bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel positive feedback mechanism of ABI5 phosphorylation by mitogen activated protein kinase-3 regulates ABA signaling inArabidopsis
Authors: Bhagat Prakash Kumar , Verma Deepanjali , Verma Neetu , Sinha Alok Krishna 
Published: February 2021

AbstractSeed germination is the crucial physiological process regulated by both environmental and endogenous phytohormones. ABA negatively regulates seed germination, post-germination growth and floral transition, however, the cross talk between multiple regulatory pathways are still unclear. Here, we show that ABA activates two MAP kinases, AtMPK3/AtMPK6 and selectively regulates the transcript of AtMPK3 through ABI5, a master regulator of ABA signaling. As a feedback loop, AtMPK3 interacts and phosphorylates ABI5 at the serine-314 position. ABI5 phosphorylation by MAP kinases positively regulates ABI5 nuclear localization and negatively regulates its dimerization. Subcellular localization of ABI5 phospho-null protein further suggests the role of phosphorylation in regulation of its cytoplasmic stability and its nuclear dimerization. Overexpression of phosphor-null ABI5 inabi5-8mutant restored the ABA sensitivity during seed germination and delayed the floral transition as compared to phospho-mimic ABI5. Additionally, overexpression of constitutive phosphorylated ABI5 inabi5-8mutants suggest that phosphorylation makes ABI5 partially inactive. Furthermore, phospho-null ABI5 plants showed drought sensitive phenotype whereas,mpk3,mkk4,mkk5,abi5-8and phosphor-mimic plants showed drought tolerant phenotype. Our findings present a new insight between MAP kinase cascade and ABA signaling which collectively regulates the ABA response through ABI5 phosphorylation.
Temperature drives variation in flying insect biomass across a German malaise trap network
Authors: Welti Ellen A.R. , Zajicek Petr , Ayasse Manfred , Bornholdt Tim , Buse Jörn , Dziock Frank , Engelmann Rolf A. , Englmeier Jana , Fellendorf Martin , Förschler Marc I. , Frenzel Mark , Fricke Ute , Ganuza Cristina , Hippke Mathias , Hoenselaar Günter , Kaus-Thiel Andrea , Mandery Klaus , Marten Andreas , Monaghan Michael T. , Morkel Carsten , Müller Jörg , Puffpaff Stephanie , Redlich Sarah , Richter Ronny , Botero Sandra Rojas , Scharnweber Tobias , Scheiffarth Gregor , Yáñez Paul Schmidt , Schumann Rhena , Seibold Sebastian , Steffan-Dewenter Ingolf , Stoll Stefan , Tobisch Cynthia , Twietmeyer Sönke , Uhler Johannes , Vogt Juliane , Weis Dirk , Weisser Wolfgang W. , Wilmking Martin , Haase Peter 
Published: February 2021

ABSTRACTAmong the many concerns for biodiversity in the Anthropocene, recent reports of flying insect loss are particularly alarming, given their importance as pollinators and as a food source for many predators. Few insect monitoring programs cover large spatial scales required to provide more generalizable estimates of insect responses to global change drivers.We ask how climate and surrounding habitat affect flying insect biomass and day of peak biomass using data from the first year of a new standardized distributed monitoring network at 84 locations across Germany comprising spatial gradient of land-cover types from protected to urban areas.Flying insect biomass increased linearly with monthly temperature across Germany. However, the effect of temperature on flying insect biomass flipped to negative in the hot months of June and July when local temperatures most exceeded long-term averages.Land-cover explained little variation in insect biomass, but biomass was lowest in forested sites. Grasslands, pastures and orchards harbored the highest insect biomass. The date of peak biomass was primarily driven by surrounding land-cover type, with grasslands especially having earlier insect biomass phenologies.Standardized, large-scale monitoring is pivotal to uncover underlying processes of insect decline and to develop climate-adapted strategies to promote insect diversity. In a temperate climate region, we find that the benefits of temperature on flying insect biomass diminish in a German summer at locations where temperatures most exceeded long-term averages. These results highlighting the importance of local adaptation in climate change-driven impacts on insect communities.
EGR4-dependent decrease of UTF1 is associated with failure to reserve spermatogonial stem cells in infertile men
Authors: Di Persio Sara , Tekath Tobias , Siebert-Kuss Lara Marie , Cremers Jann-Frederik , Wistuba Joachim , Li Xiaolin , Meyer zu Hörste Gerd , Drexler Hannes CA , Wyrwoll Margot Julia , Tüttelmann Frank , Dugas Martin , Kliesch Sabine , Schlatt Stefan , Laurentino Sandra , Neuhaus Nina 
Published: February 2021

