bluuebunny/crossref_metadata_2025_split huggingface dataset:
Forest structure and degradation drive canopy gap sizes across the Brazilian Amazon
Authors: Rodrigues Reis Cristiano , Jackson Toby. D. , Gorgens Eric Bastos , Dalagnol Ricardo , Jucker Tommaso , Nunes Matheus Henrique , Ometto Jean Pierre , Aragão Luiz E. O. C. , Estraviz Rodriguez Luiz Carlos , Coomes David. A. 
Published: May 2021

AbstractCanopy gaps are openings in the forest canopy resulting from branch fall and tree mortality events. Light reaches the lower layers of the canopy through these gaps, enabling understory trees to grow and maintaining the high heterogeneity and biodiversity of tropical forests. The size-frequency distribution of canopy gaps follows a power-law distribution, and the slope of this power-law (α) is a key indicator of forest structure and dynamics.We detected canopy gaps using a unique LiDAR data set consisting of 650 transects randomly distributed across the Brazilian Amazon Forest providing an unprecedented perspective on forest structural variation over 2500 km2of forest. We then investigated how α varied with forest structure, elevation, soil fertility, water deficit, wind gust speed and lightning intensity.We found that human modified forests had more large gaps than intact forests. Within the intact forests we observed a large-scale Northwest to Southeast pattern in α (more large gaps in the Southeast), which aligns with recent work on tree mortality rates. The two most important variables in predicting α were median canopy height and maximum modeled height, which had opposite effects on the number of large gaps. Forests with higher median canopy height contain fewer large gaps but the presence of very tall trees was associated with more large gaps. Environmental variables were of secondary importance in our model, with larger gaps occurring in drier forests with high soil fertility, wind speed, and lightning intensity.The distribution of large gaps in the forest canopy varies substantially over the Brazilian Amazon as a result of canopy structure and mortality rates. We mapped this variation and found more large gaps in human modified forests, forests on fertile soils and those exposed to higher wind, lightning and drought stress. Increasing extreme weather events due to climate change may therefore increase the number of large gaps in currently intact forests, causing them to resemble human modified forests.
scShaper: ensemble method for fast and accurate linear trajectory inference from single-cell RNA-seq data
Authors: Smolander Johannes , Junttila Sini , Venäläinen Mikko S. , Elo Laura L. 
Published: May 2021

AbstractComputational models are needed to infer a representation of the cells, i.e. a trajectory, from single-cell RNA-sequencing data that model cell differentiation during a dynamic process. Although many trajectory inference methods exist, their performance varies greatly depending on the dataset and hence there is a need to establish more accurate, better generalizable methods. We introduce scShaper, a new trajectory inference method that enables accurate linear trajectory inference. The ensemble approach of scShaper generates a continuous smooth pseudotime based on a set of discrete pseudotimes. We demonstrate that scShaper is able to infer accurate trajectories for a variety of nonlinear mathematical trajectories, including many for which the commonly used principal curves method fails. A comprehensive benchmarking with state-of-the-art methods revealed that scShaper achieved superior accuracy of the cell ordering and, in particular, the differentially expressed genes. Moreover, scShaper is a fast method with few hyperparameters, making it a promising alternative to the principal curves method for linear pseudotemporal ordering. scShaper is available as an R package athttps://github.com/elolab/scshaper.
Caspase-mediated regulation and cellular heterogeneity of the cGAS/STING pathway in Kaposi’s sarcoma-associated herpesvirus infection
Authors: Tabtieng Tate , Lent Rachel C. , Kaku Machika , Sanchez Alvaro Monago , Gaglia Marta Maria 
Published: May 2021

AbstractAs a result of the ongoing virus-host arms race, viruses have evolved numerous immune subversion strategies, many of which are aimed at suppressing the production of type I interferons (IFNs). Apoptotic caspases have recently emerged as important regulators of type I IFN signaling in both non-infectious contexts and during viral infection. Despite being widely considered anti-viral factors since they can trigger cell death, several apoptotic caspases promote viral replication by suppressing innate immune response. Indeed, we previously discovered that the AIDS-associated oncogenic gammaherpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV) exploits caspase activity to suppress the antiviral type I IFN response and promote viral replication. However, the mechanism of this novel viral immune evasion strategy is poorly understood, particularly how caspases antagonize IFN signaling during KSHV infection. Here we show that caspase activity inhibits the DNA sensor cGAS during KSHV lytic replication to block type I IFN induction. Furthermore, we use single-cell RNA-sequencing to reveal that the potent antiviral state conferred by caspase inhibition is mediated by an exceptionally small percentage of IFN-β-producing cells, thus uncovering further complexity of IFN regulation during viral infection. Collectively, these results provide insight into multiple levels of cellular type I IFN regulation that viruses co-opt for immune evasion. Unraveling these mechanisms can inform targeted therapeutic strategies for viral infections and reveal cellular mechanisms of regulating interferon signaling in the context of cancer and chronic inflammatory diseases.ImportanceType I interferons are key factors that dictate the outcome of infectious and inflammatory diseases. Thus, intricate cellular regulatory mechanisms are in place to control IFN responses. While viruses encode their own immune-regulatory proteins, they can also usurp existing cellular interferon regulatory functions. We found that caspase activity during lytic infection with the AIDS-associated oncogenic gammaherpesvirus Kaposi’s sarcoma-associated herpesvirus inhibits the DNA sensor cGAS to block the antiviral type I IFN response. Moreover, single-cell RNA-sequencing analyses unexpectedly revealed that an exceptionally small subset of infected cells (<5%) produce IFN, yet this is sufficient to confer a potent antiviral state. These findings reveal new aspects of type I IFN regulation and highlight caspases as a druggable target to modulate cGAS activity.
A multimodal study of a first episode psychosis cohort: potential markers of antipsychotic treatment resistance
Authors: Yang Kun , Longo Luisa , Narita Zui , Cascella Nicola , Nucifora Frederick C. , Coughlin Jennifer M. , Nestadt Gerald , Sedlak Thomas W. , Mihaljevic Marina , Wang Min , Kenkare Anshel , Nagpal Anisha , Sethi Mehk , Kelly Alexandra , Di Carlo Pasquale , Kamath Vidyulata , Faria Andreia , Barker Peter , Sawa Akira 
Published: May 2021

AbstractTreatment resistant (TR) psychosis is considered to be a significant cause of disability and functional impairment. Numerous efforts have been made to identify the clinical predictors of TR. However, the exploration of molecular and biological markers is still at an early stage. To understand the TR condition and identify potential molecular and biological markers, we analyzed demographic information, clinical data, structural brain imaging data, and molecular brain imaging data in 7 Tesla magnetic resonance spectroscopy, from a first episode psychosis cohort that includes 138 patients. Age, gender, race, smoking status, duration of illness, and antipsychotic dosages were controlled in the analyses. We found that TR patients had a younger age at onset, more hospitalizations, more severe negative symptoms, a significant reduction in the volumes of the hippocampus (HP) and superior frontal gyrus (SFG), and a significant reduction in glutathione (GSH) levels in the anterior cingulate cortex (ACC), when compared to non-TR patients. The combination of multiple markers provided a better classification between TR and non-TR patients compared to any individual marker. Our study shows that ACC GSH, HP and SFG volumes, and age at onset could potentially be trait biomarkers for TR diagnosis, while hospitalization and negative symptoms could be used to evaluate the progression of the disease. Multimodal cohorts are essential in obtaining a comprehensive understanding of brain disorders.
Mitochondrial mutations inCaenorhabditis elegansshow signatures of oxidative damage and an AT-bias
Authors: Waneka Gus , Svendsen Joshua M. , Havird Justin C. , Sloan Daniel B. 
Published: May 2021

ABSTRACTRapid mutation rates are typical of mitochondrial genomes (mtDNAs) in animals, but it is not clear why. The difficulty of obtaining measurements of mtDNA mutation that are not biased by natural selection has stymied efforts to distinguish between competing hypotheses about the causes of high mtDNA mutation rates. Several studies which have measured mtDNA mutations in nematodes have yielded small datasets with conflicting conclusions about the relative abundance of different substitution classes (i.e. the mutation spectrum). We therefore leveraged Duplex Sequencing, a high-fidelity DNA sequencing technique, to characterizede novomtDNA mutations inCaenorhabditis elegans.This approach detected nearly an order of magnitude more mtDNA mutations than documented in any previous nematode mutation study. Despite an existing extreme AT bias in theC. elegansmtDNA (75.6% AT), we found that a significant majority of mutations increase genomic AT content. Compared to some prior studies in nematodes and other animals, the mutation spectrum reported here contains an abundance of CG→AT transversions, supporting the hypothesis that oxidative damage may be a driver of mtDNA mutations in nematodes. Further, we found an excess of G→T and C→T changes on the coding DNA strand relative to the template strand, consistent with increased exposure to oxidative damage. Analysis of the distribution of mutations across the mtDNA revealed significant variation among protein-coding genes and as well as among neighboring nucleotides. This high-resolution view of mitochondrial mutations inC. eleganshighlights the value of this system for understanding relationships among oxidative damage, replication error, and mtDNA mutation.
H3K27 Acetylated Nucleosomes Facilitate HMGN Protein Localization at Regulatory Sites to Modulate The Interaction of Transcription Factors with Chromatin
Authors: Zhang Shaofei , Postnikov Yuri , Lobanov Alexei , Furusawa Takashi , Deng Tao , Bustin Michael 
Published: May 2021

ABSTRACTNucleosomes containing acetylated H3K27 are a major epigenetic mark of active chromatin and identify cell-type specific chromatin regulatory regions which serve as binding sites for transcription factors. Here we show that the ubiquitous nucleosome binding proteins HMGN1 and HMGN2 bind preferentially to H3K27ac nucleosomes at cell-type specific chromatin regulatory regions. HMGNs bind directly to the acetylated nucleosome; the H3K27ac residue and linker DNA facilitate the preferential binding of HMGNs to the modified nucleosomes. Loss of HMGNs increases the levels of H3K27me3 and the histone H1 occupancy at enhancers and promoters and alters the interaction of transcription factors with chromatin. These experiments indicate that the H3K27ac epigenetic mark affects the interaction of architectural protein with chromatin regulatory sites and provide insights into the molecular mechanism whereby ubiquitous chromatin binding proteins, which bind to chromatin without DNA sequence specificity, localize to regulatory chromatin and modulate cell-type specific gene expression.
Stereotypic expansion of Tregulatoryand Th17cells during infancy is disrupted by HIV exposure and gut epithelial damage
Authors: Dzanibe Sonwabile , Lennard Katie , Kiravu Agano , Seabrook Melanie S.S. , Alinde Berenice , Holmes Susan P. , Blish Catherine A. , Jaspan Heather B. , Gray Clive M. 
Published: May 2021

AbstractFew studies have investigated immune cell ontogeny throughout the neonatal and early paediatric period, where there is often increased vulnerability to infections. Here, we evaluated the dynamics of two critical T cell populations, regulatory (Treg) cells and Th17 cells, over the first 36 weeks of life. Firstly, we observed distinct CD4+T cells phenotypes between cord blood and peripheral blood, collected within 12 hours of birth, showing that cord blood is not a surrogate for newborn blood. Secondly, both Treg and Th17 cells expanded in a synchronous fashion over 36 weeks of life. However, comparing infants exposed to HIVin utero, but remaining uninfected (iHEU), with HIV-unexposed uninfected control infants (iHUU), there was a lower frequency of peripheral blood Treg cells at birth, resulting in a delayed expansion, and then declining again at 36 weeks. Focusing on birth events, we found that Treg cells co-expressing CCR4 and α4β7 inversely correlated with plasma concentrations of CCL17 (the ligand for CCR4) and intestinal fatty acid binding protein (iFABP), IL-7 and CCL20. This was in contrast to Th17 cells, which showed a positive association with these plasma analytes. Thus, despite the stereotypic expansion of both cell subsets over the first few months of life, there was a disruption in the balance of Th17 to Treg cells at birth likely being a result of gut damage and homing of newborn Treg cells from the blood circulation to the gut.Key pointsPhenotypic differences between cord and birth peripheral blood CD4 cells.Synchronous increase of Th17-Treg cells is disrupted by HIV/ART exposure.Intrauterine HIV exposure was associated with epithelial gut damage.
Binocular Mirror-Symmetric Microsaccadic Sampling EnablesDrosophilaHyperacute 3D-Vision
Authors: Kemppainen Joni , Scales Ben , Haghighi Keivan Razban , Takalo Jouni , Mansour Neveen , McManus James , Leko Gabor , Saari Paulus , Hurcomb James , Antohi Andra , Suuronen Jussi-Petteri , Blanchard Florence , Hardie Roger C. , Song Zhuoyi , Hampton Mark , Eckermann Marina , Westermeier Fabian , Frohn Jasper , Hoekstra Hugo , Lee Chi-Hon , Huttula Marko , Mokso Rajmund , Juusola Mikko 
Published: May 2021

AbstractNeural mechanisms behind stereopsis, which requires simultaneous disparity inputs from two eyes, have remained mysterious. Here we show how ultrafast mirror-symmetric photomechanical contractions in the frontal forward-facing left and right eye photoreceptors giveDrosophilasuper-resolution 3D-vision. By interlinking multiscalein vivoassays with multiscale simulations, we reveal how these photoreceptor microsaccades - by verging, diverging and narrowing the eyes’ overlapping receptive fields - channel depth information, as phasic binocular image motion disparity signals in time. We further show how peripherally, outside stereopsis, microsaccadic sampling tracks a flying fly’s optic flow field to better resolve the world in motion. These results change our understanding of how insect compound eyes work and suggest a general dynamic stereo-information sampling strategy for animals, robots and sensors.Significance statementTo move efficiently, animals must continuously work out their x,y,z-positions in respect to real-world objects, and many animals have a pair of eyes to achieve this. How photoreceptors actively sample the eyes’ optical image disparity is not understood because this fundamental information-limiting step has not been investigatedin vivoover the eyes’ whole sampling matrix. This integrative multiscale study will advance our current understanding of stereopsis from static image disparity comparison to a new morphodynamic active sampling theory. It shows how photomechanical photoreceptor microsaccades enableDrosophilasuper-resolution 3D-vision and proposes neural computations for accurately predicting these flies’ depth-perception dynamics, limits, and visual behaviors.
Ultrasound stimulation of the motor cortex during tonic muscle contraction
Authors: Heimbuch Ian S. , Fan Tiffany , Wu Allan , Faas Guido C. , Charles Andrew C. , Iacoboni Marco 
Published: May 2021

AbstractTranscranial ultrasound stimulation (tUS) shows potential as a noninvasive brain stimulation (NIBS) technique, offering increased spatial precision compared to other NIBS techniques. However, its reported effects on primary motor cortex (M1) are limited. We aimed to better understand tUS effects in human M1 by performing tUS of the hand area of M1 (M1hand) during tonic muscle contraction of the index finger. Stimulation during muscle contraction was chosen because of the transcranial magnetic stimulation-induced phenomenon known as cortical silent period (cSP), in which transcranial magnetic stimulation (TMS) of M1hand involuntarily suppresses voluntary motor activity. Since cSP is widely considered an inhibitory phenomenon, it presents an ideal parallel for tUS, which has often been proposed to preferentially influence inhibitory interneurons. Recording electromyography (EMG) of the first dorsal interosseous (FDI) muscle, we investigated effects on muscle activity both during and after tUS. We found no change in FDI EMG activity concurrent with tUS stimulation. Using single-pulse TMS, we found no difference in M1 excitability before versus after sparsely repetitive tUS exposure. Using acoustic simulations in models made from structural MRI of the participants that matched the experimental setups, we estimated in-brain pressures and generated an estimate of cumulative tUS exposure experienced by M1hand for each subject. We were unable to find any correlation between cumulative M1hand exposure and M1 excitability change. We also present data that suggest a TMS-induced MEP always preceded a near-threshold cSP.
LOSS OF PLASMA MEMBRANE LIPID ASYMMETRY CAN INDUCE ORDERED DOMAIN (RAFT) FORMATION
Authors: Kakuda Shinako , Suresh Pavana , Li Guangtao , London Erwin 
Published: May 2021

