bluuebunny/crossref_metadata_2025_split huggingface dataset:
Boreal Forest Height Mapping using Sentinel-1 Time Series and improved LSTM model
Authors: Ge Shaojia , Gu Hong , Su Weimin , Rauste Yrjö , Praks Jaan , Antropov Oleg 
Published: September 2022

AbstractHere, a novel semi-supervised Long Short-Term Memory (LSTM) model is developed and demonstrated for predicting forest tree height using time series of Sentinel-1 images. The model uses a Helix-Elapse (HE) projection approach to capture relationship between forest temporal patterns and Sentinel-1 time series, when the acquisition time intervals are irregular. A skip-link based LSTM block is introduced and a novel backbone network, Helix-LSTM, is proposed to retrieve temporal features at different receptive scales. Additionally, a novel semi-supervised strategy, Cross-Pseudo Regression, is employed to achieve better model performance. The developed model is compared versus basic LSTM model, attention-based bidirectional LSTM and several other established regression approaches used in forest variable mapping, demonstrating consistent improvement of forest height prediction accuracy. The study site is located in Central Finland and represents boreal forestland. At best, the achieved accuracy of forest height mapping was 28.3% rRMSE for pixel-level predictions, and 18.0% rRMSE on stand level. We expect that the developed model can also be used for modeling relationships between other forest variables and satellite image time series.
Conserved whole-brain spatiomolecular gradients shape adult brain functional organization
Authors: Vogel Jacob W , Alexander-Bloch Aaron , Wagstyl Konrad , Bertolero Maxwell , Markello Ross , Pines Adam , Sydnor Valerie J , Diaz-Papkovich Alex , Hansen Justine , Evans Alan C , Bernhardt Boris , Misic Bratislav , Satterthwaite Theodore , Seidlitz Jakob 
Published: September 2022

AbstractCortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, how these gradients relate to adult brain function, and whether they are maintained in the adult brain, remains unknown. Here we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral and medial-lateral axes of early developmental patterning. The interaction of these spatiomolecular gradients i) accurately predicts the location of unseen brain tissue samples, ii) delineates known functional territories, and iii) explains the topographical variation of diverse cortical features. The spatiomolecular gradients are distinct from canonical cortical functional hierarchies differentiating primary sensory cortex from association cortex, but radiate in parallel with the axes traversed by local field potentials along the cortex. We replicate all three molecular gradients in three independent human datasets as well as two non-human primate datasets, and find that each gradient shows a distinct developmental trajectory across the lifespan. The gradients are composed of several well known morphogens (e.g., PAX6 and SIX3), and a small set of genes shared across gradients are strongly enriched for multiple diseases. Together, these results provide insight into the developmental sculpting of functionally distinct brain regions, governed by three robust transcriptomic axes embedded within brain parenchyma.
Large variations in afforestation-related climate cooling and warming effects across short distances
Authors: Rohatyn Shani , Rotenberg Eyal , Tatarinov Fyodor , Carmel Yohay , Yakir Dan 
Published: September 2022

AbstractClimate-related benefits of afforestation depend on the balance of the often-contrasting effects of biogeochemical (carbon sequestration) and biogeophysical (energy balance) effects. These effects are known to vary at the continental scale (e.g., from boreal to tropical regions). Here, we show based on a four-year study that the biogeochemical vs. biogeophysical balance in paired forested and non-forested ecosystems across short distances and steep aridity gradient (∼200Km, aridity index 0.64 to 0.18) can change dramatically. The required time for the forestation cooling effects via carbon sequestration, to surpass its warming effects, associated with the forests reduced albedo and suppressed longwave radiation, decreased from >200 years in the driest sites to ∼70 years in the intermediate and ∼40 years in the wettest sites. Climate-related benefits of forestation, previously considered at large-spatial scales, should be considered at high-spatial resolutions in climate-change mitigation programs aimed at taking advantage of the vast non-forested dry regions.TeaserClimate-related effects of afforestation can vary between cooling and warming effects across 200 km.
SHEPHARD: a modular and extensible software architecture for analyzing and annotating large protein datasets
Authors: Ginell Garrett M. , Flynn Aidan J. , Holehouse Alex S. 
Published: September 2022

ABSTRACTThe emergence of high-throughput experiments and high-resolution computational predictions has led to an explosion in the quality and volume of protein sequence annotations at proteomic scales. Unfortunately, integrating and analyzing complex sequence annotations remains logistically challenging. Here we present SHEPHARD, a software package that makes large-scale integrative protein bioinformatics trivial. SHEPHARD is provided as a stand-alone package and with a pre-compiled set of human annotations in a Google Colab notebook.
Representing cells as sentences enables natural-language processing for single-cell transcriptomics
Authors: Dhodapkar Rahul M. 
Published: September 2022

AbstractGene expression matrices commonly used in single-cell transcriptomics, cannot be directly analyzed with tools developed for natural languages. By restructuring these matrices as abundance-ordered sequences of genes, we generate cell sentences: rank-normalized, positionally encoded expression data. We show that these cell sentences can be analyzed using existing tools from natural language processing to unify cell and gene representations across species.
Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM
Authors: Valerie Nicholas C.K. , Sanjiv Kumar , Mortusewicz Oliver , Zhang Si Min , Alam Seher , Pires Maria J. , Stigsdotter Hannah , Rasti Azita , Langelier Marie-France , Rehling Daniel , Throup Adam , Desroses Matthieu , Onireti Jacob , Wakchaure Prasad , Almlöf Ingrid , Boström Johan , Bevc Luka , Benzi Giorgia , Stenmark Pål , Pascal John M. , Helleday Thomas , Page Brent D.G. , Altun Mikael 
Published: September 2022

AbstractCellular target engagement technologies are reforming drug discovery by enabling quantification of intracellular drug binding; however, simultaneous assessment of drug-associated phenotypes has proven challenging. CeTEAM (cellular targetengagement byaccumulation ofmutant) is a platform that can concomitantly evaluate drug-target interactions and phenotypic responses for holistic assessment of drug pharmacology using conditionally-stabilized drug biosensors. We observe that drug-responsive proteotypes are prevalent among reported mutants of known drug targets. CeTEAM-compatible mutants follow structural and biophysical logic that permits intra-protein and paralogous expansion of the biosensor pool, as exemplified by alanine scanning of leucines within the PARP1 helical domain and transfer of PARP1 destabilization to the analogous PARP2 residue. We then apply CeTEAM to uncouple target engagement from divergent cellular activities of MTH1 inhibitors, dissect NUDT15-associated thiopurine metabolism with the R139C pharmacogenetic variant, and profile the live-cell dynamics of PARP1/2 binding and DNA trapping by PARP inhibitors. Further, PARP1-derived biosensors facilitated high-throughput screening of drug-like libraries for PARP1 binders, as well as multimodalex vivoanalysis and non-invasive tracking of PARPi binding in live animals. Our data suggests that CeTEAM can facilitate real-time, comprehensive characterization of target engagement by bridging drug binding events and their biological consequences.
A p21-GFP zebrafish model of senescence for rapid testing of senolyticsin vivo
Authors: Morsli Samir , Henriques Catarina M. , Ellis Pamela S , Mortiboys Heather , Baxendale Sarah , Loynes Catherine , Renshaw Stephen A. , Bellantuono Ilaria 
Published: September 2022

AbstractSenescence drives the onset and severity of multiple ageing-associated diseases as well as frailty. As a result, there has been an increased interest in mechanistic studies and in the search for compounds targeting senescent cells, known as senolytics. Mammalian models are commonly used to test senolytics and generate functional and toxicity data at the level of organs and systems, yet this is expensive and time consuming. Zebrafish share high homology in genes associated with human ageing and disease. They can be genetically-modified relatively easily. In larvae, most organs develop within 5 days of fertilisation and are transparent, which allows tracking of fluorescent cellsin vivoin real time, testing drug off-target toxicity and assessment of cellular and phenotypic changes. Here, we have generated a transgenic zebrafish line that expresses green fluorescent protein (GFP) under the promoter of a key senescence marker, p21. We show an increase in p21:GFP+cells in larvae following exposure to ionising radiation and with natural ageing. p21:GFP+cells display other markers of senescence, including senescence-associated β-galactosidase and IL6. The observed increase in senescent cells following irradiation is associated with a reduction in the thickness of muscle fibres and mobility, two important ageing phenotypes. We also show that quercetin and dasatinib, two senolytics currently in clinical trials, reduce the number of p21:GFP+cells, in a rapid 5-day assay. This model provides an important tool to study senescence in a living organism, allowing the rapid selection of senolytics before moving to more expensive and time-consuming mammalian systems.
Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells
Authors: Liu Heng , Xu Cheng , Diplas Bill H. , Brown Alexandrea , Strickland Laura M. , Ling Jinjie , McLendon Roger E. , Keir Stephen T. , Ashley David M. , He Yiping , Waitkus Matthew S. 
Published: September 2022

AbstractTelomere maintenance mechanisms are a hallmark of cancer and are required to enable the replicative immortality of malignant cells. While most cancers activate the enzyme telomerase for telomere maintenance, a subset of cancers (~10-15%) use telomerase-independent mechanisms termed alternative lengthening of telomeres (ALT). ALT is characterized by elevated replication stress at telomeres, telomere synthesis via homology directed-repair mechanisms, and is frequently associated with mutations in the ATRX gene. Because ALT is absent in non-malignant proliferating cells, therapeutic strategies targeting ALT-mediated telomere synthesis is an area of significant translational and clinical interest. We previously showed that a subset of adult GBM patients with ATRX-expressing ALT-positive tumors harbored loss-of-function mutations in the SMARCAL1 gene. SMARCAL1 is an annealing helicase involved in replication fork remodeling and the resolution of replication stress. In this study, we used a patient-derived ALT-positive GBM cell line with native SMARCAL1 deficiency to investigate the role of SMARCAL1 in ALT-mediated telomere synthesis and gliomagenesis in vivo. Our results show that inducible rescue of SMARCAL1 expression suppresses ALT indicators and inhibits de novo telomere synthesis in GBM and osteosarcoma cells, suggesting that SMARCAL1 deficiency plays a functional role in ALT induction in cancers that natively lack SMARCAL1 function. Further, SMARCAL1-deficient ALT-positive cells can be serially propagated in vivo in the absence of detectable telomerase activity, suggesting that the SMARCAL1-deficient ALT phenotype maintains telomeres in a manner that promotes tumorigenesis. In summary, we show that SMARCAL1 loss-of-function mutations are permissive to ALT and promote gliomagenesis. We also established isogenic model systems that permit the dynamic modulation of ALT activity, which will be valuable for future studies aimed at understanding the molecular mechanisms of ALT and for identifying novel anti-cancer therapeutics that target the ALT phenotype.
Homeostatic cytokines reciprocally modulate the emergence of prenatal effector PLZF+CD4+ T cells in humans
Authors: Locher Veronica , Park Sara , Bunis Daniel , Makredes Stephanie , Burt Trevor D. , Fragiadakis Gabriela K. , Halkias Joanna 
Published: September 2022

AbstractThe development of human adaptive immunity progresses faster than previously appreciated, with the emergence of memory CD4+ T cells alongside regulatory T (Treg) cells by the second trimester of pregnancy. We previously identified a prenatal-specific subset of PLZF+ CD4+ T cells with heightened effector potential that accounted for most memory T cells in the developing intestine and accumulated in the cord blood of infants exposed to prenatal inflammatory pathologies. However, the signals that drive their tissue distribution and effector maturation are unknown. In this report, we define the transcriptional and functional heterogeneity of prenatal PLZF+ CD4+ T cells and identify compartmentalization of Th-like effector function across the small intestine (SI) and mesenteric lymph nodes (MLN). We find that IL-7, which is more abundant in the SI relative to the MLN, drives the preferential expansion of naïve PLZF+ CD4+ T cells via JAK/STAT and MEK/ERK signaling. Exposure to IL-7 induces a subset of PLZF+ CD4+ T cells to acquire a memory-phenotype and rapid effector function, identifying the human analogue of memory-phenotype CD4+ T cells. Further, IL-7 modulates the differentiation of Th1- and Th17-like PLZF+ CD4+ T cells, and thus likely contributes to the anatomic compartmentalization of prenatal CD4+ T cell effector function.
Systems biology illuminates alternative metabolic niches in the human gut microbiome
Authors: Noecker Cecilia , Sanchez Juan , Bisanz Jordan E. , Escalante Veronica , Alexander Margaret , Trepka Kai , Heinken Almut , Liu Yuanyuan , Dodd Dylan , Thiele Ines , DeFelice Brian , Turnbaugh Peter J. 
Published: September 2022

SUMMARYHuman gut bacteria perform diverse metabolic functions with consequences for host health. The prevalent and disease-linked Actinobacterium Eggerthella lenta performs several unusual chemical transformations, but it does not metabolize sugars and its core growth strategy remains unclear. To obtain a comprehensive view of the metabolic network of E. lenta, we generated several complementary resources: defined culture media, metabolomics profiles of strain isolates, and a curated genome-scale metabolic reconstruction. Stable isotope-resolved metabolomics revealed that E. lenta uses acetate as a key carbon source while catabolizing arginine to generate ATP, traits which could be recapitulated in silico by our updated metabolic model. We compared these in vitro findings with metabolite shifts observed in E. lenta-colonized gnotobiotic mice, identifying shared signatures across environments and highlighting catabolism of the host signaling metabolite agmatine as an alternative energy pathway. Together, our results elucidate a distinctive metabolic niche filled by E. lenta in the gut ecosystem.
Genomics of PDGFR-rearranged hypereosinophilic syndrome
Authors: Rheinbay Esther , Qi Meifang , Bouyssou Juliette M. , Oler Andrew J. , Thumm Lauren , Makiya Michelle , Maric Irina , Klion Amy D. , Lane Andrew A. 
Published: September 2022

AbstractA subset of patients with hypereosinophilia have a clonal hematologic neoplasm. These neoplastic hypereosinophilic syndromes (HES) can harbor somatic DNA rearrangements involving a PDGF receptor gene, PDGFRA or PGDFRB, most frequently FIP1L1::PDGFRA. Patients with PDGFR-rearranged HES are overwhelmingly males, and the hypereosinophilia responds robustly to the multi-kinase inhibitor imatinib. Unbiased genomics of PDGFR-rearranged HES have not been comprehensively studied. Here, we compared whole genome sequencing of eosinophil DNA from patients with PDGFR-rearranged HES at diagnosis (tumor) versus matched “normal” DNA. Other than the PDGFR rearrangement itself, we detected no recurrent coding somatic point mutations, insertions/deletions, or DNA copy number alterations in the neoplastic eosinophils; instead, there were additional somatic events private to each tumor. The tumors had a linear clonal structure with the PDGFR rearrangement as the initial driver event. We mapped the breakpoints of a novel IQGAP2::PDGFRB::UVRAG intra- and inter-chromosomal fusion event in one patient. Non-coding analysis found no recurrent abnormalities, including in eosinophilic leukemia-associated promoters or enhancers. The sex chromosomes showed no recurrent alterations to provide an obvious explanation for the disease’s extreme male bias. We conclude that neoplastic HES has relatively simple genomics and that the only unambiguous recurrent driver event is the PDGFR rearrangement itself.Key PointsPDGFR-rearranged hypereosinophilic neoplasms have simple, linear genetic structure with the rearrangement as the likely initiating eventThere are no obvious recurrent additional or sex-biased genomic events that cooperate with PDGFR rearrangement to drive the neoplasm
A Novel Gene REPTOR2 Activates the Autophagic Degradation of Wing Disc in Pea Aphid
Authors: Yuan Erliang , Guo Huijuan , Chen Weiyao , Du Bingru , Mi Yingjie , Qi Zhaorui , Yuan Yiyang , Zhu-Salzman Keyan , Ge Feng , Sun Yucheng 
Published: September 2022

AbstractWing dimorphism is an evolutionarily adaptive trait to maximize insect fitness under various environments, by which the population could be balanced between migration and reproduction. Most studies concern the regulatory mechanisms underlying the stimulation of wing morph in aphids, but relatively little research addresses the molecular basis of wing loss. Here, we found that the wing disc of wingless-destined pea aphids degenerated 30 h post birth by autophagic rather than apoptotic degeneration, whereas winged-destined aphids developed normally. Activation of autophagy in 1st instar nymphs reduced the proportion of winged aphids, and suppression of autophagy increased the proportion. The REPTOR2 gene associated with TOR signaling pathway was identified by RNA-seq as a differentially expressed gene between the two morphs, with higher expression in the thorax of wingless-destined aphids. Further genetic analysis indicated that REPTOR2 could be a novel gene derived from a gene duplication event exclusively in pea aphid on autosome A1 but translocated to the sex chromosome. Knockdown of REPTOR2 reduced autophagy in the wing disc and increased the proportion of winged aphids. In agreement with REPTOR’s canonical negative regulatory role of TOR on autophagy, winged-destined aphids had higher TOR expression in the wing disc. Suppression of TOR activated autophagy of the wing disc and decreased the proportion of winged aphids, and vice versa. These results revealed that the TOR signaling pathway controlled degradation of the wing disc in pea aphids, and that REPTOR2 could modulate this autophagic degradation.
Endothelial cell-derived, secreted long non-coding RNAsGadlor1andGadlor2aggravate pathological cardiac remodeling via intercellular crosstalk
Authors: Keles Merve , Grein Steve , Froese Natali , Wirth Dagmar , Trogisch Felix A. , Wardman Rhys , Hemanna Shruthi , Weinzierl Nina , Koch Philipp-Sebastian , Uhlig Stefanie , Lomada Santosh , Dittrich Gesine M. , Szaroszyk Malgorzata , Haustein Ricarda , Hegermann Jan , Martin-Garrido Abel , Bauersachs Johann , Frank Derk , Frey Norbert , Bieback Karen , Cordero Julio , Dobreva Gergana , Wieland Thomas , Heineke Joerg 
Published: September 2022

AbstractBackgroundPathological overload triggers maladaptive myocardial remodeling that leads to heart failure. Recent studies have shown that long non-coding RNAs (lncRNAs) regulate cardiac remodeling. This study investigates two recently discovered, secreted lncRNAs,Gadlor1andGadlor2(Gadlor 1/2).MethodsWe generated compoundGadlor1/2 knock-out (KO) mice and compared their response to pressure overload by transverse aortic constriction (TAC) to that of wild-type (WT) littermates. Endothelial cells, fibroblasts and cardiomyocytes were isolated from the hearts of both genotypes after TAC and their transcriptome was investigated by RNA sequencing.Gadlortarget proteins were identified by RNA antisense purification coupled with mass spectrometry (RAP-MS) in cardiomyocytes. In addition, we investigated the effects of cardiac overexpression ofGadlor1/2.ResultsGadlor1/2are jointly upregulated in failing mouse hearts as well as in the myocardium of heart failure patients. Cardiac overexpression ofGadlor1andGadlor2aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. CompoundGadlor1/2KO mice, in turn, exerted markedly reduced myocardial hypertrophy, fibrosis and dysfunction, but more angiogenesis during short and long-standing pressure overload. Paradoxically,Gadlor1/2KO mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia.Gadlor1andGadlor2, which are mainly expressed in endothelial cells (ECs) in the heart, where they inhibit pro-angiogenic gene-expression, are strongly secreted within extracellular vesicles (EVs). These EVs transferGadlorlncRNAs to cardiomyocytes, where they bind and activate calmodulin-dependent kinase II, induce pro-hypertrophic gene-expression and enhance calcium re-uptake into the sarcoplasmic reticulum.ConclusionGadlor1andGadlor2are lncRNAs that are mainly enriched in EC-derived EVs and are jointly upregulated in mouse and human hearts during pathological overload. We reveal a crucial endothelial cell-cardiomyocyte crosstalk, which aims at restoring calcium homeostasis in cardiomyocytes during overload at the cost of aggravated hypertrophy and fibrosis.