bluuebunny/crossref_metadata_2025_split huggingface dataset:
The structure of pathogenic huntingtin exon-1 defines the bases of its aggregation propensity
Authors: Elena-Real Carlos A. , Sagar Amin , Urbanek Annika , Popovic Matija , Morató Anna , Estaña Alejandro , Fournet Aurélie , Lund Xamuel L. , Shi Zhen-Dan , Costa Luca , Thureau Aurélien , Allemand Frédéric , Swenson Rolf E. , Milhiet Pierre-Emmanuel , Barducci Alessandro , Cortés Juan , Sinnaeve Davy , Sibille Nathalie , Bernadó Pau 
Published: October 2022

AbstractHuntington’s Disease is a neurodegenerative disorder caused by a CAG expansion of the first exon of theHTTgene, resulting in an extended poly-glutamine (poly-Q) tract in the N-terminus of the protein huntingtin (httex1). The structural changes occurring to the poly-Q when increasing its length remain poorly understood mainly due to its intrinsic flexibility and the strong compositional bias of the protein. The systematic application of site-specific isotopic labeling has enabled residue-specific NMR investigations of the poly-Q tract of pathogenic httex1 variants with 46 and 66 consecutive glutamines. The integrative analysis of the data reveals that the poly-Q tract adopts long α-helical conformations stabilized by glutamine side-chain to backbone hydrogen bonds.19F-NMR of site-specifically incorporated fluoro-glutamines and molecular dynamics simulations demonstrate that the mechanism propagating α-helical conformations towards the poly-Q from the upstream N17 domain is independent of the poly-Q track length. Aggregation and atomic force microscopy experiments show that the presence of long and persistent α-helices in the poly-Q tract is a stronger signature in defining the aggregation kinetics and the structure of the resulting fibrils than the number of glutamines. The ensemble of our observations provides a structural perspective of the pathogenicity of expanded httex1 and paves the way to a deeper understanding of poly-Q related diseases.
Quantitative super-resolution imaging of platelet degranulation reveals differential release of VWF and VWF propeptide from alpha-granules
Authors: Swinkels Maurice , Hordijk Sophie , Bürgisser Petra E. , Slotman Johan A. , Carter Tom , Leebeek Frank W.G. , Jansen A.J. Gerard , Voorberg Jan , Bierings Ruben 
Published: October 2022

AbstractBackgroundPlatelet alpha-granules contain Von Willebrand factor (VWF), which is stored in eccentric alpha-granule nanodomains, and VWF propeptide (VWFpp). Differential release of VWF and VWFpp has been reported from endothelial cells. It is unclear if this also occurs during platelet alpha-granule exocytosis. We have recently developed a 3D super-resolution imaging workflow for quantification of platelet alpha-granule content based on Structured Illumination Microscopy (SIM). With this we can study alpha-granule cargo release following platelet activation in hundreds of platelets simultaneously.AimsTo study release of VWF and VWFpp from alpha-granules using quantitative super-resolution microscopy.MethodsPlatelets were activated with PAR-1 activating peptide (PAR-1 ap) or collagen-related peptide (CRP-XL). Alpha-tubulin, VWF, VWFpp, SPARC and fibrinogen were imaged using 3D-SIM, followed by semi-automated analysis in FIJI. Uptake of anti-VWF nanobody during degranulation was used to identify alpha-granules that partially released content.ResultsVWF+ and VWFpp+ structures overlapped nearly completely (∼90%) in resting platelets, implying they are stored in similar eccentric alpha-granule nanodomains. A subset of VWF+/VWFpp+-structures was released completely at 0.6 µM PAR-1 ap, but at higher concentration (20 µM) significantly more VWFpp (85.3±1.6%) was released than VWF (37.6±1.4%). Release of other cargo was intermediate at 20 µM (SPARC: 62.2±1.4%; fibrinogen: 51.9±2.9%), providing further evidence for differential cargo release. Similar results were obtained using CRP-XL. Anti-VWF nanobody was taken up by VWF+/VWFpp-structures and increased with stimulus strength, demonstrating these were post-exocytotic structures.ConclusionsVWF and VWFpp are differentially released from alpha-granules. This may affect how platelet-derived VWF and VWFpp contribute to formation and stabilization of hemostatic clots.Key pointsVWFpp and VWF are localized in the same, eccentric alpha-granule subdomain in resting platelets and do not overlap with other alpha-granule cargo proteins such as fibrinogenVWFpp and VWF are differentially secreted from individual alpha-granules upon activation with platelet agonists PAR-1 activating peptide and collagen-related peptide
Assembly of the 81.6 Mb centromere of pea chromosome 6 elucidates the structure and evolution of metapolycentric chromosomes
Authors: Macas Jiří , Robledillo Laura Ávila , Kreplak Jonathan , Novák Petr , Koblížková Andrea , Vrbová Iva , Burstin Judith , Neumann Pavel 
Published: October 2022

