bluuebunny/crossref_metadata_2025_split huggingface dataset:
Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis
Authors: Wright Amanda L. , Della Gatta Paul A. , Le Sheng , Berning Britt A. , Mehta Prachi , Jacobs Kelly R. , Gul Hossai , Gil Rebecca San , Hedl Thomas J. , Riddell Winonah R. , Watson Owen , Keating Sean S. , Venturato Juliana , Chung Roger S. , Atkin Julie D. , Lee Albert , Shi Bingyang , Blizzard Catherine A. , Morsch Marco , Walker Adam K. 
Published: August 2019

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, ‘rNLS’, mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS mice. Finally, riluzole treatment beginning after disease onset in rNLS mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in rNLS mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways directly related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.Significance StatementAccumulation of cytoplasmic TDP-43 protein is the hallmark pathology of ALS. Riluzole is the most widely used drug for ALS treatment, but provides only a short extension of lifespan. We demonstrate here in the rNLS mouse model, which mimics TDP-43 pathology, that riluzole does not ameliorate progressive alterations in motor strength and coordination, muscle atrophy, glutamate receptor levels, or TDP-43 protein levels and solubility, and does not prolong animal survival. Riluzole similarly did not affect decreased levels of glutamate receptor subunits GluA2/GluA3 in rNLS mice. The inability of riluzole to rescue pathological or phenotypic changes in this TDP-43 model provides further impetus for the discovery of improved therapies targeting the key drivers of ALS pathogenesis.
Cloning of Two Gene Clusters Involved in the Catabolism of 2,4-Dinitrophenol byParaburkholderiasp. Strain KU-46 and Characterization of the Initial DnpAB Enzymes and a Two-Component Monooxygenase DnpC1C2
Authors: Yamamoto Taisei , Liu Yaxuan , Kohaya Nozomi , Hasegawa Yoshie , Lau Peter C.K. , Iwaki Hiroaki 
Published: August 2019

AbstractBesides an industrial pollutant, 2,4-dinitrophenol (DNP) has been used illegally as a weight loss drug that had claimed human lives. Little is known about the metabolism of DNP, particularly among Gram-negative bacteria. In this study, two non-contiguous genetic loci ofParaburkholderia(formerlyBurkholderia) sp. strain KU-46 genome were identified and four key initial genes (dnpA,dnpB, anddnpC1C2) were characterized to provide molecular and biochemical evidence for the degradation of DNP via the formation of 4-nitrophenol (NP), a pathway that is unique among DNP utilizing bacteria. Reverse transcription PCR analysis indicated that thednpAgene encoding the initial hydride transferase (28 kDa), and thednpBgene encoding a nitrite-eliminating enzyme (33 kDa), are inducible by DNP and the two genes are organized in an operon. Purified DnpA and DnpB from overexpression clones inEscherichia colieffected the transformation of DNP to NP via the formation of hydride-Meisenheimer complex of DNP. The function of DnpB appears new since all homologs of DnpB sequences in the protein database are annotated as putative nitrate ABC transporter substrate-binding proteins. The gene cluster responsible for the degradation of DNP after NP formation was designateddnpC1C2DXFER.DnpC1 and DnpC2 were functionally characterized as the respective FAD reductase and oxygenase components of the two-component NP monooxygenase. Both NP and 4-nitrocatechol were shown to be substrates, producing hydroquinone and hydroxyquinol, respectively. Elucidation of thehqdA1A2BCDgene cluster allows the delineation of the final degradation pathway of hydroquinone to ß-ketoadipate prior to its entry to the tricarboxylic acid cycle.ImportanceThis study fills a gap in our knowledge and understanding of the genetic basis and biochemical pathway for the degradation of 2,4-dinitrophenol (DNP) in Gram-negative bacteria, represented by the prototypicalParaburkholderiasp. strain KU-46 that metabolizes DNP through the formation of 4-nitrophenol, a pathway unseen by other DNP utilizers. The newly cloned genes could serve as DNA probes in biomonitoring as well as finding application in new biocatalyst development to access green chemicals. By and large, knowledge of the diverse strategies used by microorganisms to degrade DNP will contribute to the development of bioremediation solutions since DNP is an industrial pollutant used widely in the chemical industry for the synthesis of pesticides, insecticides, sulfur dyes, wood preservatives, and explosives, etc. (119 words)
aMpLiTuDe MoDuLaTeD noise for tinnitus suppression in tonal and noise-like tinnitus
Authors: Schoisswohl S. , Arnds J. , Schecklmann M. , Langguth B. , Schlee W. , Neff P. 
Published: August 2019

