bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4
Authors: Fan Yao , Zha Rongrong , Sano Tomohiko , Zhao Xinyu , Liu Shengzhi , Woollam Mark D. , Wu Di , Sun Xun , Li Kexin , Egi Motoki , Li Fangjia , Minami Kazumasa , Siegel Amanda P. , Horiuchi Takashi , Liu Jing , Agarwal Mangilal , Sudo Akihiro , Nakshatri Harikrishna , Li Bai-Yan , Yokota Hiroki 
Published: May 2021

AbstractMechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.
Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication
Authors: Tu Wen Juan , McCuaig Robert D. , Melino Michelle , Rawle Daniel J. , Le Thuy T. , Yan Kexin , Suhrbier Andreas , Johnston Rebecca L. , Koufariotis Lambros T. , Waddell Nicola , Cross Emily M. , Tsimbalyuk Sofiya , Bain Amanda , Ahern Elizabeth , Collinson Natasha , Phipps Simon , Forwood Jade K. , Seddiki Nabila , Rao Sudha 
Published: May 2021

AbstractTreatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus–ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus–ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.
CRISPECTOR provides accurate estimation of genome editing translocation and off-target activity from comparative NGS data
Authors: Amit Ido , Iancu Ortal , Levy-Jurgenson Alona , Kurgan Gavin , McNeill Matthew S. , Rettig Garrett R. , Allen Daniel , Breier Dor , Ben Haim Nimrod , Wang Yu , Anavy Leon , Hendel Ayal , Yakhini Zohar 
Published: May 2021

AbstractControlling off-target editing activity is one of the central challenges in making CRISPR technology accurate and applicable in medical practice. Current algorithms for analyzing off-target activity do not provide statistical quantification, are not sufficiently sensitive in separating signal from noise in experiments with low editing rates, and do not address the detection of translocations. Here we present CRISPECTOR, a software tool that supports the detection and quantification of on- and off-target genome-editing activity from NGS data using paired treatment/control CRISPR experiments. In particular, CRISPECTOR facilitates the statistical analysis of NGS data from multiplex-PCR comparative experiments to detect and quantify adverse translocation events. We validate the observed results and show independent evidence of the occurrence of translocations in human cell lines, after genome editing. Our methodology is based on a statistical model comparison approach leading to better false-negative rates in sites with weak yet significant off-target activity.
Offspring survival changes over generations of captive breeding
Authors: Farquharson Katherine A. , Hogg Carolyn J. , Grueber Catherine E. 
Published: May 2021

AbstractConservation breeding programs such as zoos play a major role in preventing extinction, but their sustainability may be impeded by neutral and adaptive population genetic change. These changes are difficult to detect for a single species or context, and impact global conservation efforts. We analyse pedigree data from 15 vertebrate species – over 30,000 individuals – to examine offspring survival over generations of captive breeding. Even accounting for inbreeding, we find that the impacts of increasing generations in captivity are highly variable across species, with some showing substantial increases or decreases in offspring survival over generations. We find further differences between dam and sire effects in first- versus multi-generational analysis. Crucially, our multispecies analysis reveals that responses to captivity could not be predicted from species’ evolutionary (phylogenetic) relationships. Even under best-practice captive management, generational fitness changes that cannot be explained by known processes (such as inbreeding depression), are occurring.
Immunotranscriptomic profiling the acute and clearance phases of a human challenge dengue virus serotype 2 infection model
Authors: Hanley John P. , Tu Huy A. , Dragon Julie A. , Dickson Dorothy M. , Rio-Guerra Roxana del , Tighe Scott W. , Eckstrom Korin M. , Selig Nicholas , Scarpino Samuel V. , Whitehead Stephen S. , Durbin Anna P. , Pierce Kristen K. , Kirkpatrick Beth D. , Rizzo Donna M. , Frietze Seth , Diehl Sean A. 
Published: May 2021

