bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endogenous but not sensory-driven activity controls migration, morphogenesis and survival of adult-born neurons in the mouse olfactory bulb
Authors: Li Kaizhen , Figarella Katherine , Su Xin , Kovalchuk Yury , Gorzolka Jessika , Neher Jonas J. , Mojtahedi Nima , Casadei Nicolas , Hedrich Ulrike B. S. , Garaschuk Olga 
Published: April 2021

SummaryThe development and survival of adult-born neurons is believed to be driven by sensory signaling. By genetically manipulating excitability of adult-born cells (via cell-specific overexpression of either Kv1.2 or Kir2.1 K+channels), longitudinalin vivomonitoring of their Ca2+signaling and transcriptome analyses, we show that endogenous but not sensory-driven activity governs migration, morphogenesis, survival, and functional integration of adult-born juxtaglomerular neurons in the mouse olfactory bulb. The proper development of these cells required fluctuations of cytosolic Ca2+levels, phosphorylation of CREB, and pCREB-mediated gene expression. Attenuating Ca2+fluctuations via K+channel overexpression strongly downregulated genes involved in neuronal migration, differentiation, and morphogenesis and upregulated apoptosis-related genes, thus locking adult-born cells in the vulnerable and immature state. Together, the data reveal signaling pathways connecting the endogenous intermittent neuronal activity/Ca2+fluctuations as well as proper Kv1.2/Kir2.1 K+channel function to migration, maturation, and survival of adult-born neurons.
RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control
Authors: Mohan Harihar Milaganur , Pithadia Amit , Trzeciakiewicz Hanna , Crowley Emily V. , Pacitto Regina , Safren Nathaniel , Zhang Chengxin , Zhou Xiaogen , Zhang Yang , Basrur Venkatesha , Paulson Henry L. , Sharkey Lisa M. 
Published: April 2021

AbstractThe brain expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been implicated in numerous neurodegenerative diseases including ALS/FTD. UBQLN2 typically resides in the cytoplasm but in disease can translocate to the nucleus, as in Huntington’s disease where it promotes the clearance of mutant Huntingtin protein. How UBQLN2 translocates to the nucleus and clears aberrant nuclear proteins, however, is not well understood. In a mass spectrometry screen to discover UBQLN2 interactors, we identified a family of small (13 kDa), highly homologous uncharacterized proteins, RTL8, and confirmed the interaction between UBQLN2 and RTL8 bothin vitrousing recombinant proteins andin vivousing mouse brain tissue. Under endogenous and overexpressed conditions, RTL8 localizes to nucleoli. When co-expressed with UBQLN2, RTL8 promotes nuclear translocation of UBQLN2. UBQLN2 and RTL8 colocalize within ubiquitin-enriched subnuclear structures containing PQC components. The robust effect of RTL8 on the nuclear translocation and subnuclear localization of UBQLN2 does not extend to the other brain-expressed ubiquilins, UBQLN1 and UBQLN4. Moreover, compared to UBQLN1 and UBQLN4, UBQLN2 preferentially stabilizes RTL8 levels in human cell lines and in mouse brain, supporting functional heterogeneity among UBQLNs. As a novel UBQLN2 interactor that recruits UBQLN2 to specific nuclear compartments, RTL8 may regulate UBQLN2 function in nuclear protein quality control.
Dynamic interplay between a TonB dependent heme transporter and a TonB protein in a membrane environment
Authors: Somboon Kamolrat , Melling Oliver , Lejeune Maylis , Pinheiro Glaucia M.S. , Paquelin Annick , Bardiaux Benjamin , Nilges Michael , Delepelaire Philippe , Khalid Syma , Izadi-Pruneyre Nadia 
Published: April 2021