AbstractBackgroundAcoustic stimulation offers a potential treatment approach for tinnitus but also in-sights in its basic mechanisms by short-term tinnitus suppression called residual inhibition (RI). The effects of RI were found to be depending on intensity, length or sound types covering the individual tinnitus characteristics. In patients with tonal tinnitus RI was increased with amplitude modulated (AM) pure tones at the individual tinnitus frequency while the effects of modulated noise sounds have not been systematically researched.ObjectivesThe aim of the present study was to investigate whether in patients with noise-like tinnitus RI can be increased by AM noise-like stimuli according to the individual tinnitus frequency range.MethodsFor this purpose the individual tinnitus characteristics (noise-like and tonal tinnitus) were assessed via customizable noise-band matching, in order to generate bandpass filtered stimuli according to the individual tinnitus sound (individualized bandpass filtered sounds; IBP). Subsequent, various stimuli differing in bandpass filtering and AM were tested with respect to their potential to induce RI. Patients were acoustically stimulated with seven different types of stimuli for three minutes each and had to rate the loudness of their tinnitus after each stimuli.ResultsResults indicate a general efficacy of noise stimuli for the temporary suppression of tinnitus, but no significant differences between AM and unmodulated IBP. Significantly better effects were observed for the subgroup with noise-like tinnitus (n=14), especially directly after stimulation offset.ConclusionsThe study at hand provides further insights in potential mechanisms behind RI for different types of tinnitus. Beyond that, derived principles may qualify for new or extend current tinnitus sound therapies.
FusB energises import across the outer membrane through direct interaction with its ferredoxin substrate
Authors: Wojnowska Marta , Walker Daniel 
Published: August 2019

AbstractPhytopathogenic Pectobacterium spp. import ferredoxin into the periplasm for proteolytic processing and iron release via the ferredoxin uptake system. Although the ferredoxin receptor FusA and the processing protease, FusC, have been identified, the mechanistic basis of ferredoxin import is poorly understood. In this work we demonstrate that protein translocation across the outer membrane is dependent on the TonB-like protein FusB. In contrast to the loss of FusC, loss of FusB or FusA abolishes ferredoxin transport to the periplasm, demonstrating that FusA and FusB work in concert to transport ferredoxin across the outer membrane. In addition to interaction with the TonB-box region of FusA, FusB also forms a complex with the ferredoxin substrate, with complex formation required for substrate transport. These data suggest that ferredoxin transport requires energy transduction from the cytoplasmic membrane via FusB for both removal of the FusA plug domain and for substrate translocation through the FusA barrel.
Localizing genomic regions contributing to the extremes of externalizing behavior: ADHD, aggressive and antisocial behaviors
Authors: Rodríguez-López Mariana L. , Pol Hilleke Hulshoff , Franke Barbara , Klein Marieke 
Published: August 2019

AbstractAttention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder, which in some cases occurs comorbid with aggressive and antisocial behavior (AGG; ASB). The three externalizing behaviors are moderately to highly heritable and are genetically correlated. However, the genomic regions underlying this correlation are unknown. In this study, we aimed to localize genetic loci shared between ADHD, AGG, and ASB, using two complementary approaches.GWAS summary statistics for ADHD, AGG, and ASB were used for (1) cross-trait gene-based meta-analysis association analyses and (2) local genetic correlation analyses to identify shared genetic loci. Results of both complementary methods were combined to retrieve overlapping genes. Biological functionality of prioritized genes was assessed by exploring gene expression patterns in brain tissues and testing for gene-based association with (subcortical) brain regions.We confirmed previous findings that ADHD, AGG, and ASB were positively genetically correlated at a global level. We identified eleven significant genes in cross-trait gene-based meta-analyses, 31 loci shared between traits; 34 genes were identified when both approaches were combined.This study emphasizes the complex genetic architecture underlying global genetic correlations at the locus level. Converging evidence from these cross-trait analyses highlights novel candidate genes underlying biological mechanisms shared by ADHD, AGG, and ASB.
Single-cell tracing of the first hematopoietic stem cell generation in human embryos
Authors: Zeng Yang , He Jian , Bai Zhijie , Li Zongcheng , Gong Yandong , Liu Chen , Ni Yanli , Du Junjie , Ma Chunyu , Bian Lihong , Lan Yu , Liu Bing 
Published: August 2019