AbstractCentromeres in the legume generaPisumandLathyrusexhibit unique morphological characteristics, including extended primary constrictions and multiple separate domains of centromeric chromatin. These so-called metapolycentromeres resemble an intermediate form between monocentric and holocentric types, and therefore provide a great opportunity for studying the transitions between different types of centromere organizations. However, because of the exceedingly large and highly repetitive nature of metapolycentromeres, highly contiguous assemblies needed for these studies are lacking. Here, we report on the assembly and analysis of a 177.6 Mb region of pea (Pisum sativum) chromosome 6, including the 81.6 Mb centromere region (CEN6) and adjacent chromosome arms. Genes, DNA methylation profiles, and most of the repeats were uniformly distributed within the centromere, and their densities in CEN6 and chromosome arms were similar. The exception was an accumulation of satellite DNA in CEN6, where it formed multiple arrays up to 2 Mb in length. Centromeric chromatin, characterized by the presence of the CENH3 protein, was predominantly associated with arrays of three different satellite repeats; however, five other satellites present in CEN6 lacked CENH3. The presence of CENH3 chromatin was found to determine the spatial distribution of the respective satellites during the cell cycle. Finally, oligo-FISH painting experiments, performed using probes specifically designed to label the genomic regions corresponding to CEN6 inPisum,Lathyrus, andViciaspecies, revealed that metapolycentromeres evolved via the expansion of centromeric chromatin into neighboring chromosomal regions and the accumulation of novel satellite repeats. However, in some of these species, centromere evolution also involved chromosomal translocations and centromere repositioning.SignificanceDespite their conserved function, plant centromeres exhibit considerable variation in their morphology and sequence composition. For example, centromere activity is restricted to a single region in monocentric chromosomes, but is distributed along the entire chromosome length in holocentric chromosomes. The principles of centromere evolution that led to this variation are largely unknown, partly due to the lack of high-quality centromere assemblies. Here, we present an assembly of the pea metapolycentromere, a unique type of centromere that represents an intermediate stage between monocentric and holocentric organizations. This study not only provides a detailed insight into sequence organization, but also reveals possible mechanisms for the formation of the metapolycentromere through the spread of centromeric chromatin and the accumulation of satellite DNA.
Aggregation and Defence
Authors: Durieux David M. , Gemmell Brad J. 
Published: October 2022

AbstractCassiopeasp., the Upside-Down Jellyfish, are considered to be sedentary epibenthic organisms which exhibit little to no movement on the seafloor. In this study, we use time-lapse videography of a Cassiopea population in the Florida Keys to demonstrate that Cassiopea sp. exhibit a greater degree of benthic locomotion than previously understood, with animals covering distances up to 178 cm per day. In addition, Cassiopea seem to aggregate on the bottom, with average number of neighbours consistently higher than would be expected for random distributions. Given the ability of Cassiopea to release nematocysts directly into the water column, we present this aggregation as a potential defensive behaviour in this species.
Bayesian Pharmacometrics Analysis of Baclofen for Alcohol Use Disorder
Authors: Baldy Nina , Hashemi Meysam , Simon Nicolas , Jirsa Viktor K. 
Published: October 2022

