bluuebunny/crossref_metadata_2025_split huggingface dataset:
A DNA nanoscope that identifies and precisely localizes over a hundred unique molecular features with nanometer accuracy
Authors: Gopalkrishnan Nikhil , Punthambaker Sukanya , Schaus Thomas E. , Church George M. , Yin Peng 
Published: August 2020

AbstractTechniques that can both spatially map out molecular features and discriminate many targets would be highly valued for their utility in studying fundamental nanoscale processes. In spite of decades of development, no current technique can achieve both nanoscale resolution and discriminate hundreds of targets. Here, we report the development of a novel bottom-up technology that: (a) labels a sample with DNA barcodes, (b) measures pairwise-distances between labeled sites and writes them into DNA molecules, (c) reads the pairwise-distances by sequencing and (d) robustly integrates this noisy information to reveal the geometry of the underlying sample. We demonstrate our technology on DNA origami, which are complex synthetic nanostructures. We both spatially localized and uniquely identified over a hundred densely packed unique elements, some spaced just 6 nm apart, with an average spatial localization accuracy (RMS deviation) of ~2 nm. The bottom-up, sequencing-enabled mechanism of the DNA nanoscope is fundamentally different from top-down imaging, and hence offers unique advantages in precision, throughput and accessibility.
BNIP3 phosphorylation by JNK1/2 promotes mitophagy via enhancing its stability under hypoxia
Authors: He Yun-Ling , Gong Sheng-Hui , Cheng Xiang , Zhao Ming , Zhao Tong , Zhao Yong-Qi , Fan Ming , Zhu Ling-Ling , Wu Li-Ying 
Published: August 2020

AbstractMitophagy is an important metabolic mechanism that modulates mitochondrial quality and quantity by selectively removing damaged or unwanted mitochondria. BNIP3, a mitochondrial outer membrane protein, is a mitophagy receptor that mediates mitophagy under various stresses, particularly hypoxia, since BNIP3 is a hypoxia-responsive protein. However, the underlying mechanisms that regulate BNIP3 and thus mediate mitophagy under hypoxic conditions remain elusive. Here, we demonstrate that in hypoxia JNK1/2 phosphorylates BNIP3 at Ser 60/Thr 66, which hampers proteasomal degradation of BNIP3 and drives mitophagy by facilitating the direct binding of BNIP3 to LC3, while PP1/2A represses mitophagy by dephosphorylating BNIP3 and triggering its proteasomal degradation. These findings reveal the intrinsic mechanisms cells use to regulate mitophagy via the JNK1/2-BNIP3 pathway in response to hypoxia. Thus, the JNK1/2-BNIP3 signaling pathway strongly links mitophagy to hypoxia and may be a promising therapeutic target for hypoxia-related diseases.
A subset of pediatric thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration ofEGFR
Authors: Sievers Philipp , Sill Martin , Schrimpf Daniel , Stichel Damian , Reuss David E. , Sturm Dominik , Hench Jürgen , Frank Stephan , Krskova Lenka , Vicha Ales , Zapotocky Michal , Bison Brigitte , Harter Patrick N. , Snuderl Matija , Kramm Christof M. , Reifenberger Guido , Korshunov Andrey , Jabado Nada , Wesseling Pieter , Wick Wolfgang , Solomon David A. , Perry Arie , Jacques Thomas S. , Jones Chris , Witt Olaf , Pfister Stefan M. , von Deimling Andreas , Jones David T. W. , Sahm Felix 
Published: August 2020

AbstractBackgroundMalignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in theEGFRgene have recently been identified in a distinct subset of pediatric bithalamic gliomas with a unique DNA methylation pattern.MethodsHere, we investigated an epigenetically homogeneous cohort of malignant gliomas (n=58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in order to elucidate the overlap with this recently identified subtype of pediatric bithalamic gliomas.ResultsEGFRgene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions inEGFRwere found in 20/30 tumors with available sequencing data (67%; five of them co-occurring withEGFRamplification). Additionally, eight of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (six of them with a concomitantEGFRalteration). All tumors tested showed loss of H3K27me3 staining, with evidence ofEZHIPoverexpression in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations.ConclusionsOur findings present a distinct molecular class of pediatric malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized byEGFRalteration, but additionally showing a broader spectrum ofEGFRalterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation orEZHIPoverexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.Key pointsThis study confirms a distinct new subset of pediatric diffuse midline glioma with H3K27me3 loss, with or without H3 K27 mutationThe poor outcome of these tumors is in line with the broader family of pediatric diffuse midline gliomas with H3 K27 mutation orEZHIPoverexpressionFrequentEGFRalterations in these tumors may represent a therapeutic target in this subsetImportance of the StudyMalignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Here, we highlight a distinct molecular class of pediatric malignant gliomas characterized byEGFRalteration and global H3K27me3 loss that appears to be mediated by either H3 K27 mutation orEZHIPoverexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.
Microbiota Accelerates Age-Related CpG Island Methylation in Colonic Mucosa
Authors: Sun Ang , Cole Lauren , Maegawa Shinji , Park Pyoung Hwa , Keith Kelsey , Madzo Jozef , Jelinek Jaroslav , Jobin Christian , Issa Jean-Pierre J. 
Published: August 2020

AbstractDNA methylation is an epigenetic mark that is altered in cancer and aging tissues. The effects of extrinsic factors on DNA methylation remain incompletely understood. Microbial dysbiosis is a hallmark of colorectal cancer, and infections have been linked to aberrant DNA methylation in cancers of the GI tract. To determine the microbiota’s impact on DNA methylation, we studied the methylomes of colorectal mucosa in germ-free (no microbiota) and specific-pathogen-free (controlled microbiota) mice, as well as in Il-10 KO mice (Il10−/−) which are prone to inflammation and tumorigenesis in the presence of microbiota. The presence of microbiota was associated with changes in 5% of the methylome andIl10−/−mice showed alterations in 4.1% of the methylome. These changes were slightly more often hypo than hypermethylation and affected preferentially CpG sites located in gene bodies and intergenic regions. Mice with both Il-10 KO and microbiota showed much more pronounced alterations, affecting 18% of the methylome. When looking specifically at CpG island methylation alterations, a hallmark of aging and cancer, 0.4% were changed by the microbiota, 0.4% were changed byIl10−/−, while 4% were changed by both simultaneously. These effects are comparable to what is typically seen when comparing colon cancer to normal. We next compared these methylation changes to those seen in aging, and after exposure to the colon carcinogen Azoxymethane (AOM). Aging was associated with alterations in 18% of the methylome, and aging changes were accelerated in theIl10−/−/SPF mice. By contrast, AOM induced profound hypomethylation that was distinct from the effects of aging or of the microbiota. CpG sites modified by the microbiota were over-represented among DNA methylation changes in colorectal cancer. Thus, the microbiota affects the DNA methylome of colorectal mucosa in patterns reminiscent of what is observed in aging and in colorectal cancer.
Nanoencapsulation of clove oil and study of physico-chemical properties, cytotoxic, haemolytic and antioxidant activities
Authors: Nagaraju Pramod G , Sengupta Parineeta , Poornima Priyadarshini C. G. , Rao Pooja J 
Published: August 2020

