanoparticle cellular internalization. Our results highlight nanoparticle features of importance for transport within plant tissues, providing a mechanistic overview of how nanoparticles can be designed to achieve efficacious bio-cargo delivery for future developments in plant nanobiotechnology.
A Degenerate PCNA-Interacting Peptide (DPIP) box targets RNF168 to replicating DNA to limit 53BP1 signaling
Authors: Yang Yang , Jayaprakash Deepika , Hollingworth Robert , Chen Steve , Jablonski Amy E. , Gao Yanzhe , Anand Jay Ramanlal , Mutter-Rottmayer Elizabeth , An Jing , Cheng Xing , Pearce Kenneth H. , Blanchet Sophie-Anne , Fradet-Turcotte Amélie , Stewart Grant S. , Vaziri Cyrus 
Published: March 2021

AbstractThe E3 ligase RNF168 has been suggested to have roles at DNA replication forks in addition to its canonical functions in DNA double-strand break (DSB) signaling. However, the precise role of RNF168 in DNA replication remains unclear. Here we demonstrate that RNF168 is recruited to DNA replication factories independent of the canonical DSB response pathway regulators and identify a degenerate PCNA-Interacting Peptide (DPIP) motif in the C-terminus of RNF168 which mediates its binding to PCNA. An RNF168 mutant harboring substitutions in the DPIP box fails to interact with PCNA and is not recruited to sites of DNA synthesis, yet fully retains its ability to promote DSB-induced 53BP1 foci. Surprisingly, the RNF168 DPIP mutant also retains the ability to support ongoing DNA replication fork movement, demonstrating that PCNA-binding is dispensable for normal S-phase functions. However, replisome-associated RNF168 functions to suppress the DSB-induced 53BP1 DNA damage response during S-phase. Moreover, we show that WT RNF168 can perform PCNA ubiquitylation independently of RAD18 and also synergizes with RAD18 to amplify PCNA ubiquitylation. Taken together, our results identify non-canonical functions of RNF168 at the replication fork and demonstrate new mechanisms of cross talk between the DNA damage and replication stress response pathways.
Mechano-transductionviathe pectin-FERONIA complex regulates ROP6 GTPase signaling inArabidopsis
Authors: Tang Wenxin , Lin Wenwei , Li Binqi , Yang Zhenbiao 
Published: March 2021

SUMMARYDuring growth and morphogenesis, plant cells respond to mechanical stresses resulting from spatiotemporal changes in the cell wall that bear high internal turgor pressure. Microtubule (MT) arrays are re-organized to align in the direction of maximal tensile stress to guide the synthesis of cellulose, reinforcing the local cell wall. However, how mechanical forces regulate MT re-organization remains largely unknown. Here, we demonstrate that mechanical signaling that is based on the CrRLK1L subfamily receptor kinase FERONIA (FER) regulates the reorganization of cortical MT in cotyledon epidermal pavement cells (PC) inArabidopsis. Recessive mutations inFERcompromised MT response to mechanical perturbations such as single cell ablation, compression and Isoxaben treatment in these pavement cells. These perturbations promoted the activation of ROP6 GTPase that acts directly downstream of FER. Furthermore, defects in the ROP6 signaling pathway negated the reorganization of cortical MTs induced by these stresses. Finally, reduction in highly demethylesterified pectin, which binds the extracellular malectin domain of FER and is required for FER-mediated ROP6 activation, also impacted mechanical induction of cortical MT reorganization. Taken together our results suggest that the FER-pectin complex senses and/or transduce mechanical forces to regulate MT organization through activating the ROP6 signaling pathway inArabidopsis.
Sponges are highly resistant to radiation exposure and cancer
Authors: Fortunato Angelo , Taylor Jake , Scirone Jonathan , Aktipis Athena , Maley Carlo C. 
Published: March 2021