AbstractAlcohol use disorder (AUD) also called alcohol dependence is a major public health problem, which affects almost 10% of the world’s population. Baclofen as a selective GABABreceptor agonist has emerged as a promising drug for the treatment of AUD, however, its optimal dosage varies according to individuals, and its exposure-response relationship has not been well established yet. In this study, we use a principled Bayesian workflow to estimate the parameters of a pharmacokinetic (PK) population model from Baclofen administration to patients with AUD. By monitoring various convergence diagnostics, the probabilistic methodology is first validated on synthetic longitudinal datasets and then, applied to infer the PK model parameters based on the clinical data that were retrospectively collected from outpatients treated with oral Baclofen. We show that state-of-the-art advances in automatic Bayesian inference using self-tuning Hamiltonian Monte Carlo (HMC) algorithms with a leveraged level of information in priors provide accurate predictions on Baclofen plasma concentration in individuals. This approach may pave the way to render non-parametric HMC sampling methods sufficiently easy and reliable to use in clinical schedules for personalized treatment of AUD.
Discovery of intratumoral oncolytic bacteria toward targeted anticancer theranostics
Authors: Goto Yamato , Iwata Seigo , Miyako Eijiro 
Published: October 2022

AbstractUnveiling the different biomedical functions of tumor-resident microbiota has remained challenging for the development of advanced anticancer medicines. Here we show that isolated intratumoral bacteria with its association with natural purple photosynthetic bacteria have a high innate biocompatibility and drastic immunogenic anticancer efficacies. They preferentially grow and proliferate within targeted tumor milieu, which effectively causes immune cells to infiltrate the tumor and provoke strong anticancer responses in various syngeneic mouse models including those of colorectal cancer, sarcoma, metastatic lung cancer, and extensive drug-resistant breast cancer. Furthermore, these functional bacteria-treated mice, that exhibit excellent anticancerous responses of tumors, have significantly prolonged survival rates with effective immunological memory. Notably, light-harvesting nanocomplexes of microbial consortium of intratumoral bacteria and purple photosynthetic bacteria is capable of tumor diagnosis using bio-optical-window near-infrared light, making them useful theranostic agents for highly targeted immunological elimination of the tumor and for precisely marking tumor location.
Importance of Glutamine in Synaptic Vesicles Revealed by Functional Studies of SLC6A17 and Its Mutations Pathogenic for Intellectual Disability
Authors: Jia Xiaobo , Zhu Jiemin , Bian Xiling , Liu Sulin , Yu Sihan , Liang Wenjun , Jiang Lifen , Mao Renbo , Rao Yi 
Published: October 2022

AbstractHuman mutations in the gene encoding the solute carrier (SLC) 6A17 caused intellectual disability (ID). The physiological role of SLC6A17 and pathogenesis of Slc6a17-based-ID were both unclear. Here we report learning deficits in SLC6A17 knockout and point mutants. Biochemistry, proteomics and electron microscopy (EM) support SLC6A17 protein localization in synaptic vesicles (SVs). Chemical analysis of SVs by liquid chromatography coupled to mass spectrometry (LC-MS) revealed glutamine (Gln) in SVs containing SLC6A17. Virally mediated overexpression of SLC6A17 increased Gln in SVs. Either genetic or virally mediated targeting of SLC6A17 reduced Gln in SVs. One ID mutation caused SLC6A17 mislocalization while the other caused defective Gln transport. Multidisciplinary approaches with 7 types of genetically modified mice have shown Gln as an endogenous substrate of SLC 6A17, uncovered Gln as a new molecule in SVs, established the necessary and sufficient roles of SLC6A17 in Gln transport into SVs, and suggested SV Gln decrease as the key pathogenetic mechanism in human ID.
The temporal regulation inter-leaves from domesticated-tomato contrasts with timelessness of its wild ancestors
Authors: Siqueira João Antonio , Martins Auxiliadora O. , Wakin Thiago , Silva Marcelle Ferreira , Batista-Silva Willian , Brito Fred A.L. , Fernie Alisdair R. , Nunes-Nesi Adriano , Araújo Wagner L. 
Published: October 2022