AbstractThe therapeutic properties of clove oil is known for centuries, however, the pungent nature, chemical instability and low water solubility impose limitations in harnessing its therapeutic potential. Hence, nanoencapsulation of clove oil was performed to overcome the above constraints and control its in-vitro release. The stability of nanoemulsion depends on various factors where the surfactant and its hydrophile/lipofile balance (HLB) play a key role. The non-ionic surfactants Tween 20, 40 and 80 with HLB of 16.7, 15.6 and 15, respectively, were used to study the stability of clove oil nanoemulsion (CON). The creaming index of CON prepared with Tween 20, 40 and 80 was 22.75 and 17.5 and 1.5%, respectively, after 8 days of storage at room temperature. Tween 20 and 40 produced particles > 300 nm while Tween 80 resulted in particles of size ∼150 nm. Transmission electron microscopic image of spray dried CON prepared with Tween 80 showed particle size in the range 150-190 nm after one month of storage at room temperature. The in vitro release studies showed 76% and 42% cumulative release of CON and native clove oil (NC), respectively at pH 7.4. The cellular toxicity of CON was significantly reduced by four fold compared to NC at a concentration of 60 µg/mL when tested on Caco2 cells. Similarly, haemolytic activity on red blood cells revealed less than 10% haemolysis signifying the compatibility of CON for its nutraceutical applications. In addition, CON also exhibited higher in-vitro antioxidant compared to NC as shown by DPPH and ABTS radical scavenging activity. Collectively, we have developed a unique method for NC nanoencapsulation using cost effective polysaccharide (maltodextrin) and surfactant for stabilizing the nanoemulsion for increased bioactivity.
De NovoMutation in an Enhancer ofEBF3in simplex autism
Authors: Padhi Evin M. , Hayeck Tristan J. , Mannion Brandon , Chatterjee Sumantra , Byrska-Bishop Marta , Musunuri Rajeeva , Narzisi Giuseppe , Abhyankar Avinash , Cheng Zhang , Hunter Riana D. , Akiyama Jennifer , Fries Lauren E. , Ng Jeffrey , Stong Nick , Allen Andrew S. , Dickel Diane E. , Bernier Raphael A. , Gorkin David U. , Pennacchio Len A. , Zody Michael C. , Turner Tychele N. 
Published: August 2020

AbstractPrevious research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution ofde novoprotein-coding variants within specific genes. The role ofde novononcoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2,671 families with autism, with a specific focus onde novovariation in enhancers with previously characterizedin vivoactivity. We identified three independentde novomutations limited to individuals with autism in the enhancer hs737. These mutations result in similar phenotypic characteristics, affect enhancer activityin vitro, and preferentially occur in AAT motifs in the enhancer with predicted disruptions of transcription factor binding. We also find that hs737 is enriched for copy number variation in individuals with NDDs, is dosage sensitive in the human population, is brain-specific, and targets the NDD geneEBF3that is genome-wide significant for protein codingde novovariants, demonstrating the importance of understanding all forms of variation in the genome.One Sentence SummaryWhole-genome sequencing in thousands of families reveals variants relevant to simplex autism in a brain enhancer of the well-established neurodevelopmental disorder geneEBF3.
Comprehensive benchmarking of software for mapping whole genome bisulfite data: from read alignment to DNA methylation analysis
Authors: Nunn Adam , Otto Christian , Stadler Peter F. , Langenberger David 
Published: August 2020

AbstractWhole genome bisulfite sequencing is currently at the forefront of epigenetic analysis, facilitating the nucleotide-level resolution of 5-methylcytosine (5mC) on a genome-wide scale. Specialised software have been developed to accommodate the unique difficulties in aligning such sequencing reads to a given reference, building on the knowledge acquired from model organisms such as human, orArabidopsis thaliana. As the field of epigenetics expands its purview to non-model plant species, new challenges arise which bring into question the suitability of previously established tools.Herein, nine short-read aligners are evaluated:Bismark,BS-Seeker2,BSMAP,BWA-meth,ERNE-BS5,GEM3,GSNAP,Last, andsegemehl. Precision-recall of simulated alignments, in comparison to real sequencing data obtained from three natural accessions, reveals on-balance thatBWA-methandBSMAPare able to make the best use of the data during mapping. The influence of difficult-to-map regions, characterised by deviations in sequencing depth over repeat annotations, is evaluated in terms of the mean absolute deviation of the resulting methylation calls in comparison to a realistic methylome. Downstream methylation analysis is responsive to the handling of multi-mapping reads relative to mapping quality (MAPQ), and potentially susceptible to bias arising from the increased sequence complexity of densely-methylated reads.
Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells
Authors: Hooikaas Peter Jan , Damstra Hugo G.J. , Gros Oane J. , van Riel Wilhelmina E. , Martin Maud , Smits Yesper T.H. , van Loosdregt Jorg , Kapitein Lukas C. , Berger Florian , Akhmanova Anna 
Published: August 2020

