bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sniff-synchronized, gradient-guided olfactory search by freely moving mice
Authors: Findley Teresa M , Wyrick David G , Cramer Jennifer L , Brown Morgan A , Holcomb Blake , Attey Robin , Yeh Dorian , Monasevitch Eric , Nouboussi Nelly , Cullen Isabelle , Songco Jeremea , King Jared F , Ahmadian Yashar , Smear Matthew C 
Published: May 2020

AbstractFor many organisms, searching for relevant targets such as food or mates entails active, strategic sampling of the environment. Finding odorous targets may be the most ancient search problem that motile organisms evolved to solve. While chemosensory navigation has been well characterized in micro-organisms and invertebrates, spatial olfaction in vertebrates is poorly understood. We have established an olfactory search assay in which freely-moving mice navigate noisy concentration gradients of airborne odor. Mice solve this task using concentration gradient cues and do not require stereo olfaction for performance. During task performance, respiration and nose movement are synchronized with tens of milliseconds precision. This synchrony is present during trials and largely absent during inter-trial intervals, suggesting that sniff-synchronized nose movement is a strategic behavioral state rather than simply a constant accompaniment to fast breathing. To investigate the spatiotemporal structure of these active sensing movements, we used machine learning methods to parse motion trajectories into elementary movement motifs. Motifs fall into two clusters, which correspond to investigation and approach states. Investigation motifs lock precisely to sniffing, such that the individual motifs preferentially occur at specific phases of the sniff cycle. This work clarifies sensorimotor strategies for mouse olfactory search and guides ongoing work into the underlying neural mechanisms.
VIL1, a Polycomb-associated protein, modulates high ambient temperature response via H3K27me3 and H2A.Z inArabidopsis thaliana
Authors: Bordiya Yogendra , Kim Junghyun , Xi Yanpeng , Kim Dong-Hwan , Pyo Youngjae , Zhao Bo , Zong Wei , Ricci William A. , Zhang Xiaoyu , Sung Sibum 
Published: May 2020

AbstractAdapting to the everchanging environment is key to a successful life for an organism. Eukaryotes reprogram their transcriptome in order to adapt to an unfavorable environment. To achieve this reprogramming, plants and animals employ multiple responses including epigenetic regulation. In the search for mutations compromised in high ambient temperature response, we found that VIL1, a PHD finger protein displays aberrant development at high temperature. RNA-seq analysis shows thatvil1fails to downregulate heat suppressed genes. H2A.Z ChIP-seq showed that unlike wild type,vil1fails to evict H2A.Z from heat responsive genes. We also found thatvil1suppresses constitutive thermo-morphogenic phenotype ofarp6. Supporting this phenotype, RNA-seq analysis revealed that constitutive heat responsive transcriptome ofarp6reverted back to the wild-type levels inarp6vil1. This observation suggests an antagonistic relationship between VIL1 and ARP6. We found that this antagonism can be explained in part by interaction between H3K27me3 and H2A.Z.
Single-Molecule Imaging and Microfluidic Platform Reveal Molecular Mechanisms of Leukemic Cell Rolling
Authors: Alwan Bader Al , AbuZineh Karmen , Nozue Shuho , Rakhmatulina Aigerim , Aldehaiman Mansour , Al-Amoodi Asma S. , Serag Maged F. , Aleisa Fajr A. , Merzaban Jasmeen S. , Habuchi Satoshi 
Published: May 2020

ABSTRACTHematopoietic stem/progenitor cell (HSPC) and leukemic cell homing is an important biological phenomenon that occurs through key interactions between adhesion molecules. Tethering and rolling of the cells on endothelium, the crucial initial step of the adhesion cascade, is mediated by interactions between selectins expressed on endothelium to their ligands expressed on HSPCs/leukemic cells in flow. Although multiple factors that affect the rolling behavior of the cells have been identified, molecular mechanisms that enable the essential slow and stable cell rolling remain elusive. To investigate the molecular mechanisms of cell rolling, an experimental platform that enables molecular level characterization of the adhesion molecules in the context of space, time, and force is required. Here, using a microfluidics-based single-molecule live cell fluorescence imaging, we reveal that unique spatiotemporal dynamics of selectin ligands on the membrane tethers and slings, which are distinct from that on the cell body, play an essential role in the rolling of the cell. Our results suggest that the spatial confinement of the selectin ligands to the tethers and slings together with the rapid scanning of a large area by the selectin ligands, increases the efficiency of selectin-ligand interactions during cell rolling, resulting in slow and stable rolling of the cell on the selectins. Our findings provide novel insights and contribute significantly to the molecular-level understanding of the initial and essential step of the homing process.
Ectopic expression of pericentric HSATII RNA results in nuclear RNA accumulation, MeCP2 recruitment, and cell division defects
Authors: Landers Catherine C. , Rabeler Christina A. , Ferrari Emily K. , D’Alessandro Lia R. , Kang Diana D. , Malisa Jessica , Bashir Safia M. , Carone Dawn M. 
Published: May 2020