AbstractThere are no reports of cancer in sponges, despite them having somatic cell turnover, long lifespans and no specialized adaptive immune cells. In order to investigate whether sponges are cancer resistant, we exposed a species of sponge,Tethya wilhelma, to X-rays. We found thatT. wilhelmacan withstand 600 Gy of X-ray radiation. That is approximately 100 times the lethal dose for humans. A single high dose of X-rays did not induce cancer in sponges, providing the first experimental evidence of cancer resistance in the phylum, Porifera. Following X-ray exposure, we found an overexpression of genes involved in DNA repair, signaling transduction pathways and epithelial to mesenchymal transition. Sponges have the highest level of radiation resistance that has yet been observed in animals that have sustained somatic cell turnover. This may make them an excellent model system for studying cancer resistance and developing new approaches for cancer prevention and treatment.
The SAGA and NuA4 component Tra1 regulatesCandida albicansdrug resistance and pathogenesis
Authors: Razzaq Iqra , Berg Matthew D. , Jiang Yuwei , Genereaux Julie , Uthayakumar Deeva , Kim Grace H. , Brandl Christopher J. , Lajoie Patrick , Shapiro Rebecca S. 
Published: March 2021

AbstractCandida albicansis the most common cause of death from fungal infections. Emergence of resistant strains reducing the efficacy of first line therapy with echinocandins such as caspofungin calls for the identification of alternative therapeutic strategies. Tra1 is an essential component of the SAGA and NuA4 transcriptional co-activator complexes. As a PIKK family member, Tra1 is characterized by a C-terminal phosphoinositide 3-kinase domain. InSaccharomyces cerevisiae,the assembly and function of SAGA and NuA4 is compromised by a version of Tra1 (Tra1Q3) with three arginine residues in the putative ATP-binding cleft changed to glutamine, Whole transcriptome analysis of theS. cerevisiae tra1Q3strain highlights Tra1’s role in global transcription, stress response and cell wall integrity. As a result,tra1Q3increases susceptibility to multiple stressors, including caspofungin. Moreover, the sametra1Q3allele in the pathogenic yeastCandida albicanscauses similar phenotypes, suggesting that Tra1 broadly mediates the antifungal response across yeast species. Transcriptional profiling inC. albicansidentified 68 genes that were differentially expressed when thetra1Q3strain was treated with caspofungin, as compared to gene expression changes induced by eithertra1Q3or caspofungin alone. Included in this set were genes involved in cell wall maintenance, adhesion and filamentous growth. Indeed, thetra1Q3allele reduces filamentation and other pathogenesis traits inC. albicans. We identifiedEVP1, which encodes a putative plasma membrane protein, amongst the Tra1-regulated genes, DisruptingEVP1results in reduced filamentation and infection capacity inC. albicans. Thus,Tra1 emerges as a promising therapeutic target for fungal infections.ImportanceFungal pathogens such asCandida albicansare important agents of infectious disease, with increasing rates of drug resistance, and limited available antifungal therapeutics. In this study, we characterize the role ofC. albicansTra1, a critical component of acetyltransferase complexes, involved in transcriptional regulation and responses to environmental stress. We findC. albicansgenetic mutants with impaired Tra1 function have reduced tolerance to cell-wall targeting stressors, including the clinically-important antifungal caspofungin. We further use RNA-sequencing to profile the global fungal response to thetra1mutation, and identify a previously uncharacterizedC. albicansgene,EVP1. We find that bothTRA1andEVP1play an important role in phenotypes associated with fungal pathogenesis, including cellular morphogenesis, biofilm formation, and toxicity towards host immune cells. Together, this work describes the key role for Tra1 in regulating fungal drug tolerance and pathogenesis, and positions this protein as a promising therapeutic target for fungal infections.
Potential Role of Red Palm Oil Supplemented Diet on Oxidative Stress Enzymes inPlasmodium BergheiInduced Malaria
Authors: Adeleke Temitope Daniel , Adejumobi Olawale Abiodun , Akinola Franklin Folasele , Salau Oluwatosin Abidemi , Uthman-Izobo Oyeronke Suebat 
Published: March 2021

AbstractBackgroundMalaria parasites are very vulnerable to oxidative stress during the part of their life cycle when they inhabit the erythrocytes. Studies have shown that dietary intake of antioxidant plays a role in stabilizing oxidative stress.MethodsThe objective of this research work was to examine the antioxidative effect of red palm oil onPlasmodium bergheimalaria induced oxidative stress. Sixty (60) mice were distributed into five groups. Group A served as the negative control (healthy mice with normal feed); group B as positive control (healthy mice fed with red palm oil without malaria parasite.while the other groups (C to E) served as the test groups. Group C served as group of healthy mice fed with red palm oil (pelletized), infected with malaria parasite without antimalaria drug. Group D served as group of healthy mice fed with red palm oil (pelletized), infected with malaria parasite and treated with amodiaquine. Group E served as group of healthy mice fed with normal feed, infected with malaria parasite and treated with amodiaquine. The parasitemia levels were estimated on days 1,4 and 5. The activity of oxidative stress enzymes biomarkers were determined spectrophotometrically.ResultGroup A showed a statistically significant increase in the activity of SOD (1.90 ± 0.16 units/mg protein), GST (1.68 ± 0.086 units/L) compared to group C, SOD (3.54 ± 0.83 units/mg protein), GST (2.12 ± 0.20 units/L). Group B showed a statistical significant decrease in the activities of SOD (3.22 ± 0.33 units/mg protein), Catalase (49.11 ± 2.35 µmol/min), GSH-R (31.50 ± 2.48 units/L) compared to group E, SOD (2.18 ± 0.39 units/mg protein), Catalase (44.07 ± 3.88 µmol/min), GSH-R (27.75 ± 1.64 units/L).ConclusionThe dietary intake of red palm oil helps to reduce free radical mediated injury to the tissue thus preventing oxidative stress induced by malaria or any other factors.
Comparative genomics reveals evolutionary drivers of sessile life and left-right shell asymmetry in bivalves
Authors: Zhang Yang , Mao Fan , Xiao Shu , Yu Haiyan , Xiang Zhiming , Xu Fei , Li Jun , Wang Lili , Xiong Yuanyan , Chen Mengqiu , Bao Yongbo , Deng Yuewen , Huo Quan , Zhang Lvping , Liu Wenguang , Li Xuming , Ma Haitao , Zhang Yuehuan , Mu Xiyu , Liu Min , Zheng Hongkun , Wong Nai-Kei , Yu Ziniu 
Published: March 2021

AbstractBivalves are species-rich mollusks with prominent protective roles in coastal ecosystems. Across these ancient lineages, colony-founding larvae anchor themselves either by byssus production or by cemented attachment. The latter mode of sessile life is strongly molded by left-right shell asymmetry during larval development ofOstreoidaoysters such asCrassostrea hongkongensis. Here, we sequenced the genome ofC. hongkongensisin high resolution and compared it to reference bivalve genomes to unveil genomic determinants driving cemented attachment and shell asymmetry. Importantly, loss of the homeobox geneantennapedia(Antp) and broad expansion of lineage-specific extracellular gene families are implicated in a shift from byssal to cemented attachment in bivalves. Evidence from comparative transcriptomics shows that the left-right asymmetricalC. hongkongensisplausibly diverged from the symmetricalPinctada fucatain expression profiles marked by elevated activities of orthologous transcription factors and lineage-specific shell-related gene families includingtyrosinases, which may cooperatively govern asymmetrical shell formation inOstreoidaoysters.
PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer
Authors: Talwelkar Sarang S. , Mäyränpää Mikko I. , Schüler Julia , Linnavirta Nora , Hemmes Annabrita , Adinolfi Simone , Kankainen Matti , Sommergruber Wolfgang , Levonen Anna-Liisa , Räsänen Jari , Knuuttila Aija , Verschuren Emmy W. , Wennerberg Krister 
Published: March 2021