AbstractWhen a T cell and an antigen-presenting cell form an immunological synapse, rapid dynein-driven translocation of the centrosome towards the contact site leads to reorganization of microtubules and associated organelles. Currently, little is known about how the regulation of microtubule dynamics contributes to this process. Here, we show that the knockout of KIF21B, a kinesin-4 linked to autoimmune disorders, causes microtubule overgrowth and perturbs centrosome translocation. KIF21B restricts microtubule length by inducing microtubule pausing typically followed by catastrophe. Catastrophe induction with vinblastine prevented microtubule overgrowth and was sufficient to rescue centrosome polarization in KIF21B-knockout cells. Biophysical simulations showed that a relatively small number of KIF21B molecules can restrict microtubule length and promote an imbalance of dynein-mediated pulling forces that allows the centrosome to translocate past the nucleus. We conclude that proper control of microtubule length is important for allowing rapid remodeling of the cytoskeleton and efficient T cell polarization.
Hericerin derivatives fromHericium erinaceusexert BDNF-like neurotrophic activity in central hippocampal neurons and enhance memory
Authors: Martínez-Mármol Ramón , Chai YeJin , Khan Zahra , Kim Seon Beom , Hong Seong Min , Gormal Rachel S. , Lee Dae Hee , Lee Jae Kang , Lee Mi Kyeong , Kim Sun Yeou , Meunier Frédéric A. 
Published: August 2020

AbstractThe traditional medicinal mushroomHericium erinaceushas long been known for enhancing the peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. It was also reported to protect against ageing-dependent cognitive decline in wildtype and in Alzheimer’s disease mouse models suggesting a yet to be defined action on neurons of the central nervous system. Here, we purified and identified biologically active compounds fromH. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons.N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom together with its hydrophobic derivative hericene A, were highly potent in inducing extensive axon outgrowth and neurite branching in the absence of serum demonstrating high neurotropic activity. NDPIH also induced enlarged growth cones suggestive of a brain-derived neurotrophic factor (BDNF)-like activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA12 prevented NDPIH-induced neurotrophic activity providing evidence that NDPIH actsviaTrkB receptors to mediate its neurotrophic effect in central neurons. Finally,in vivotreatment withH. erinaceuscrude extract and hericene A significantly increased BDNF and downstream pathway and enhanced learning and memory in the novel object recognition memory test. Our results suggest that hericene A can promote BDNF-like activity in neuronsin vitroandin vivothereby enhancing recognition memory.
Tropism of SARS-CoV-2 in commonly used laboratory cell lines and their proteomic landscape during infection
Authors: Saccon Elisa , Chen Xi , Mikaeloff Flora , Rodriguez Jimmy Esneider , Szekely Laszlo , Sá Vinhas Beatriz , Krishnan Shuba , Byrareddy Siddappa N. , Frisan Teresa , Végvári Ákos , Mirazimi Ali , Neogi Ujjwal , Gupta Soham 
Published: August 2020

AbstractThe present pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is driving intense research activities to understand the basic biology of the virus and determine effective therapeutic strategies. The commonly used laboratory cell lines of human origin are the first line of experimental models to study the pathogenicity and performing antiviral assays. Thus, to find suitable cell models to study SARS-CoV-2, we assessed the tropism and cytopathogenicity of the first Swedish isolate of SARS-CoV-2 in six different cell lines of human origin and compared their growth characteristics to other globally isolated strains. Overall, Calu-3, Caco2, Huh7, and 293FT cell lines showed a high to moderate level of susceptibility to the majority of virus isolates. In Caco2 cells the virus can achieve high titers in the absence of any prominent cytopathic effect. The protein expression profile during SARS-CoV-2 infection revealed cell-type-specific regulation of cellular pathways. Type-I interferon signaling was identified as the common dysregulated cellular response in Caco2, Calu-3 and Huh7 cells. Overall, cell-type specific variability was noted for cytopathogenicity, susceptibility and cellular response to SARS-CoV-2. This study provides important clues regarding SARS-CoV-2 pathogenesis and can represent as a guide for future studies to design therapeutics.
Thermodynamic and mechanistic insights into coupled binding and unwinding of collagen by matrix metalloproteinase 1
Authors: Manka Szymon W. , Brew Keith 
Published: August 2020

AbstractLocal unwinding of the collagen triple helix is a necessary step for initiating the collagen degradation cascade in extracellular matrices. A few matrix metalloproteinases (MMPs) are known to support this key process, but its energetic aspects remain unknown. Here, we captured the thermodynamics of the triple helix unwinding by monitoring interactions between a collagen peptide and MMP-1(E200A) – an active-site mutant of an archetypal vertebrate collagenase – at increasing temperatures, using isothermal titration calorimetry (ITC). Coupled binding and unwinding manifests as a curved relationship between the total enthalpy change and temperature of the reaction, producing increasingly negative heat capacity change (ΔΔCp≈ −36.3 kcal/molK2). A specially designed solid-phase binding and cleavage assay (SPBCA) reported strain in the catalytically relevant unwound state, suggesting that this state is distinct from the horizon of sampled conformations of the collagenase-susceptible site. MMP-1 appears to blend selected fit with induced fit mechanisms to catalyse collagen unwinding prior to cleavage of individual collagen chains.Graphical AbstractHighlightsThe unwinding of the collagen triple helix by matrix metalloproteinases (MMPs) is critical for collagen catabolism, but how MMPs harness bioavailable energy for this energetically expensive process is enigmaticRising temperature causes linear increases of the negative heat capacity change associated with the interaction of MMP-1 with a collagenase-susceptible triple-helical peptide, indicating enrichment of hydrophobic contacts during the triple helix unwindingThe complex of MMP-1 with locally unwound collagen holds considerable structural strain, which becomes relieved upon cleavage of the unwound collagen strand(s)MMP-1 consumes heat to drive specific (structurally distinct) collagen unwinding by increasing entropy associated with evolving hydrophobic anchor points between the enzyme and the substrateThe prototypic collagenase MMP-1 appears to blend conformational selection with induced fit, shedding light on the thermodynamic principles by which MMPs trigger collagen breakdown and supporting general mechanistic conclusions concerning conformational changes coupled to protein-protein binding
Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart
Authors: Gyuricza Isabela Gerdes , Chick Joel M. , Keele Gregory R. , Deighan Andrew G. , Munger Steven C. , Korstanje Ron , Gygi Steven P. , Churchill Gary A. 
Published: August 2020

ABSTRACTInvestigation of the molecular mechanisms of aging in the human heart is challenging due to confounding factors, such as diet and medications, as well limited access to tissues. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyzed transcriptome and proteome data from hearts of genetically diverse mice at ages 6, 12 and 18 months to characterize molecular changes that occur in the aging heart. Transcripts and proteins reveal distinct biological processes that are altered through the course of natural aging. Transcriptome analysis reveals a scenario of cardiac hypertrophy, fibrosis, and reemergence of fetal gene expression patterns. Proteome analysis reveals changes in energy metabolism and protein homeostasis. We found that for many protein complexes there is a decline in correlation between their component proteins with age, indicating age-related loss of stoichiometry. Some of the most affected complexes are themselves involved in protein homeostasis, which potentially contributes to a viscious cycle of progressive breakdown in protein quality control with age. In addition, we identified genetic loci that modulate age-related changes in a variety of cellular processes, including protein degradation and sorting, suggesting that genetic variation can alter the rate of molecular aging.
A Liquid-to-Solid Phase Transition Enhances the Catalytic Activity of SARM1
Authors: Loring Heather S. , Thompson Paul R. 
Published: August 2020

ABSTRACTSterile alpha and toll/interleukin receptor (TIR) motif–containing protein 1 (SARM1) is a neuronally expressed NAD+glycohydrolase whose activity is increased in response to various stressors. The consequent depletion of NAD+triggers axonal degeneration (i.e., Wallerian degeneration), which is a characteristic feature of neurological diseases, including peripheral neuropathies and traumatic brain injury. Notably, SARM1 knockout mice show minimal degeneration in models of peripheral neuropathy and traumatic brain injury, making SARM1 a promising therapeutic target. However, the development of SARM1 inhibitors has been challenging as the purified enzyme is largely inactive. Herein, we report that SARM1 activity is increased ∼2000–fold by a liquid-to-solid phase transition. These findings provide critical insights into SARM1 biochemistry with important implications for the situationin vivo. Moreover, they will facilitate the discovery of novel SARM1–targeted therapeutics.Graphical Abstract