AbstractDespite the high incidence of male infertility, about 70% of infertile men do not receive a causative diagnosis. To gain insights into the regulatory mechanisms governing human germ cell function in normal and impaired spermatogenesis (cryptozoospermic patients, crypto), we combined single cell RNA sequencing (>30.000 cells), proteome, and histomorphometric analyses of testicular tissues. We found major alterations in the crypto spermatogonial compartment with increased numbers of the most undifferentiated spermatogonia (PIWIL4+State 0 cells). We also observed a transcriptional switch within the spermatogonial compartment driven by the increased and prolonged expression of the transcription factorEGR4.Intriguingly, EGR4-regulated genes included the chromatin-associated transcriptional repressorUTF1, which was downregulated. Histomorphometrical analyses showed that these transcriptional changes were mirrored at the protein level and accompanied by a change in the chromatin structure of spermatogonia. This resulted in a reduction of Adarkspermatogonia - characterized by tightly compacted chromatin and serving as reserve stem cells. These findings suggest that crypto patients are at a disadvantage especially in cases of gonadotoxic damage as they have less cells safeguarding the genetic integrity of the germline. We hypothesize that the more relaxed chromatin status of spermatogonia is dependent on decreased UTF1 expression caused by EGR4 activation. These identified regulators of the spermatogonial compartment will be highly interesting targets to uncover genetic causes of male infertility.One Sentence SummaryReserve spermatogonial stem cell depletion in infertile men is regulated by an EGR4-dependent UTF1 decrease, which changes chromatin morphology.
The MAP She1 coordinates directional spindle positioning by spatially restricting dynein activity
Authors: Ecklund Kari H. , Bailey Megan E. , Dietvorst Carsten K. , Asbury Charles L. , Markus Steven M. 
Published: February 2021

ABSTRACTDynein motors move the mitotic spindle to the cell division plane in many cell types, including in budding yeast, in which dynein is assisted by numerous factors including the microtubule-associated protein (MAP) She1. Evidence suggests that She1 plays a role in polarizing dynein-mediated spindle movements toward the daughter cell; however, how She1 performs this function is unknown. We find that She1 assists dynein in maintaining the spindle close to the bud neck, such that at anaphase onset the chromosomes are segregated to mother and daughter cells. She1 does so by attenuating the initiation of dynein-mediated spindle movements specifically within the mother cell, ensuring such movements are polarized toward the daughter cell. Our data indicate that this activity relies on She1 binding to the microtubule-bound conformation of the dynein microtubule-binding domain, and to astral microtubules within mother cells. Our findings reveal how an asymmetrically localized MAP directionally tunes dynein activity by attenuating motor activity in a spatially confined manner.
Spc1 regulates substrate selection for signal peptidase
Authors: Yim Chewon , Chung Yeonji , Kim Jeesoo , Nilsson IngMarie , Kim Jong-Seo , Kim Hyun 
Published: February 2021

AbstractSignal peptidase (SPase) cleaves the signal sequences (SSs) of secretory precursors. It contains an evolutionarily conserved membrane protein subunit, Spc1 that is dispensable for the catalytic activity of SPase, and its role remains elusive. In the present study, we investigated the function of yeast Spc1. First, we set up anin vivoSPase cleavage assay using secretory protein CPY variants with SSs modified in thenandhregions. When comparing the SS cleavage efficiencies of these variants in cells with or without Spc1, we found that signal-anchored sequences become more susceptible to cleavage by SPase without Spc1. Further, SPase-mediated processing of transmembrane (TM) segments in model membrane proteins was reduced upon overexpression of Spc1. Spc1 was co-immunoprecipitated with membrane proteins carrying uncleaved signal-anchored or TM segments. These results suggest a role of Spc1 in shielding TM segments from SPase action, thereby contributing to accurate substrate selection for SPase.
Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice
Authors: Zhang Jingliang , Chen Xiaoling , Eaton Muriel , Lai Shirong , Park Anthony , Ahmad Talha S. , Wu Jiaxiang , Ma Zhixiong , Que Zhefu , Lee Ji Hea , Xiao Tiange , Li Yuansong , Wang Yujia , Olivero-Acosta Maria I. , Schaber James A. , Jayant Krishna , Huang Zhuo , Lanman Nadia A. , Skarnes William C. , Yang Yang 
Published: February 2021