AbstractTracing the emergence of the first hematopoietic stem cells (HSCs) in human embryos, particularly the scarce and transient precursors thereof, is so far challenging, largely due to technical limitations and material rarity. Here, using single-cell RNA sequencing, we constructed the first genome-scale gene expression landscape covering the entire course of endothelial-to-HSC transition during human embryogenesis. The transcriptomically defined HSC-primed hemogenic endothelial cells (ECs) were captured at Carnegie stage 12-14 in an unbiased way, showing an unambiguous arterial EC feature with the up-regulation ofRUNX1,MYBandANGPT1. Importantly, subcategorizing CD34+CD45−ECs into CD44+population strikingly enriched hemogenic ECs by over 10-fold. We further mapped the developmental path from arterial ECs via HSC-primed hemogenic ECs to hematopoietic stem progenitor cells, and revealed a distinct expression pattern of genes that were transiently over-represented upon the hemogenic fate choice of arterial ECs, includingEMCN,PROCRandRUNX1T1. We also uncovered another temporally and molecularly distinct intra-embryonic hemogenic EC population, which was detected mainly at earlier CS 10 and lacked the arterial feature. Finally, we revealed the cellular components of the putative aortic niche and potential cellular interactions acting on the HSC-primed hemogenic ECs. The cellular and molecular programs and interactions that underlie the generation of the first HSCs from hemogenic ECs in human embryos, together with distinguishing HSC-primed hemogenic ECs from others, will shed light on the strategies for the production of clinically useful HSCs from pluripotent stem cells.
RBA for eukaryotic cells: foundations and theoretical developments
Authors: Goelzer Anne , Fromion Vincent 
Published: August 2019

AbstractResource allocation models were recently identified as new ways to investigate cell design principles. In particular, the Resource Balance Analysis (RBA) framework is the first constraint-based modelling method capable of accurate quantitative predictions of the genome-wide resource allocation. Initially developed and validated on bacteria, the objective of this paper is to provide the mathematical fundations of the extension of the RBA framework to eukaryotic cells. We especially investigate the way to handle the cellular compartments in order to formalize eventually the functioning of organelles. It turns out that the final RBA problem for eukaryotic cells is close to the one of prokaryotic cells from a theoretical point of view. The mathematical properties that were already identified on the prokaryotic RBA framework can be easily transposed to eukaryotic cells. In particular, the eukaryotic RBA problem can be solved easily at the cell scale by Linear Programming. This paves the way to future developments of RBA models for eukaryotic cells.
Marker-assisted introgression of multiple resistance genes confers broad spectrum resistance against bacterial leaf blight and blast diseases in Putra-1 rice variety
Authors: Chukwu Samuel C. , Rafii Mohd Y. , Ramlee Shairul I. , Ismail Siti I. , Oladosu Yusuff , Muhammad Isma’ila 
Published: August 2019

AbstractThis experiment was conducted with the aim of introgressing multiple resistance genes against bacterial leaf blight (BLB) and blast diseases through marker-assisted backcross breeding. Two dominant (Xa4andXa21) and two recessive (xa5andxa13) BLB resistance genes were introgressed into a Malaysian elite rice variety Putra-1 with genetic background of three blast resistance (Piz, Pi2andPi9) genes and high yielding. Eight polymorphic tightly linked functional and SSR markers were used for foreground selection of target genes. 79 polymorphic SSR markers were used in background selection. The plants were challenged at initial stage of breeding and challenged again at BC2F2with the most virulent Malaysian pathotypes ofXoo(P7.7) andMagnaporthe oryzae(P7.2) to test their resistance. Results obtained from foreground marker analysis showed that the BC1F1and BC2F1both fitted into the Mendel’s single gene segregation ratio of 1:1 for bothXooand blast resistance. At BC2F2, result obtained indicated that foreground marker segregation fitted into the expected Mendelian ratio of 1:2:1 for blast resistance only. Marker-assisted background selection revealed high percentage of recurrent parent genome recovery (95.9%). It was concluded that resistance toXoopathotype P7.7 in IRBB60 was neither due to two independent gene action nor epistasis but substantially due to single nuclear gene action. Also, the inheritance of blast resistance in the pyramided lines to pathotype P7.2 was also attributed to single gene action. The incorporation of four bacterial leaf blight and three blast resistance genes (Xa4+xa5+xa13+Xa21+Pi9+Pi2+Piz) in the newly developed lines provides for broad spectrum and durable resistance against the two major diseases studied.
Evolution of an amniote-specific mechanism for modulating ubiquitin signalling via phosphoregulation of the E2 enzyme UBE2D3
Authors: Roman-Trufero Monica , Ito Constance M , Pedebos Conrado , Magdalou Indiana , Wang Yi-Fang , Karimi Mohammad M , Moyon Benjamin , Webster Zoe , Gregorio Aida di , Azuara Veronique , Khalid Syma , Speck Christian , Rodriguez Tristan , Dillon Niall 
Published: August 2019

AbstractGenetic variation in the enzymes that catalyse post-translational modification of proteins is a potentially important source of phenotypic variation during evolution. Ubiquitination is one such modification that affects turnover of virtually all of the proteins in the cell in addition to roles in signalling and epigenetic regulation. UBE2D3 is a promiscuous E2 enzyme that acts as a ubiquitin donor for E3 ligases that catalyse ubiquitination of developmentally important proteins. We have used protein sequence comparison of UBE2D3 orthologues to identify a position in the C-terminal α-helical region of UBE2D3 that is occupied by a conserved serine in amniotes and by alanine in anamniote vertebrate and invertebrate lineages. Acquisition of the serine (S138) in the common ancestor to modern amniotes created a phosphorylation site for Aurora B. Phosphorylation of S138 disrupts the structure of UBE2D3 and reduces the level of the protein in mouse ES cells (ESCs). Substitution of S138 with the anamniote alanine (S138A) increases the level of UBE2D3 in ESCs as well as being a gain of function early embryonic lethal in mice. When mutant S138A ESCs were differentiated into extra-embryonic primitive endoderm (PrE), levels of the PDGFRα and FGFR1 receptor tyrosine kinases (RTKs) were reduced and PreE differentiation was compromised. Proximity ligation analysis showed increased interaction between UBE2D3 and the E3 ligase CBL and between CBL and the RTKs. Our results identify a sequence change that altered the ubiquitination landscape at the base of the amniote lineage with potential effects on amniote biology and evolution.
Non-junctional Cadherin3 regulates cell migration and contact inhibition of locomotion via domain-dependent opposing regulations of Rac1
Authors: Ichikawa Takehiko , Stuckenholz Carsten , Davidson Lance A. 
Published: August 2019

AbstractClassical cadherins are well-known primary adhesion molecules responsible for physically connecting neighboring cells and signaling the cell-cell contact. Recent studies have suggested novel signaling roles for “non-junctional” cadherins (Niessen and Gottardi, 2008; Padmanabhan et al., 2017); however, the function of cadherin signaling independent of cell-cell contacts remains unknown. In this study, we used mesendoderm cells and tissues from gastrula stageXenopus laevisembryos to demonstrate that extracellular and cytoplasmic cadherin domains regulate Rac1 in opposing directions in the absence of cell-cell contacts. Furthermore, we found that non-junctional cadherins regulate contact inhibition of locomotion (CIL) during gastrulation through alterations in the stability of the cytoskeleton. Live FRET imaging of Rac1 activity illustrated how non-junction cadherin3 (formerly C-cadherin) spatio-temporally regulates CIL. Our study provides novel insights into adhesion-independent signaling by cadherin3 and its role in regulating single and collective cell migrationin vivo.
Isolation and functional characterisation of lamina propria leukocytes from helminth-infected, murine small intestine
Authors: Webster Holly C. , Andrusaite Anna T. , Shergold Amy L. , Milling Simon W.F. , Perona-Wright Georgia 
Published: August 2019

AbstractThe use of helminth infections as tools to understand the type 2 immune response is a well-established technique and important to many areas of immunological research. The phenotype and function of immune cell populations at the site of infection is a key determinant of pathogen clearance. However, infections with helminths such as the murine nematodeHeligomosmoides polygryruscause increased mucus production and thickening of the intestinal wall, which can result in extensive cell death when isolating and analysing cells from the lamina propria (LP). Populations of larger immune cells such as macrophages and dendritic cells are often trapped within mucus or dying tissues. Here we describe an optimised protocol for isolating LP leukocytes from the small intestine ofH.polygyrus-infected mice, and we demonstrate phenotypic and functional identification of myeloid and CD4+T cell subsets using cytokine staining and flow cytometry. Our protocol may provide a useful experimental method for the immunological analysis of the affected tissue site during helminth infections.
High-throughput sequencing analysis of bacterial diversity in raw and pasteurized goat milk
Authors: Huang Feng , Liu Siqi , Zhou Xiaokang , Wang Pengfei , He Rengchun , Zhou Zhiyang , Zou Caixia 
Published: August 2019

AbstractThe aim of this study was to evaluate the microbial composition of both raw and pasteurized goat milk using high-throughput DNA sequencing. This analysis revealed that the dominant phylum found in the raw milk was Proteobacteria, and the dominant genus was Kluyvera; Proteobacteria and Kluyvera constituted up to 67.66% and 28.85% of the total bacteria population, respectively. The microorganisms in goat milk predominantly consist of Gram-negative bacteria. Notably, Akkermansia and Faecalibacterium were identified in goat milk for the first time. In addition, the results also indicate that some bacteria in pasteurized goat milk may exist in a viable but nonculturable (VBNC) state. This study provides a theoretical basis that may aid the community in better understanding bacterial diversity in goat milk. The results of this study will help us to improve the quality and safety of goat milk.ImportanceThe microbial diversity in goat milk and pasteurized goat milk at different refrigeration stages was described. Several bacterial species that have not previously been reported in goat milk were identified, including many VBNC bacteria. The findings provided the necessary microbial information for quality and safety of goat milk and dairy products.