AbstractThe envelope of Gram-negative bacteria is composed of a double membrane separated by the periplasmic space. This organization imposes geometrical and distance constraints that are key for the mechanism of action of multicomponent systems spanning the envelope. However, consideration of all three compartments by experimental approaches is still elusive. Here we used the state-of-the-art molecular dynamics simulation in anEscherichia colienvelope model to obtain a dynamic view of molecular interactions between the outer membrane heme transporter HasR and the inner membrane TonB-like protein HasB. Their interaction allows the transfer of the inner membrane proton motive force derived energy to the transporter for heme internalization. The simulations which incorporate both membranes show the key role of periplasmic domains of both proteins, and their dynamics in the complex formation and stability. They revealed a previously unidentified atomic network of interactions, as well as the sequences of the interactions and their variations with the presence of external substrates. Experimental validation (mutations, phenotypic andin vitroassays) confirms the robustness of our approach and provides verification of the simulation-predicted interactions. Based on structural and sequence conservation, the network of interaction revealed in this study is expected to occur in other nutrient import systems. The integrative approach presented here is highly useful to study the dynamic interplay between components of any other bacterial transmembrane systems.
Physical Characterization of Triolein and Implications for Its Role in Lipid Droplet Biogenesis
Authors: Kim Siyoung , Voth Gregory A. 
Published: April 2021

ABSTRACTLipid droplets (LDs) are neutral lipid storing organelles surrounded by a phospholipid (PL) monolayer. At present, how LDs are formed in the endoplasmic reticulum (ER) bilayer is poorly understood. In this study, we present a revised all-atom (AA) triolein (TG) model, the main constituent of the LD core, and characterize its properties in a bilayer membrane to demonstrate the implications of its behavior in LD biogenesis. In bilayer simulations, TG resides at the surface, adopting PL-like conformations (denoted in this work as SURF-TG). Free energy sampling simulation results estimate the barrier for TG relocating from the bilayer surface to the bilayer center to be ∼2 kcal/mol in the absence of an oil lens. SURF-TG is able to modulate membrane properties by increasing PL ordering, decreasing bending modulus, and creating local negative curvature. The other neutral lipid, dioleoyl-glycerol (DAG), also reduces the membrane bending modulus and populates the negative curvature regions. A phenomenological coarse-grained (CG) model is also developed to observe larger scale SURF-TG-mediated membrane deformation. The CG simulations confirm that TG nucleates between the bilayer leaflets at a critical concentration when SURF-TG is evenly distributed. However, when one monolayer contains more SURF-TG, the membrane bends toward the other leaflet, followed by TG nucleation if a concentration is higher than the critical threshold. The central conclusion of this study is that SURF-TG is a negative curvature inducer, as well as a membrane modulator. To this end, a model is proposed in which the accumulation of SURF-TG in the luminal leaflet bends the ER bilayer toward the cytosolic side, followed by TG nucleation.
Structural and molecular determinants for the interaction of ExbB fromSerratia marcescensand HasB, a TonB paralog
Authors: Biou Valérie , Adaixo Ricardo Jorge Diogo , Chami Mohamed , Coureux Pierre-Damien , Laurent Benoist , Ntsogo Enguéné Véronique Yvette , de Amorim Gisele Cardoso , Izadi-Pruneyre Nadia , Malosse Christian , Chamot-Rooke Julia , Stahlberg Henning , Delepelaire Philippe 
Published: April 2021

AbstractExbB and ExbD are cytoplasmic membrane proteins that associate with TonB to convey the energy of the proton-motive force to outer membrane receptors in Gram-negative bacteria for iron uptake. The opportunistic pathogenSerratia marcescens(Sm) possesses both TonB and a heme-specific TonB paralog, HasB. ExbBSmhas a long periplasmic extension absent in other bacteria such asE. coli (Ec). Long ExbB’s are found in several genera of Alphaproteobacteria, most often in correlation with ahasBgene. We investigated specificity determinants of ExbBSmand HasB. We determined the cryo-EM structures of ExbBSmand of the ExbB-ExbDSmcomplex fromS. marcescens. ExbBSmalone is a stable pentamer, and its complex includes two ExbD monomers. We showed that ExbBSmextension interacts with HasB and is involved in heme acquisition and we identified key residues in the membrane domain of ExbBSmand ExbBEc, essential for function and likely involved in the interaction with TonB/HasB. Our results shed light on the new class of inner membrane energy machinery formed by ExbB,ExbD and HasB.
Chemoenzymatic Generation of Phospholipid Membranes Mediated by Type I Fatty Acid Synthase
Authors: Khanal Satyam , Brea Roberto J. , Burkart Michael D. , Devaraj Neal K. 
Published: April 2021