AbstractScn2aencodes voltage-gated sodium channel NaV1.2, which mediates neuronal firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability contributing to autism. In this paradigm, however, why about a third of patients with NaV1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe NaV1.2 deficiency. Using a unique gene-trap knockout mouse model ofScn2a, we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved inScn2a-related seizures. This increased excitability is autonomous, and is reversible by genetic restoration ofScn2aexpression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including KV1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain NaV1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions.TEASERSevere NaV1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels.HIGHLIGHTSSevere NaV1.2 deficiency results in enhanced excitability of medium spiny neurons (MSNs) and pyramidal neurons in adult mice;Increased neuronal excitability in MSNs is accompanied by elevated voltage threshold;NaV1.2 deficiency-related hyperexcitability is reversible with the restoration ofScn2aexpression, and is autonomous;The expression of the KV1.1 channel has a compensatory reduction in neurons with NaV1.2 deficiency, and KV channels openers normalize the neuronal excitability;The enhanced excitability in brain slices translates to elevatedin vivofiring commonly associated with seizures.
Dnmt1a is essential for gene body methylation and the regulation of zygotic genome activation in the wasp
Authors: Arsala Deanna , Wu Xin , Yi Soojin V. , Lynch Jeremy A. 
Published: February 2021

AbstractGene body methylation (GBM) is an ancestral aspect of DNA methylation (Sarda, Zeng, Hunt, & Yi, 2012; Yi, 2012; Zemach, McDaniel, Silva, & Zilberman, 2010) whose role in development has been obscured by the more prominent roles of promoter and CpG island methylation. The wasp Nasonia has little promoter and CpG island methylation, yet retains strong GBM (Park et al., 2011; Wang et al., 2013; Werren et al., 2010), making it an excellent model for elucidating the role of GBM. Here we show that Nasonia DNA methyl transferase 1a (Nv-Dnmt1a) knockdown leads to failures in cellularization and gastrulation of the embryo. Both of these disrupted events are hallmarks of the maternal-zygotic transition (MZT) in insects. Analysis of the embryonic transcriptome and methylome revealed strong reduction of GBM and widespread disruption of gene expression during embryogenesis after Nv-Dnmt1a knockdown. There was a strong correlation between loss of GBM and reduced gene expression in thousands of methylated loci, while affected unmethylated genes tended to be upregulated. We propose that reduced GBM and subsequent lower expression levels of methylated genes was the direct effect of Nv-Dnmt1 knockdown, and that this disruption led to widespread downstream dysregulation of MZT, and manifesting in developmental failure at gastrulation.Significance StatementThe importance of gene-body methylation (GBM) in development is unclear, due to the difficulty in teasing apart the effects of cis-regulatory methylation from those of GBM in vertebrate model systems. Unlike vertebrate models, the methylation machinery in the jewel waspNasonia vitripennisappears to exclusively mediate GBM, thus simplifying interpretation of the role of GBM in development. Knockdown of DNMT1 (Nv-Dnmt1a) inNasonialeads to embryonic lethality, which we show is caused by a failure of cellularization and gastrulation. Nv-Dnmt1a knockdown resulted in a global loss of GBM in the embryo, which was strongly correlated with a down-regulation of gene expression. We propose that GBM facilitated by Nv-Dnmt1a is required for proper zygotic genome activation in the wasp.
Colonic epithelial adaptation to EGFR-independent growth induces chromosomal instability and is accelerated by prior injury
Authors: Chen Tiane , Zeineldin Maged , Johnson Blake , Dong Yi , Narkar Akshay , Li Taibo , Zhu Jin , Li Rong , Larman Tatianna C. 
Published: February 2021

ABSTRACTAlthough much is known about the gene mutations required to drive colorectal cancer (CRC) initiation, the tissue-specific selective microenvironments in which neoplasia arises remains less characterized. Here, we determined whether modulation of intestinal stem cell niche morphogens alone can exert a neoplasia-relevant selective pressure on normal colonic epithelium. Using adult stem cell-derived murine colonic epithelial organoids (colonoids), we employed a strategy of sustained withdrawal of EGF and EGFR inhibition to select for and expand survivors. EGFR-signaling-independent (iEGFR) colonoids emerged over rounds of selection and expansion. Colonoids derived from a mouse model of chronic mucosal injury showed an enhanced ability to adapt to EGFR inhibition. Whole-exome and transcriptomic analyses of iEGFR colonoids demonstrated acquisition of deleterious mutations and altered expression of genes implicated in EGF signaling, pyroptosis, and CRC. iEGFR colonoids acquired dysplasia-associated cytomorphologic changes, an increased proliferative rate, and the ability to survive independently of other required niche factors. These changes were accompanied by emergence of aneuploidy and chromosomal instability; further, the observed mitotic segregation errors were significantly associated with loss of interkinetic nuclear migration, a fundamental and dynamic process underlying intestinal epithelial homeostasis. This study provides key evidence that chromosomal instability and other phenotypes associated with neoplasia can be induced ex vivo via adaptation to EGF withdrawal in normal and stably euploid colonic epithelium, without introducing cancer-associated driver mutations. In addition, prior mucosal injury accelerates this evolutionary process.Key definitionsColonoids: adult stem cell-derived colonic epithelial organoidsiEGFR: in vitro selective conditions devoid of EGF (epidermal growth factor) and including an EGFR (EGF receptor) inhibitor 1iEGFR colonoids: colonoids tolerant to iEGFR culture conditions with growth and survival similar to unselected passage-matched controlsINM: Interkinetic nuclear migration
Quantifying the severity of adverse drug reactions using social media
Authors: Lavertu Adam , Hamamsy Tymor , Altman Russ B 
Published: February 2021

AbstractAdverse drug reactions (ADRs) impact the health of 100,000s of individuals annually in the United States with associated costs in the hundreds of billions. The monitoring and analysis of the severity of adverse drug reactions is limited by the current qualitative and categorical system of severity classifications. Previous efforts have generated quantitative estimates for a subset of ADRs, but were limited in scope due to the time and costs associated with the efforts. We present a semi-supervised approach that estimates ADR severity by using a lexical network of ADR word embeddings and label propagation. We use this method to estimate the severity of 28,113 ADRs, representing 12,198 unique ADR concepts from MedDRA. Our Severity of Adverse Events Derived from Reddit (Saedr) scores have good correlations with real-world outcomes. Saedrscores had Spearman correlations with ADR case outcomes in FAERS of 0.595, 0.633, and −0.748 for death, serious outcome, and no outcome, respectively. We investigate different methods for defining initial seed term sets and evaluate their impact on severity estimates. We analyzed severity distributions for ADRs based on their appearance in Boxed Warning drug label sections, as well as ADRs with sex-specific associations. We find that ADRs discovered postmarket have significantly greater severity compared to those discovered in the clinical trial. We create quantitative Drug RIsk Profile (Drip) scores for 968 drugs that have a Spearman correlation of 0.377 with drugs ranked by FAERS cases resulting in death, where the given drug was the primary suspect. We make the Saedrand Dripscores publicly available in order to enable more quantitative analysis of pharmacovigilance data.
Mechanoreceptor synapses in the brainstem shape the central representation of touch
Authors: Lehnert Brendan P. , Santiago Celine , Huey Erica L. , Emanuel Alan J. , Renauld Sophia , Africawala Nusrat , Alkislar Ilayda , Zheng Yang , Bai Ling , Koutsioumpa Charalampia , Hong Jennifer T. , Magee Alexandra R. , Harvey Christopher D. , Ginty David D. 
Published: February 2021