SUMMARYCells, tissues, and organs are characterized by harbouring complex systems allowing communication between one another. Plant domestication was demonstrated to have structured the circadian rhythms, while also synchronising flowering and metabolism. Here, we demonstrate that the domesticated tomato (Solanum lycopersicum) manifests more synchronized rhythmicity across the whole plant. Consequently, the leaf development program is more coordinated in this species than in its wild relatives, whereinS. lycopersicumyoung leaves develop slowly in comparison to mature leaves. Young leaves from wild tomatoes display higher photosynthesis than mature leaves, while large metabolite accumulations occur across plant segments. Consequently, the diel metabolite levels are rather similar between young and mature leaves in the wild tomatoS. pennellii, whereas the expression patterns for circadian clock genes are widely contrasting between both leaves. We further demonstrated that additions of genes related to domestication into the wild tomatoS. pimpinellifoliumappear to synchronize the development of young and mature leaves to be rather similar to that observed forS. lycopersicum. Collectively, the strengthening of inter-organs relationships on domesticated tomato indicates a synchronized biology, which is most likely fundamental to explaining its elevated yield.
Comprehensive interrogation of aDrosophilaembryonic patterning network reveals the impact of chromatin state on tissue-specific burst kinetics and RNA Polymerase II promoter-proximal pause release
Authors: Hunt George , Vaid Roshan , Pirogov Sergei , Pfab Alexander , Ziegenhain Christoph , Sandberg Rickard , Reimegård Johan , Mannervik Mattias 
Published: October 2022

AbstractFormation of tissue-specific transcriptional programs underlies multicellular development, but how the chromatin landscape influences transcription is not fully understood. Here we comprehensively resolve differential transcriptional and chromatin states duringDrosophiladorsoventral (DV) patterning. We find that RNA Polymerase II pausing is established at DV promoters prior to zygotic genome activation (ZGA), that pausing persists irrespective of cell fate, but that release into productive elongation is tightly regulated and accompanied by tissue-specific P-TEFb recruitment. DV enhancers acquire distinct tissue-specific chromatin states through CBP-mediated histone acetylation that predict the transcriptional output of target genes, whereas promoter states are more tissue invariant. Transcriptome-wide inference of burst kinetics in different cell types revealed that while DV genes are generally characterized by a high burst size, either burst size or frequency can differ between tissues. The data suggest that pausing is established by pioneer transcription factors prior to ZGA and that release from pausing is imparted by enhancer chromatin state to regulate bursting in a tissue-specific manner in the early embryo. Our results uncover how developmental patterning is orchestrated by tissue-specific bursts of transcription from Pol II primed promoters in response to enhancer regulatory cues.
Calcitic prisms of the giant seashellPinna nobilisform light guide arrays
Authors: Amini Shahrouz , Zhu Tingting , Biswas Abin , Charsooghi Mohammad A. , Kim Kyoohyun , Reber Simone , Dauphin Yannicke , Fratzl Peter 
Published: October 2022

AbstractThe shells of thePinnidaefamily are based on a double layer of single-crystal-like calcitic prisms and inner aragonitic nacre, a structure known for its outstanding mechanical performance. However, on the posterior side, shells are missing the nacreous layer, which raises the question of whether there could be any functional role in giving up this mechanical performance. Here, we demonstrate that the prismatic part of thePinna nobilisshell exhibits unusual optical properties, whereby each prism acts as an individual optical fiber guiding the ambient light to the inner shell cavity by total internal reflection. This pixelated light channeling enhances both spatial resolution and contrast while reducing angular blurring, an apt combination for acute tracking of a moving object. Our findings may offer insights into the evolutionary aspects of light-sensing and imaging by biological materials and introduce a conceptual framework for the development of bio-inspired multifunctional ceramics and architectured light-tracking materials.
Staphylococcus aureusFtsZ and PBP4 bind to the conformationally dynamic N-terminal domain of GpsB
Authors: Sacco Michael D. , Hammond Lauren R. , Noor Radwan E. , Bhattacharya Dipanwita , Madsen Jesper J. , Zhang Xiujun , Butler Shane G. , Kemp M. Trent , Jaskolka-Brown Aiden C. , Khan Sebastian J. , Gelis Ioannis , Eswara Prahathees J. , Chen Yu 
Published: October 2022