AbstractAbout 20–25% of dengue virus (DENV) infections become symptomatic ranging from self-limiting fever to shock. Immune gene expression changes during progression to severe dengue have been documented in hospitalized patients; however, baseline or kinetic information is difficult to standardize in natural infection. Here we profile the host immunotranscriptome response in humans before, during, and after infection with a partially attenuated rDEN2Δ30 challenge virus (ClinicalTrials.gov NCT02021968). Inflammatory genes including type I interferon and viral restriction pathways are induced during DENV2 viremia and return to baseline after viral clearance, while others including myeloid, migratory, humoral, and growth factor immune regulation factors pathways are found at non-baseline levels post-viremia. Furthermore, pre-infection baseline gene expression is useful to predict rDEN2Δ30-induced immune responses and the development of rash. Our results suggest a distinct immunological profile for mild rDEN2Δ30 infection and offer new potential biomarkers for characterizing primary DENV infection.
High-efficiency CO2 separation using hybrid LDH-polymer membranes
Authors: Xu Xiaozhi , Wang Jiajie , Zhou Awu , Dong Siyuan , Shi Kaiqiang , Li Biao , Han Jingbin , O’Hare Dermot 
Published: May 2021

AbstractMembrane-based gas separation exhibits many advantages over other conventional techniques; however, the construction of membranes with simultaneous high selectivity and permeability remains a major challenge. Herein, (LDH/FAS)n-PDMS hybrid membranes, containing two-dimensional sub-nanometre channels were fabricated via self-assembly of unilamellar layered double hydroxide (LDH) nanosheets and formamidine sulfinic acid (FAS), followed by spray-coating with a poly(dimethylsiloxane) (PDMS) layer. A CO2transmission rate for (LDH/FAS)25-PDMS of 7748 GPU together with CO2selectivity factors (SF) for SF(CO2/H2), SF(CO2/N2) and SF(CO2/CH4) mixtures as high as 43, 86 and 62 respectively are observed. The CO2permselectivity outperforms most reported systems and is higher than the Robeson or Freeman upper bound limits. These (LDH/FAS)n-PDMS membranes are both thermally and mechanically robust maintaining their highly selective CO2separation performance during long-term operational testing. We believe this highly-efficient CO2separation performance is based on the synergy of enhanced solubility, diffusivity and chemical affinity for CO2in the sub-nanometre channels.
Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development
Authors: Morandell Jasmin , Schwarz Lena A. , Basilico Bernadette , Tasciyan Saren , Dimchev Georgi , Nicolas Armel , Sommer Christoph , Kreuzinger Caroline , Dotter Christoph P. , Knaus Lisa S. , Dobler Zoe , Cacci Emanuele , Schur Florian K. M. , Danzl Johann G. , Novarino Gaia 
Published: May 2021

AbstractDe novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). In mouse, constitutive Cul3 haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs.
Nutrient content and stoichiometry of pelagic Sargassum reflects increasing nitrogen availability in the Atlantic Basin
Authors: Lapointe B. E. , Brewton R. A. , Herren L. W. , Wang M. , Hu C. , McGillicuddy D. J. , Lindell S. , Hernandez F. J. , Morton P. L. 
Published: May 2021

AbstractThe pelagic brown macroalgaeSargassumspp. have grown for centuries in oligotrophic waters of the North Atlantic Ocean supported by natural nutrient sources, such as excretions from associated fishes and invertebrates, upwelling, and N2fixation. Using a unique historical baseline, we show that since the 1980s the tissue %N ofSargassumspp. has increased by 35%, while %P has decreased by 44%, resulting in a 111% increase in the N:P ratio (13:1 to 28:1) and increased P limitation. The highest %N and δ15N values occurred in coastal waters influenced by N-rich terrestrial runoff, while lower C:N and C:P ratios occurred in winter and spring during peak river discharges. These findings suggest that increased N availability is supporting blooms ofSargassumand turning a critical nursery habitat into harmful algal blooms with catastrophic impacts on coastal ecosystems, economies, and human health.
The role of drop shape in impact and splash
Authors: Liu Qingzhe , Lo Jack Hau Yung , Li Ye , Liu Yuan , Zhao Jinyu , Xu Lei 
Published: May 2021