AbstractMammals use glabrous (hairless) skin of their hands and feet to navigate and manipulate their environment. Cortical maps of the body surface across species contain disproportionately large numbers of neurons dedicated to glabrous skin sensation, potentially reflecting a higher density of mechanoreceptors that innervate these skin regions. Here, we find that disproportionate representation of glabrous skin emerges over postnatal development at the first synapse between peripheral mechanoreceptors and their central targets in the brainstem. Mechanoreceptor synapses undergo developmental refinement that depends on proximity of their terminals to glabrous skin, such that those innervating glabrous skin make synaptic connections that expand their central representation. In mice that do not sense gentle touch, mechanoreceptors innervating glabrous skin still make more powerful synaptic connections in the brainstem. We propose that the skin region a mechanoreceptor innervates controls refinement of its central synapses over development to shape the representation of touch in the brain.
Advancing admixture graph estimation via maximum likelihood network orientation
Authors: Molloy Erin K. , Durvasula Arun , Sankararaman Sriram 
Published: February 2021

AbstractMotivationAdmixture, the interbreeding between previously distinct populations, is a pervasive force in evolution. The evolutionary history of populations in the presence of admixture can be modeled by augmenting phylogenetic trees with additional nodes that represent admixture events. While enabling a more faithful representation of evolutionary history,admixture graphspresent formidable inferential challenges, and there is an increasing need for methods that are accurate, fully automated, and computationally efficient. One key challenge arises from the size of the space of admixture graphs. Given that exhaustively evaluating all admixture graphs can be prohibitively expensive, heuristics have been developed to enable efficient search over this space. One heuristic, implemented in the popular method TreeMix, consists of adding edges to a starting tree while optimizing a suitable objective function.ResultsHere, we present a demographic model (with one admixed population incident to a leaf) where TreeMix and any other starting-tree-based maximum likelihood heuristic using its likelihood function isguaranteedto get stuck in a local optimum and return an incorrect network topology. To address this issue, we propose a new search strategy that we term maximum likelihood network orientation (MLNO). We augment TreeMix with an exhaustive search for a MLNO, referring to this approach as OrientA-Graph. In evaluations including previously published admixture graphs, OrientAGraph outperformed TreeMix on 4/8 models (there are no differences in the other cases). Overall, OrientAGraph found graphs with higher likelihood scores and topological accuracy while remaining computationally efficient. Lastly, our study reveals several directions for improving maximum likelihood admixture graph estimation.AvailabilityOrientAGraph is available under the GNU General Public License v3.0 on Github (https://github.com/sriramlab/OrientAGraph).
Marker-free imaging of α-Synuclein aggregates in a rat model of Parkinson’s disease using Raman microspectroscopy
Authors: Sevgi Fide , Brauchle Eva M , Carvajal Berrio Daniel A , Schenke-Layland Katja , Casadei Nicolas , Salker Madhuri S , Riess Olaf , Singh Yogesh 
Published: February 2021

AbstractA hallmark of Parkinson’s disease (PD) is the formation of Lewy bodies in the brain. Lewy bodies are rich in the aggregated form of misfolded α-Synuclein (α-Syn). The brain from PD patients can only be analysed after post-mortem, limiting the diagnosis of PD to the manifestation of motor symptoms. In PD patients and animal models phosphorylated α-Syn was detected in the gut, thus, raising the hypothesizes that early-stage PD could be diagnosed based on colon tissues biopsies. Non-invasive marker-free technologies represent an ideal method to potentially detect aggregated α-Synin vivo.Raman microspectroscopy has been established for the detection of molecular changes such as alterations of protein structures. Here, the olfactory bulb in the brain and the muscularis mucosae of colon tissue sections of a human BAC-SNCA transgenic (TG) rat model was analysed using Raman imaging and microspectroscopy. Raman images from TG and WT rats were investigated using spectral, principal component and true component analysis. Spectral components indicated protein aggregates (spheroidal oligomers) in TG rat brain and colon tissues even at a young age but not in WT. In summary, we have demonstrated that Raman imaging is capable to detect α-Syn aggregates in colon tissues of a PD rat model and making it a promising tool for future use in PD pathology.