AbstractWithin the pericentric regions of human chromosomes reside large arrays of tandemly repeated satellite sequences. Expression of the human pericentric satellite HSATII is prevented by extensive heterochromatin silencing in normal cells, yet in many cancer cells, HSATII RNA is aberrantly expressed and accumulates in large nuclear fociin cis. Expression and aggregation of HSATII RNA in cancer cells is concomitant with recruitment of key chromatin regulatory proteins including methyl-CpG binding protein 2 (MeCP2). While HSATII expression has been observed in a wide variety of cancer cell lines and tissues, the effect of its expression is unknown. We tested the effect of stable expression of HSATII RNA within cells that do not normally express HSATII. Ectopic HSATII expression in HeLa and primary fibroblast cells leads to focal accumulation of HSATII RNAin cisand triggers the accumulation of MeCP2 onto nuclear HSATII RNA bodies. Further, long-term expression of HSATII RNA leads to cell division defects including lagging chromosomes, chromatin bridges, and other chromatin defects. Thus, expression of HSATII RNA in normal cells phenocopies its nuclear accumulation in cancer cells and allows for the characterization of the cellular events triggered by aberrant expression of pericentric satellite RNA.
The prolyl hydroxylase PHD3 maintains β-cell glucose metabolism during fatty acid excess
Authors: Nasteska Daniela , Cuozzo Federica , Thakker Alpesh , Bakar Rula Bany , Westbrook Rebecca , Akerman Ildem , Cantley James , Tennant Daniel A. , Hodson David J. 
Published: May 2020

ABSTRACTThe alpha ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is a hypoxia-inducible factor target that uses molecular oxygen to hydroxylate proline. While PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about effects of this highly conserved enzyme in insulin-secreting β-cells. Here, we show that deletion of PHD3 specifically in β-cells (βPHD3KO) is associated with impaired glucose homeostasis in mice fed high fat diet. In the early stages of dietary fat excess, βPHD3KO islets energetically rewire, leading to defects in the management of pyruvate fate and a shift away from glycolysis. However, βPHD3KO islets are able to maintain oxidative phosphorylation and insulin secretion by increasing utilization of fatty acids to supply the tricarboxylic acid cycle. This nutrient-sensing switch cannot be sustained and βPHD3KO islets begin to show signs of failure in response to prolonged metabolic stress, including impaired glucose-stimulated ATP/ADP rises, Ca2+fluxes and insulin secretion. Thus, PHD3 might be a pivotal component of the β-cell glucose metabolism machinery by suppressing the use of fatty acids as a primary fuel source, under obesogenic and insulin resistant states.SIGNIFICANCE STATEMENTProlyl-4-hydroxylase 3 (PHD3) is involved in the oxygen-dependent regulation of cell phenotype. A number of recent studies have shown that PHD3 might operate at the interface between oxygen availability and metabolism. To understand how PHD3 influences insulin secretion, which depends on intact glucose metabolism, we generated mice lacking PHD3 specifically in pancreatic β-cells. These mice, termed βPHD3KO, are apparently normal until fed high fat diet at which point their β-cells switch to fatty acids as a fuel source. This switch cannot be tolerated and β-cells in βPHD3KO mice eventually fail. Thus, PHD3 maintains glucose-stimulated insulin secretion in β-cells during states of fatty acid excess, such as diabetes and obesity.
Establishment of a stable transgenicg6pdM1315-1443zebrafish line with glucose-6-phosphate dehydrogenase deficiency
Authors: Shang Lu-Jun , Song Jin , Xia Hai-Xiong , Tuo Yuan-Yuan , Ren Ping-Ping , Wu Xi-Jun , Zhou Yan-Hua , Jin Jiao , Ye Chuan , He Zhi-Xu , Shu Li-Ping 
Published: May 2020

ABSTRACTGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited enzymopathy in humans and is associated with a predisposition to hemolysis. However, there are few animal models to that adequately mimic associated human disease states that could be used to evaluate strategies to address clinical syndromes attributable to G6PD deficiency. In the present study, we aimed to establish a stable transgenic zebrafish model of G6PD deficiency that recapitulates the clinical manifestations of G6PD deficiency. We incorporated a stable transgene of G6PD lacking nucleotides from 1315 to 1443 denotedTg(zgata1:g6pdM1315-1443-egfp). Functional analysis showed thatTg(zgata1:g6pdM1315-1443-egfp) transgenic zebrafish demonstrate a decrease in g6pd activity, reduced GSH levels and hemoglobin content, and increases in pericardial edema in response to α-naphthol exposure, similar to human subjects with G6PD deficiency. We detected no other significant phenotypic abnormalities compared to controls. Taken together, these observations indicate that theTg(zgata1:g6pdM1315-1443-egfp) zebrafish line mirrors key clinical manifestations of G6PD deficiency in humans. This model may facilitate mechanistic studies and promote translational research related to G6PD deficiency.
Systematic mutational analysis of epitope-grafted ED3’s immunogenicity reveals a DENV3-DENV4 bi-serospecific ED3 mutant
Authors: Sultana Mamtaz , Hasan Nazmul , Mahib Mamunur R. , Kulkarni Manjiri R. , Kuroda Yutaka , Islam Mohammad M. 
Published: May 2020

AbstractDengue viruses are classified into four serotypes (DENV1∼4), and the severe forms of dengue disease, the dengue hemorrhagic fever and shock syndrome, are caused by sero-cross-reacting antibodies. However, the residue determinants of the serospecificity and sero-cross-reactivity are yet to be identified. Here, we report an epitope grafting mutational analysis of the serospecificity and cross-serospecificity of the envelope protein domain 3 (ED3; 107 residues, ∼11.6kDa), which contains two major putative epitopes of DENVs. To this end, we constructed ED3 from DENV3 (3ED3) and DENV4 (4ED3), and six epitope-grafted variants, where we transferred epitope 1 (L304I, K305D, V309M, and S310A) and/or epitope 2 (D383N, K384S, K387T, and N389H) of 4ED3 onto 3ED3 and vice versa. Mice immunization using 3ED3 and 4ED3 generated serotype-specific antisera, as expected. Similarly, most epitope-grafted ED3s produced antisera serospecific to the template ED3 with little or no cross-recognition of ED3 of the serotype from which the epitopes were taken. This result indicated that a mere grafting of the epitope was not sufficient to transfer serospecificity, contrary to our expectations. However, one epitope grafted ED3 mutant, where epitope 1 of 3ED3 was grafted onto 4ED3 (4ED3epi1), generated antisera that was serospecific to both 4ED3 and 3ED3. The 4ED3epi1is thus a chimeric ED3 that produces antisera possessing serospecificity to both 3ED3 and 4ED3. The 4ED3epi1provides a unique tool for analyzing serospecificity and cross-reactivity in dengue, and we hope it will serve as a template for trivalent and eventually tetravalent antisera.
The mistletoeStruthanthus flexicaulisreduces dominance and increases diversity of plants in campo rupestre
Authors: França Monteiro Graziella , Barbosa Milton , Antonini Yasmine , de Oliveira Passos Marcela Fortes , Novais Samuel , Fernandes G. Wilson 
Published: May 2020

ABSTRACTThe interaction between hemiparasites and their host plants is an important structuring mechanism for plant communities. The mistletoeStruthanthus flexicaulis(Loranthaceae) is widely distributed in the campo rupestre ecosystem and likely has an important role in structuring the communities of which its hosts are part. The main goals of this study were to investigate the effects of parasitism byS. flexicaulison host plants in a degraded area of campo rupestre and to determine how parasitism affects characteristics of the structure of this plant community over time. We found that parasitized plants had smaller crowns and branch growth, and suffered lower mortality compared to non-parasitized plants. Parasitism byS. flexicaulisdecreased dominance and increased the diversity and evenness of plants in the community over time. Parasitism leads to competition with the host for water and nutrients, which may decrease the performance of the host and, consequently, leading to host death. The high mortality of the most abundant plant species led to a restructured woody plant community. These results reinforce the importance of parasitic plants as key species for maintaining species diversity in plant communities.
Queuine is a nutritional regulator ofEntamoeba histolyticaresponse to oxidative stress and a virulence attenuator
Authors: Nagaraja Shruti , Cai Maggi W. , Sun Jingjing , Varet Hugo , Sarid Lotem , Trebicz-Geffen Meirav , Shaulov Yana , Mazumdar Mohit , Legendre Rachel , Coppée Jean-Yves , Begley Thomas J. , Dedon Peter C. , Gourinath Samudrala , Guillen Nancy , Saito-Nakano Yumiko , Shimokawa Chikako , Hisaeda Hajime , Ankri Serge 
Published: May 2020

AbstractQueuosine is a naturally occurring modified ribonucleoside found in the first position of the anticodon of the transfer RNAs for Asp, Asn, His and Tyr. Eukaryotes lack pathways to synthesize queuine, the nucleobase precursor to queuosine, and must obtain it from diet or gut microbiota. Here we describe the effects of queuine on the physiology of the eukaryotic parasite,Entamoeba histolytica, the causative agent of amebic dysentery. Queuine is efficiently incorporated intoE. histolyticatRNAs by a tRNA-guanine transglycosylase (EhTGT) and this incorporation stimulates the methylation of C38in tRNAAspGUC. Queuine protects the parasite against oxidative stress (OS) and antagonizes the negative effect that oxidation has on translation by inducing the expression of genes involved in OS response, such as heat shock protein 70 (Hsp 70), antioxidant enzymes, and enzymes involved in DNA repair. On the other hand, queuine impairsE. histolyticavirulence by downregulating the expression of genes previously associated with virulence, including cysteine proteases, cytoskeletal proteins, and small GTPases. Silencing of EhTGT prevents incorporation of queuine into tRNAs and strongly impairs methylation of C38in tRNAAspGUC, parasite growth, resistance to OS, and cytopathic activity. Overall, our data reveal that queuine plays a dual role in promoting OS resistance and reducing parasite virulence.ImportanceEntamoeba histolyticais a unicellular parasite that causes amebiasis. The parasite resides in the colon and feeds on the colonic microbiota. The gut flora is implicated in the onset of symptomatic amebiasis due to alterations in the composition of the bacteria. These bacteria modulate the physiology of the parasite and affect the virulence of the parasite through unknown mechanisms. Queuine, a modified nucleobase of queuosine, is exclusively produced by the gut bacteria and leads to tRNA modification at the anticodon loops of specific tRNAs. We found that queuine induces a mild oxidative stress resistance in the parasite and attenuates its virulence. Our study highlights the importance of bacterially derived products in shaping the physiology of the parasite. The fact that queuine inhibits the virulence ofE. histolyticamay lead to new strategies for preventing and/or treating amebiasis by providing to the host queuine directly or via probiotics.
Mechanochemical control of epidermal stem cell divisions by B-plexins
Authors: Jiang Chen , Javed Ahsan , Kaiser Laura , Nava Michele M. , Zhao Dandan , Brandt Dominique T. , Fernández-Baldovinos Javier , Zhou Luping , Höß Carsten , Sawmynaden Kovilen , Oleksy Arkadiusz , Matthews David , Weinstein Lee S. , Gröne Hermann-Josef , Niessen Carien M. , Offermanns Stefan , Wickström Sara A. , Worzfeld Thomas 
Published: May 2020

ABSTRACTThe precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. However, the molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we identify a critical requirement of B-plexin transmembrane receptors in the response to crowding-induced mechanical forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail to sense mechanical compression, resulting in disinhibition of the transcriptional coactivator YAP, hyperproliferation, and tissue overgrowth. Mechanistically, we show that B-plexins mediate mechanoresponses to crowding through stabilization of adhesive cell junctions and lowering of cortical stiffness. Finally, we provide evidence that the B-plexin-dependent mechanochemical feedback is also pathophysiologically relevant to limit tumor growth in basal cell carcinoma, the most common type of skin cancer. Our data uncover a central role of B-plexins in mechanosensation to couple cell density and cell division in development and disease.
Developmental Patterning of Irritability Enhances Prediction of Psychopathology in Pre-adolescence: Improving RDoC with Developmental Science
Authors: Damme Katherine S. F. , Wakschlag Lauren S. , Briggs-Gowan Margaret J. , Norton Elizabeth S. , Mittal Vijay A. 
Published: May 2020

AbstractResearch has demonstrated the transdiagnostic importance of irritability in psychopathology pathways but the contribution of developmentally-unfolding patterns has only recently been explored. To address this question, irritability patterns of 110 youth from a large and diverse early childhood cohort were assessed at preschool age and at school age (∼2.5 years later) with a dimensional irritability scale designed to capture the normal:abnormal spectrum. Participants then returned at Pre-adolescence (∼6 years later) for an assessment with a structured clinical interview (internalizing/externalizing symptoms) and a magnetic resonance imaging scan. When only preschool age irritability was considered, this was a transdiagnostic predictor of internalizing and externalizing symptoms. However, a model including both preschool and school age irritability provided a more nuanced picture. A high preschool and decreasing school age profile of irritability predicted elevated pre-adolescenceinternalizingsymptoms, potentially reflecting emerging coping/internalizing behavior in pre-adolescence. In contrast, a stable irritability profile across these timepoints predicted increased pre-adolescenceexternalizingsymptoms. Further, preschool irritability (a period of rapid growth) did not predict pre-adolescent gray matter volume abnormality, an indicator of transdiagnostic clinical risk. However, irritability at school age (when gray matter volume growth is largely finished) demonstrated an interactive effect among regions; increased school age irritability predicted reduced volume in pre-adolescence emotional regions (e.g., amygdala, medial orbitofrontal cortex) and increased volume in other regions (e.g., cerebellum). Expanding the impact of RDoC’s approach yielding transdiagnostic phenotypes and multiple units of analysis, a developmentally informed approach provides critical new insights into the complex unfolding of mechanisms underlying emerging psychopathology.
Cdonmutation and fetal alcohol converge on Nodal signaling in a mouse model of holoprosencephaly
Authors: Hong Mingi , Christ Annabel , Christa Anna , Willnow Thomas E. , Krauss Robert S. 
Published: May 2020

AbstractHoloprosencephaly (HPE), a defect in midline patterning of the forebrain and midface, arises ~1 in 250 conceptions. It is associated with predisposing mutations in the Nodal and Hedgehog (HH) pathways, with penetrance and expressivity graded by genetic and environmental modifiers, via poorly understood mechanisms. CDON is a multifunctional co-receptor, including for the HH pathway. In mice,Cdonmutation synergizes with fetal alcohol exposure, producing HPE phenotypes closely resembling those seen in humans. We report here that, unexpectedly, Nodal, not HH, signaling is the point of synergistic interaction betweenCdonmutation and fetal alcohol. Window-of-sensitivity, genetic, and in vitro findings are consistent with a model whereby brief exposure ofCdonmutant embryos to ethanol during gastrulation transiently and partially inhibits Nodal pathway activity, with consequent effects on downstream HH signaling during midline patterning. These results illuminate mechanisms of gene-environment interaction in a multifactorial model of a common birth defect.
Isolation and characterization of multi-protein complexes enriched in the K-Cl co-transporter 2 from brain plasma membranes
Authors: Smalley Joshua L. , Kontou Georgina , Choi Catherine , Ren Qiu , Albrecht David , Abiraman Krithika , Rodriguez Santos Miguel A. , Bope Christopher E. , Deeb Tarek Z. , Davies Paul A. , Brandon Nicholas J. , Moss Stephen J. 
Published: May 2020

ABSTRACTKcc2 plays a critical role in determining the efficacy of synaptic inhibition, however, the cellular mechanism neurons use to regulate its membrane trafficking, stability and activity are ill-defined. To address these issues, we used affinity purification to isolate stable multi-protein complexes of Kcc2 from the plasma membrane of murine forebrain. We resolved these using Blue-native polyacrylamide gel electrophoresis (BN-PAGE) coupled to LC-MS/MS. Purified Kcc2 migrated as distinct molecular species of 300, 600 and 800 kDa following BN-PAGE. In excess of 90% coverage of the soluble N and C-termini of Kcc2 was obtained. The 300kDa species largely contained Kcc2, which is consistent with a dimeric quaternary structure for this transporter. Intriguingly, lower levels of Kcc1 were also found in this species suggesting the existence of “mixed” Kcc2/Kcc1 heterodimers. The 600 and 800 kDa species represented stable multi-protein complexes of Kcc2. We identified a set of novel structural, ion transporting and signaling protein interactors, that are present at both excitatory and inhibitory synapses, consistent with the proposed association of Kcc2. These included spectrins, ankyrins, and the IP3 receptor. We also identified interactors more directly associated with phosphorylation; Akap5 and Lmtk3. Finally, we used LC-MS/MS on highly purified endogenous plasma membrane Kcc2 to detect phosphorylation sites. We detected 11 sites with high confidence, including known and novel sites. Collectively our experiments demonstrate that Kcc2 is associated with components of the neuronal cytoskeleton and signaling molecules that may act to regulate transporter membrane trafficking, stability, and activity.