ABSTRACTThede novoformation of lipid membranes from minimal reactive precursors is a major goal in synthetic cell research. In nature, the synthesis of membrane phospholipids is orchestrated by numerous enzymes, including fatty acid synthases and membrane-bound acyltransferases. However, these enzymatic pathways are difficult to fully reproducein vitro. As such, the reconstitution of phospholipid membrane synthesis from simple metabolic building blocks remains a challenge. Here, we describe a chemoenzymatic strategy for lipid membrane generation that utilizes a soluble bacterial fatty acid synthase (cgFAS I) to synthesize palmitoyl-CoAin situfrom acetyl-CoA and malonyl-CoA. The fatty acid derivative spontaneously reacts with a cysteine-modified lysophospholipid by native chemical ligation (NCL), affording a non-canonical amidophospholipid that self-assembles into micron-sized membrane-bound vesicles. To our knowledge, this is the first example of reconstituting phospholipid membrane formation directly from acetyl-CoA and malonyl-CoA precursors. Our results demonstrate that combining the specificity and efficiency of a type I fatty acid synthase with a highly selective bioconjugation reaction provides a biomimetic route for thede novoformation of membrane-bound vesicles.
Spontaneous Isomerization of Asp387 in Tau is Diagnostic for Alzheimer’s Disease: An Endogenous Indicator of Reduced Autophagic Flux
Authors: Hubbard Evan E. , Heil Lilian , Merrihew Gennifer E. , Chhatwal Jasmeer P. , Farlow Martin R. , McLean Catriona A. , Ghetti Bernardino , Newell Kathy L. , Frosch Matthew P. , Bateman Randall J. , Larson Eric B. , Keene C. Dirk , Montine Thomas J. , MacCoss Michael , Julian Ryan R. 
Published: April 2021

AbstractAmino acid isomerization is a spontaneous chemical modification potentially related to the underlying causes of Alzheimer’s disease (AD). We demonstrate that data-independent acquisition mass spectrometry can be used to characterize isomerization in complex protein mixtures. Examination of a large cohort of brain tissue samples revealed a striking relationship between isomerization of tau and AD status. Surprisingly, isomerization was found to be more abundant in both autosomal dominant and sporadic AD samples relative to controls. We hypothesize that lower autophagic flux in AD brains accounts for these results. Additional data, including quantitative analysis of proteins related to autophagy, strongly support this hypothesis. For example, isomerization of tau is positively correlated with levels of p62, a recognized indicator of autophagic inhibition. In sum, the data suggest strong ties between isomerization and autophagic flux, which may therefore represent a promising target for future investigations into the therapy and prevention of AD.
Evidence for continent-wide convergent evolution and stasis throughout 150 years of a biological invasion
Authors: Wu Yihan , Colautti Robert I. 
Published: April 2021

AbstractThe extent to which evolution can rescue a species from extinction, or facilitate range expansion, depends critically on the rate, duration, and geographical extent of the evolutionary response to natural selection. Adaptive evolution can occur quickly, but the duration and geographical extent of contemporary evolution in natural systems remains poorly studied. This is particularly true for species with large geographical ranges and for timescales that lie between ‘long-term’ field experiments and the fossil record. Here, we introduce the Virtual Common Garden (VCG) to investigate phenotypic evolution in natural history collections while controlling for phenotypic plasticity in response to local growing conditions. Reconstructing 150 years of evolution inLythrum salicaria(purple loosestrife) as it invaded North America, we analyze phenology measurements of 3,429 herbarium records, reconstruct growing conditions from more than 12 million local temperature records, and validate predictions across three common gardens spanning 10 degrees of latitude. We find that phenology clines have evolved along parallel climatic gradients, repeatedly throughout the range, during the first century of evolution. Thereafter, the rate of microevolution stalls, recapitulating macroevolutionary stasis observed in the fossil record. Our study demonstrates that preserved specimens are a critical resource for investigating limits to evolution in natural populations. Our results show how natural selection and trade-offs measured in field studies predict adaptive divergence observable in herbarium specimens over 15 decades at a continental scale.
Mining Thousands of Genomes to Classify Somatic and Pathogenic Structural Variants
Authors: Layer Ryan M. , Sedlazeck Fritz J. , Pedersen Brent S. , Quinlan Aaron R. 
Published: April 2021

AbstractStructural variants (SVs) are associated with cancer progression and Mendelian disorders, but challenges with estimating SV frequency remain a barrier to somatic and de novo classification. In particular, variability in filtering and variant calling heuristics limit our ability to use SV catalogs from large cohorts. We present a method to index and search the raw alignments from thousands of samples that overcomes these limitations and supports robust SV analysis.
Reflectance spectroscopy allows rapid, accurate, and non-destructive estimates of functional traits from pressed leaves
Authors: Kothari Shan , Beauchamp-Rioux Rosalie , Laliberté Etienne , Cavender-Bares Jeannine 
Published: April 2021

AbstractMore than ever, ecologists seek to employ herbarium collections to estimate plant functional traits from the past and across biomes. However, many trait measurements are destructive, which may preclude their use on valuable specimens. Researchers increasingly use reflectance spectroscopy to estimate traits from fresh or ground leaves, and to delimit or identify taxa. Here, we extend this body of work to non-destructive measurements on pressed, intact leaves, like those in herbarium collections.Using 618 samples from 68 species, we used partial least-squares regression to build models linking pressed-leaf reflectance spectra to a broad suite of traits, including leaf mass per area (LMA), leaf dry matter content (LDMC), equivalent water thickness, carbon fractions, pigments, and twelve elements. We compared these models to those trained on fresh- or ground-leaf spectra of the same samples.Our pressed-leaf models were best at estimating LMA (R2= 0.932; %RMSE = 6.56), C (R2= 0.855; %RMSE = 9.03), and cellulose (R2= 0.803; %RMSE = 12.2), followed by water-related traits, certain nutrients (Ca, Mg, N, and P), other carbon fractions, and pigments (allR2= 0.514-0.790; %RMSE = 12.8-19.6). Remaining elements were predicted poorly (R2< 0.5, %RMSE > 20). For most chemical traits, pressed-leaf models performed better than fresh-leaf models, but worse than ground-leaf models. Pressed-leaf models were worse than fresh-leaf models for estimating LMA and LDMC, but better than ground-leaf models for LMA. Finally, in a subset of samples, we used partial least-squares discriminant analysis to classify specimens among 10 species with near-perfect accuracy (>97%) from pressed- and ground-leaf spectra, and slightly lower accuracy (>93%) from fresh-leaf spectra.These results show that applying spectroscopy to pressed leaves is a promising way to estimate leaf functional traits and identify species without destructive analysis. Pressed-leaf spectra might combine advantages of fresh and ground leaves: like fresh leaves, they retain some of the spectral expression of leaf structure; but like ground leaves, they circumvent the masking effect of water absorption. Our study has far-reaching implications for capturing the wide range of functional and taxonomic information in the world’s preserved plant collections.
Transfer Learning for Inference of Metastatic Origin from Whole Slide Histology
Authors: Schau Geoffrey F. , Ghani Hassan , Burlingame Erik A. , Thibault Guillaume , Gray Joe W. , Corless Christopher , Chang Young Hwan 
Published: April 2021

AbstractAccurate diagnosis of metastatic cancer is essential for prescribing optimal control strategies to halt further spread of metastasizing disease. While pathological inspection aided by immunohistochemistry staining provides a valuable gold standard for clinical diagnostics, deep learning methods have emerged as powerful tools for identifying clinically relevant features of whole slide histology relevant to a tumor’s metastatic origin. Although deep learning models require significant training data to learn effectively, transfer learning paradigms provide mechanisms to circumvent limited training data by first training a model on related data prior to fine-tuning on smaller data sets of interest. In this work we propose a transfer learning approach that trains a convolutional neural network to infer the metastatic origin of tumor tissue from whole slide images of hematoxylin and eosin (H&E) stained tissue sections and illustrate the advantages of pre-training network on whole slide images of primary tumor morphology. We further characterize statistical dissimilarity between primary and metastatic tumors of various indications on patch-level images to highlight limitations of our indication-specific transfer learning approach. Using a primary-to-metastatic transfer learning approach, we achieved mean class-specific areas under receiver operator characteristics curve (AUROC) of 0.779, which outperformed comparable models trained on only images of primary tumor (mean AUROC of 0.691) or trained on only images of metastatic tumor (mean AUROC of 0.675), supporting the use of large scale primary tumor imaging data in developing computer vision models to characterize metastatic origin of tumor lesions.
SKAP2 as a new regulator of oligodendroglial migration and myelin sheath formation
Authors: Ghelman Julia , Grewing Laureen , Windener Farina , Albrecht Stefanie , Zarbock Alexander , Kuhlmann Tanja 
Published: April 2021

AbstractOligodendroglial progenitor cells (OPC) are highly proliferative and migratory bipolar cells, which differentiate into complex myelin forming and axon ensheathing mature oligodendrocytes during myelination. Recent studies indicate that the oligodendroglial cell population is heterogeneous on transcriptional and functional level depending on the location in the CNS. Here, we compared intrinsic properties of OPC from spinal cord and brain on functional and transcriptional level. Spinal cord OPC demonstrated increased migration as well as differentiation capacity. Moreover, transcriptome analysis revealed differential expression of several genes between both OPC populations. In spinal cord OPC we confirmed upregulation of SKAP2, a cytoplasmatic adaptor protein known for its implication in cytoskeletal remodelling and migration in other cell types. Recent findings suggest that actin dynamics determine not only oligodendroglial migration, but also differentiation: Whereas actin polymerization is important for process extension, actin destabilization and depolymerization is required for myelin sheath formation. Downregulation or complete lack of SKAP2 in OPC resulted in reduced migration and impaired morphological maturation in oligodendrocytes. In contrast, overexpression of SKAP2 as well as constitutively active SKAP2 increased OPC migration suggesting that SKAP2 function is dependent on activation by phosphorylation. Furthermore, lack of SKAP2 enhanced the positive effect on OPC migration after integrin activation suggesting that SKAP2 acts as modulator of integrin dependent migration. In summary, we demonstrate the presence of intrinsic differences between spinal cord and brain OPC and identified SKAP2 as a new regulator of oligodendroglial migration and sheath formation.Significance statementOPC play an important role in many still incurable diseases, such as multiple sclerosis, leukodystrophies or neurodegenerative diseases. Their heterogeneity in different CNS regions has recently been identified. Here, we observed increased migration and differentiation capabilities of OPC isolated from the spinal cord compared to brain OPC and confirmed differences in the transcriptome between these two cell populations. Furthermore, we identified SKAP2 as potential modulator of actin dynamics in oligodendrocytes. Whereas knockdown or lack of SKAP2 impairs migration and myelin sheath formation in mouse and human oligodendrocytes, overexpression of wildtype or constitutively active SKAP2 enhances the migratory capacity of murine oligodendrocytes. In summary, we present SKAP2 as modulator of cytoskeletal dynamics regulating OPC migration, differentiation and myelin sheath formation.
Non-canonical mitochondrial STAT3 signaling mediates exercise-induced insulin secretion down-regulation
Authors: Leite Nayara C. , de Paula Flávia , Lubaczeuski Camila , Borck Patricia C. , Juan-Mateu Jonàs , Souza Jane C. , Eizirik Decio L. , Boschero Antonio C. , Jonas Jean-Christophe , Carneiro Everardo M. , Zoppi Claudio C. 
Published: April 2021

ABSTRACTChronic exercise protects pancreatic beta cells from diabetogenic stress, reducing insulin secretion through unknown mechanisms. We tested the hypothesis that the IL-6/mitochondrial STAT3 (pS-STAT3) axis plays a role in this protective effect. C57BL/6N mice were subjected to endurance training ahead of pancreatic islet isolation and functional analysis. Similar in vitro experiments were performed using insulin-producing INS-1E cells and islets from untrained mice, cultured with serum from trained animals and treated with or without an IL-6 receptor (IL-6R) inhibitor. Then, IL-6R/pS-STAT3 pathway activation and its effects on mitochondrial function and insulin secretion were assessed. Exercise-induced down-regulation of insulin secretion was prevented by inhibition of IL-6R signaling and following STAT3 knockdown. IL-6R activation promoted STAT3 phosphorylation and translocation to the mitochondria, increasing oxygen consumption. Accordingly, lower H2O2 content was reported in islets from trained mice and beta cells exposed to exercise-conditioned serum, while exposure to exogenous H2O2 blocked the down-regulatory effect of training on insulin secretion. Similar findings were observed in islets from obese-trained mice. Together, these findings suggest that the IL-6R/pS-STAT3 axis mediates exercise-induced down-regulation of insulin secretion through modulation of the mitochondrial redox state.