ABSTRACTIn some cases lipids in one leaflet of an asymmetric artificial lipid vesicle can suppress formation of ordered lipid domains (rafts) in the opposing leaflet. Whether suppression of domain formation might occur in plasma membranes was studied using plasma membrane vesicles (PMVs) from RBL-2H3 cells. Membrane domain formation and order was assessed by FRET and fluorescence anisotropy. Ordered domains in PMV prepared from cells by N-ethyl maleimide (NEM) treatment formed up to ~37°C, while ordered domains in symmetric vesicles formed from extracted PMV lipids were stable to 55°C, indicating that stability of ordered domains was substantially less in intact PMV. This behavior paralleled lesser ordered domain stability in artificial asymmetric lipid vesicles relative to the corresponding symmetric vesicles, suggesting that intact PMV have some degree of lipid asymmetry. This was confirmed by annexin binding showing that NEM PMV are much more asymmetric than PMV formed by dithiothreitol/paraformaldehyde treatment. Stabilization of ordered domain formation, and increased membrane order at low temperature was also observed after detergent solubilization of PMV followed by membrane reconstitution via dilution from detergent, which also should destroy asymmetry, even though membrane proteins remained associated with the reconstituted vesicles. Similar changes in domain formation and membrane order were observed after detergent reconstitution of artificial asymmetric lipid vesicles. PMV ordered domain stability was not increased by digesting peripheral domains of PMV proteins with proteinase K. We conclude loss of PMV lipid asymmetry can induce ordered domain formation. Dynamic control of asymmetry may regulate ordered domain formation in plasma membranes.
Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment
Authors: Varn Frederick S , Johnson Kevin C , Wade Taylor E , Malta Tathiane M , Sabedot Thais S , Barthel Floris P , Kim Hoon , Ahmed Nazia , Datta Indrani , Barnholtz-Sloan Jill S , Bakas Spyridon , D’Angelo Fulvio , Gan Hui K , Garofano Luciano , Huse Jason T , Khasraw Mustafa , Kocakavuk Emre , Migliozzi Simona , Ormond D. Ryan , Paek Sun Ha , Van Meir Erwin G , Walenkamp Annemiek M.E. , Watts Colin , Weller Michael , Weiss Tobias , Wesseling Pieter , Stead Lucy F , Poisson Laila M , Noushmehr Houtan , Iavarone Antonio , Verhaak Roel GW ,   The GLASS Consortium
Published: May 2021

SummaryTo interrogate the factors driving therapy resistance in diffuse glioma, we collected and analyzed RNA and/or DNA sequencing data from temporally separated tumor pairs of 292 adult patients with IDH-wild-type or IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquiredCDKN2Adeletions associated with an increase in proliferating stem-like malignant cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their malignant cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a specific myeloid cell state defined by unique ligand-receptor interactions with malignant cells. Collectively, our results uncover recurrence-associated changes that could be targetable to shape disease progression following initial diagnosis.
Revisiting the Hayflick Limit: Insights from an Integrated Analysis of Changing Transcripts, Proteins, Metabolites and Chromatin
Authors: Chan Michelle , Yuan Han , Soifer Ilya , Maile Tobias M. , Wang Rebecca Y. , Ireland Andrea , O’Brien Jonathon , Goudeau Jérôme , Chan Leanne , Vijay Twaritha , Freund Adam , Kenyon Cynthia , Bennett Bryson , McAllister Fiona , Kelley David R. , Roy Margaret , Cohen Robert L. , Levinson Arthur D. , Botstein David , Hendrickson David G. 
Published: May 2021

AbstractThe process wherein dividing cells exhaust proliferative capacity and enter into replicative senescence has become a prominent model for cellular agingin vitro. Despite decades of study, this cellular state is not fully understood in culture and even much less so during aging. Here, we revisit Leonard Hayflick’s original observation of replicative senescence in WI-38 human lung fibroblasts equipped with a battery of modern techniques including RNA-seq, single cell RNA-seq, proteomics, metabolomics, and ATAC-seq. We find evidence that the transition to a senescent state manifests early, increases gradually, and corresponds to a concomitant global increase in DNA accessibility in nucleolar and lamin associated domains. Furthermore, we demonstrate that senescent WI-38 cells acquire a striking resemblance to myofibroblasts in a process similar to the epithelial to mesenchymal transition (EMT) that is regulated by the transcription factors YAP1/TEAD1 and TGF-β2. Lastly, we show that verteporfin inhibition of YAP1/TEAD1 activity in aged WI-38 cells robustly attenuates this gene expression program.