ABSTRACTFor non-small cell lung cancer (NSCLC) patients withALK-rearranged tumors, treatment with ALK inhibitors can improve outcomes. However, clinical resistance typically develops over time, and in the majority of cases resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of anALK-rearranged clinical tumor specimen, and deployed functional drug screens to identify modulators of resistance to ALK inhibitors. This identified a role for PI3Kβ and EGFR in regulating resistance to ALK inhibition. Furthermore, inhibition of ALK elicited activation of EGFR, and inhibition of PI3Kβ rescued EGFR-mediated ALK inhibitor resistance. InALK-rearranged primary cultures, cell lines andin vivoxenograft models, combined inhibition of ALK and PI3Kβ prevented compensatory MAPK and PI3K-AKT pathway reactivation and selectively targeted the cancer cells. The combinatorial effect was seen even in the background ofTP53mutations and in epithelial-mesenchymal transformed cells. In conclusion, combinatorial ALK and PI3Kβ inhibitor treatment carries promise as a treatment forALK-rearranged NSCLC.
Combined epigenetic and metabolic inhibition blocks platinum-induced ovarian cancer stem cell enrichment
Authors: Sood Riddhi , Sriramkumar Shruthi , Muralikrishnan Vaishnavi , Xiao Sikai , Wang Weini , Hassel Christiane , Nephew Kenneth P. , O’Hagan Heather M. 
Published: March 2021

ABSTRACTHigh grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer. Platinum resistance is a common occurrence in HGSOC and a main cause of tumor relapse resulting in high patient mortality rates. Recurrent OC is enriched in aldehyde dehydrogenase (ALDH)+ ovarian cancer stem cells (OCSCs), which are resistant to platinum agents. We demonstrated that acute platinum treatment induced a DNA damage-dependent decrease in BRCA1 levels. In a parallel response associated with G2/M arrest, platinum treatment also induced an increase in expression ofNAMPT, the rate limiting regulator of NAD+production from the salvage pathway, and levels of NAD+, the cofactor required for ALDH activity. Concurrent inhibition of DNA methyltransferases (DNMTs) and NAMPT synergistically abrogated the platinum-induced increase in OCSCs. Combining pharmacological inhibitors of DNMT and NAMPT with carboplatin reduced tumorigenesis and OCSC percentagein vivo. We conclude that both epigenetic and metabolic alterations lead to platinum induced OCSC enrichment, providing preclinical evidence that in the neoadjuvant setting, combining DNMT and NAMPT inhibitors with platinum has the potential to reduce OC recurrence and avert the development of platinum resistance.
Cross-platform proteomics to advance genetic prioritisation strategies
Authors: Pietzner Maik , Wheeler Eleanor , Carrasco-Zanini Julia , Kerrison Nicola D. , Oerton Erin , Koprulu Mine , Luan Jian’an , Hingorani Aroon D. , Williams Steve A. , Wareham Nicholas J. , Langenberg Claudia 
Published: March 2021

ABSTRACTDiscovery of protein quantitative trait loci (pQTLs) has been enabled by affinity-based proteomic techniques and is increasingly used to guide genetically informed drug target evaluation. Large-scale proteomic data are now being created, but systematic, bidirectional assessment of platform differences is lacking, restricting clinical translation. We compared genetic, technical, and phenotypic determinants of 871 protein targets measured using both aptamer-(SomaScan® Platform v4) and antibody-based (Olink) assays in up to 10,708 individuals. Correlations coefficients for overlapping protein targets varied widely (median 0.38, IQR: 0.08-0.64). We found that 64% of pQTLs were shared across both platforms among all identified 608cis- and 1,315trans-pQTLs with sufficient power for replication, but with correlations of effect estimates being lower than previously reported (cis: 0.41,trans: 0.34). We identified technical, protein, and variant characteristics that contributed significantly to platform differences and found contradicting phenotypic associations attributable to those. We demonstrate how integrating phenomic and gene expression data improves genetic prioritisation strategies, including platform-specific pQTLs.