AbstractBacterial cell division is a tightly regulated process that requires the formation of a dynamic multi-protein complex. In the Firmicutes phylum, GpsB is a membrane associated protein that coordinates peptidoglycan synthesis for cell growth and division. Although GpsB has been studied in several organisms, the structure, function, and interactome ofStaphylococcus aureusGpsB is largely uncharacterized, despite being reported as uniquely essential for growth in this clinically relevant bacterium. To address this knowledge gap, we solved the crystal structure of the N-terminal domain ofS. aureusGpsB. This structure reveals an atypical asymmetric dimer, and major conformational flexibility that can be mapped to a hinge region formed by a three-residue insertion exclusive toStaphylococci. When this three-residue insertion is excised, its thermal stability increases, and the mutant no longer produces a previously reported lethal phenotype when overexpressed inBacillus subtilis. Furthermore, we provide the first biochemical, biophysical, and crystallographic evidence that the N-terminal domain of GpsB binds not only PBP4, but also FtsZ, through a conserved recognition motif located on their C-terminus, thus linking peptidoglycan synthesis with cell division. Taken together, the unique structure ofS. aureusGpsB and its direct interaction with FtsZ/PBP4 provide deeper insight into the central role of GpsB inS. aureuscell division.
Seedless fruit inAnnona squamosaL. is monogenic and conferred byINOlocus deletion in multiple accessions
Authors: Rodrigues Bruno Rafael Alves , Gasser Charles S. , Pimenta Samy , Pereira Marlon Cristian Toledo , Nietsche Silvia 
Published: October 2022

SummaryUnderstanding the genetic basis and inheritance of a trait facilitates the planning of breeding and development programs of new cultivars. In the sugar apple tree (Annona squamosaL.), the mechanism of the desirable seedless trait in the Thai seedless (Ts) and Brazilian seedless (Bs) accessions was associated with a deletion of theINNER NO OUTER(INO) locus. Genetic analysis of F1, F2and backcross descendants of crosses of Bs to fertile wild-type varieties showed that seedlessness was recessive and monogenic. Whole genome sequencing of a third accession, Hawaiian seedless (Hs), identified a 16 kilobase deletion includingINO. The finding of an identical deletion in Ts and Bs indicated a common origin among genotypes, from a single deletion event. Analysis of microsatellite markers could not preclude the possibility that all three accessions are vegetatively propagated clones. The sequence of the deletion site enabled formulation of a codominant assay for the wild-type and mutant genes that validated theINOgene deletion as the cause of seedless trait, and can be used in the selection of new seedless varieties. The study findings and obtained progenies should be useful in breeding and introgression programs of the trait into elite sugar apple lines and into otherAnnonasby means of interspecific crossings.
Disrupting peroxisomes alters lipid metabolism in melanoma and uncovers a novel therapeutic vulnerability in combination with MAPK-targeted therapies
Authors: Huang Fan , Cai Feiyang , Dahabieh Michael S. , Gunawardena Kshemaka , Talebi Ali , Dehairs Jonas , El-Turk Farah , Park Jae Yeon , Goncalves Christophe , Gagnon Natascha , Su Jie , Gaub Perrine , Joyal Jean-Sébastien , Mitchell John J , Swinnen Johannes V , Miller Wilson H. , del Rincón Sonia V. 
Published: October 2022

AbstractMelanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKi) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiates the pro-apoptotic effects of MAPKi via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Co-targeting PEX3 and UGCG selectively eliminates a subset of metabolically active, drug-tolerant CD36+melanoma persister cells, thereby sensitizing melanoma to MAPKi and delaying resistance. Increased levels of peroxisomal genes andUGCGare found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restores MAPKi sensitivity in multiple models of therapy resistance. Finally, triple therapy comprised of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor and a MAPKi demonstrates potent anti-tumor activity in pre-clinical melanoma models, thus representing a promising approach for melanoma treatment.HighlightsInhibiting peroxisome biogenesis uncovers a metabolic vulnerability in melanomaCD36+persister melanoma cells tolerate MAPK-targeted therapy through peroxisome/UGCG mediated metabolic rewiringDual blockade of PEX3 and UGCG potentiates melanoma response to MAPK-targeted therapies and restores therapeutic sensitivity in MAPKi-resistant tumorsNNC 55-0396 is a PEX3-PEX19 binding inhibitor with potent anti-tumor activity in melanoma