AbstractThe impact and splash of liquid drops on solid substrates are ubiquitous in many important fields. However, previous studies have mainly focused on spherical drops while the non-spherical situations, such as raindrops, charged drops, oscillating drops, and drops affected by electromagnetic field, remain largely unexplored. Using ferrofluid, we realize various drop shapes and illustrate the fundamental role of shape in impact and splash. Experiments show that different drop shapes produce large variations in spreading dynamics, splash onset, and splash amount. However, underlying all these variations we discover universal mechanisms across various drop shapes: the impact dynamics is governed by the superellipse model, the splash onset is triggered by the Kelvin-Helmholtz instability, and the amount of splash is determined by the energy dissipation before liquid taking off. Our study generalizes the drop impact research beyond the spherical geometry, and reveals the potential of using drop shape to control impact and splash.
Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer
Authors: Nath Aritro , Cosgrove Patrick A. , Mirsafian Hoda , Christie Elizabeth L. , Pflieger Lance , Copeland Benjamin , Majumdar Sumana , Cristea Mihaela C. , Han Ernest S. , Lee Stephen J. , Wang Edward W. , Fereday Sian , Traficante Nadia , Salgia Ravi , Werner Theresa , Cohen Adam L. , Moos Philip , Chang Jeffrey T. , Bowtell David D. L. , Bild Andrea H. 
Published: May 2021

AbstractThe evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To understand the selection of factors driving heterogeneity before and through adaptation to treatment, we profile single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during therapy. We analyze scRNA-seq data from two independent patient cohorts to reveal that HGSOC is driven by three archetypal phenotypes, defined as oncogenic states that describe the majority of the transcriptome variation. Using a multi-task learning approach to identify the biological tasks of each archetype, we identify metabolism and proliferation, cellular defense response, and DNA repair signaling as consistent cell states found across patients. Our analysis demonstrates a shift in favor of the metabolism and proliferation archetype versus cellular defense response archetype in cancer cells that received multiple lines of treatment. While archetypes are not consistently associated with specific whole-genome driver mutations, they are closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism and proliferation archetype as resistance is acquired to multiple lines of therapy.
Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility
Authors: Dhara S. , Chhangawala S. , Chintalapudi H. , Askan G. , Aveson V. , Massa A. L. , Zhang L. , Torres D. , Makohon-Moore A. P. , Lecomte N. , Melchor J. P. , Bermeo J. , Cardenas A. , Sinha S. , Glassman D. , Nicolle R. , Moffitt R. , Yu K. H. , Leppanen S. , Laderman S. , Curry B. , Gui J. , Balachandran V. P. , Iacobuzio-Donahue C. , Chandwani R. , Leslie C. S. , Leach S. D. 
Published: May 2021

AbstractUnlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed “ATAC-array”, an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.
Clump sequencing exposes the spatial expression programs of intestinal secretory cells
Authors: Manco Rita , Averbukh Inna , Porat Ziv , Bahar Halpern Keren , Amit Ido , Itzkovitz Shalev 
Published: May 2021

AbstractSingle-cell RNA sequencing combined with spatial information on landmark genes enables reconstruction of spatially-resolved tissue cell atlases. However, such approaches are challenging for rare cell types, since their mRNA contents are diluted in the spatial transcriptomics bulk measurements used for landmark gene detection. In the small intestine, enterocytes, the most common cell type, exhibit zonated expression programs along the crypt-villus axis, but zonation patterns of rare cell types such as goblet and tuft cells remain uncharacterized. Here, we present ClumpSeq, an approach for sequencing small clumps of attached cells. By inferring the crypt-villus location of each clump from enterocyte landmark genes, we establish spatial atlases for all epithelial cell types in the small intestine. We identify elevated expression of immune-modulatory genes in villus tip goblet and tuft cells and heterogeneous migration patterns of enteroendocrine cells. ClumpSeq can be applied for reconstructing spatial atlases of rare cell types in other tissues and tumors.
Identification of microbial markers across populations in early detection of colorectal cancer
Authors: Wu Yuanqi , Jiao Na , Zhu Ruixin , Zhang Yida , Wu Dingfeng , Wang An-Jun , Fang Sa , Tao Liwen , Li Yichen , Cheng Sijing , He Xiaosheng , Lan Ping , Tian Chuan , Liu Ning-Ning , Zhu Lixin 
Published: May 2021

AbstractAssociations between gut microbiota and colorectal cancer (CRC) have been widely investigated. However, the replicable markers for early-stage adenoma diagnosis across multiple populations remain elusive. Here, we perform an integrated analysis on 1056 public fecal samples, to identify adenoma-associated microbial markers for early detection of CRC. After adjusting for potential confounders, Random Forest classifiers are constructed with 11 markers to discriminate adenoma from control (area under the ROC curve (AUC) = 0.80), and 26 markers to discriminate adenoma from CRC (AUC = 0.89), respectively. Moreover, we validate the classifiers in two independent cohorts achieving AUCs of 0.78 and 0.84, respectively. Functional analysis reveals that the altered microbiome is characterized with increased ADP-l-glycero-beta-d-manno-heptose biosynthesis in adenoma and elevated menaquinone-10 biosynthesis in CRC. These findings are validated in a newly-collected cohort of 43 samples using quantitative real-time PCR. This work proves the validity of adenoma-specific markers across multi-populations, which would contribute to the early diagnosis and treatment of CRC.
PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling
Authors: Ma Ning , Wang Yi-Kang , Xu Sheng , Ni Qian-Zhi , Zheng Qian-Wen , Zhu Bing , Cao Hui-Jun , Jiang Hao , Zhang Feng-Kun , Yuan Yan-Mei , Zhang Er-Bin , Chen Tian-Wei , Xia Ji , Ding Xu-Fen , Chen Zhen-Hua , Zhang Xiu-Ping , Wang Kang , Cheng Shu-Qun , Qiu Lin , Li Zhi-Gang , Yu Yong-Chun , Wang Xiao-Fan , Zhou Bin , Li Jing-Jing , Xie Dong 
Published: May 2021

AbstractNon-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, however, no drug treatment has been approved for this disease. Thus, it is urgent to find effective therapeutic targets for clinical intervention. In this study, we find that liver-specific knockout of PPDPF (PPDPF-LKO) leads to spontaneous fatty liver formation in a mouse model at 32 weeks of age on chow diets, which is enhanced by HFD. Mechanistic study reveals that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interferes with the interaction between Raptor and CUL4B-DDB1, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibits HFD-induced mTOR signaling activation and hepatic steatosis in mice. These results suggest that PPDPF is a regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD.
Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase
Authors: Hayes Robert P. , Heo Mee Ra , Mason Mark , Reid John , Burlein Christine , Armacost Kira A. , Tellers David M. , Raheem Izzat , Shaw Anthony W. , Murray Edward , McKenna Philip M. , Abeywickrema Pravien , Sharma Sujata , Soisson Stephen M. , Klein Daniel 
Published: May 2021

AbstractAll herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies include nucleoside and non-nucleoside inhibitors (NNI) that target the DNA-bound state of herpesvirus polymerase and block replication. Here we report the ternary complex crystal structure of Herpes Simplex Virus 1 DNA polymerase bound to DNA and a 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 Å resolution. PNU bound at the polymerase active site, displacing the template strand and inducing a conformational shift of the fingers domain into an open state. These results demonstrate that PNU inhibits replication by blocking association of dNTP and stalling the enzyme in a catalytically incompetent conformation, ultimately acting as a nucleotide competing inhibitor (NCI). Sequence conservation of the NCI binding pocket further explains broad-spectrum activity while a direct interaction between PNU and residue V823 rationalizes why mutations at this position result in loss of inhibition.
Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives
Authors: Amporndanai Kangsa , Meng Xiaoli , Shang Weijuan , Jin Zhenmig , Rogers Michael , Zhao Yao , Rao Zihe , Liu Zhi-Jie , Yang Haitao , Zhang Leike , O’Neill Paul M. , Samar Hasnain S. 
Published: May 2021

AbstractThe SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of Mpro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses.