bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterisation of the Ubiquitin-ESCRT pathway in Asgard archaea sheds new light on origins of membrane trafficking in eukaryotes
Authors: Hatano Tomoyuki , Palani Saravanan , Papatziamou Dimitra , Souza Diorge P. , Salzer Ralf , Tamarit Daniel , Makwana Mehul , Potter Antonia , Haig Alexandra , Xu Wenjue , Townsend David , Rochester David , Bellini Dom , Hussain Hamdi M. A. , Ettema Thijs , Löwe Jan , Baum Buzz , Robinson Nicholas P. , Balasubramanian Mohan 
Published: August 2021

SUMMARYThe ESCRT machinery performs a critical role in membrane remodelling events in all eukaryotic cells, including in membrane trafficking, membrane repair, cytokinetic abscission, in viral egress, and in the generation of extracellular vesicles. While the machinery is complex in modern day eukaryotes, where it comprises dozens of proteins, the system has simpler and more ancient origins. Indeed, homologues of ESCRT-III and the Vps4 ATPase, the proteins that execute the final membrane scission reaction, play analogous roles in cytokinesis and potentially in extracellular vesicle formation in TACK archaea where ESCRT-I and II homologues seem to be absent. Here, we explore the phylogeny, structure, and biochemistry of homologues of the ESCRT machinery and the associated ubiquitylation system found in genome assemblies of the recently discovered Asgard archaea. In these closest living prokaryotic relatives of eukaryotes, we provide evidence for the ESCRT-I and II sub-complexes being involved in the ubiquitin-directed recruitment of ESCRT-III,_as it is in eukaryotes. This analysis suggests a pre-eukaryotic origin for the Ub-coupled ESCRT system and a likely path of ESCRT evolution via a series of gene duplication and diversification events.
Nicotinate degradation in a microbial eukaryote: a novel, complete pathway extant in Aspergillus nidulans
Authors: Bokor Eszter , Ámon Judit , Varga Mónika , Szekeres András , Hegedűs Zsófia , Jakusch Tamás , Flipphi Michel , Vágvölgyi Csaba , Gácser Attila , Scazzocchio Claudio , Hamari Zsuzsanna 
Published: August 2021

AbstractSeveral strikingly different aerobic and anaerobic pathways of nicotinate utilization had been described in bacteria. No similar work is extant in any eukaryote. Here we elucidate a complete eukaryotic nicotinate utilization pathway, by constructing single or multiple gene deleted strains and identifying metabolic intermediates by ultra-high performance liquid chromatography – high-resolution mass spectrometry. Enzymes catalyzing each step and all intermediate metabolites were identified. We previously established that the cognate eleven genes organized in three clusters constitute a regulon, strictly dependent on HxnR, a pathway-specific transcription factor. The first step, hydroxylation of nicotinic acid to 6-hydroxynicotinic acid is analogous to that occurring in bacterial pathways and is catalyzed by an independently evolved molybdenum-containing hydroxylase. The following enzymatic steps have no prokaryotic equivalents: 6-hydroxynicotinic acid is converted to 2,3,6-trihydroxypyridine through 2,5-dihydroxypiridine and the trihydroxylated pyridine ring is then saturated to 5,6-dihydroxypiperidine-2-one followed by the oxidation of the C6 hydroxyl group resulting in 3-hydroxypiperidine-2,6-dione. The latter two heterocyclic compounds are newly identified cellular metabolites, while 5,6-dihydroxypiperidine-2-one is a completely new chemical compound. Ring opening between C and N results in α-hydroxyglutaramate, an unprecedented compound in prokaryotic nicotinate catabolic routes. The pathway extant in A. nidulans, and in many other ascomycetes, is different from any other previously analyzed in bacteria. Our earlier phylogenetic analysis of Hxn proteins together with the complete novel biochemical pathway we now describe further illustrates the convergent evolution of catabolic pathways between fungi and bacteria.Significance StatementThis eukaryotic nicotinate catabolic pathway illustrates the convergent evolution of prokaryotic and microbial eukaryotic metabolism. It brings to light newly identified metabolites and step processing enzymes. The identification of hitherto undescribed metabolites - which could serve as precursor biosynthetic molecules - is potentially relevant to both pharmaceutical and agrochemical industries.
Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models
Authors: Fu Fumin , Pietropaolo Michael , Cui Lei , Pandit Shilpa , Li Weiyan , Tarnavski Oleg , Shetty Suraj S. , Liu Jing , Lussier Jennifer M. , Murakami Yutaka , Grewal Prabhjit K. , Deyneko Galina , Turner Gordon M. , Taggart Andrew K.P. , Waters M. Gerard , Coughlin Shaun , Adachi Yuichiro 
Published: August 2021

AbstractThe mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to better characterize atrial fibrillation (AF), we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined are poor representations of human AF, and raise a cautionary note about the use of any murine model to study AF.
The effect of 0.01% atropine on ocular axial elongation for myopia children: a meta-analysis
Authors: Yu Yan , Liu Jiasu 
Published: August 2021

AbstractObjectivesThis meta-analysis aimed to identify the therapeutic effect of 0.01% atropine with on ocular axial elongation for myopia children.MethodsWe searched PubMed, Cochrane Library, and CBM databases from inception to July 2021. Meta-analysis was conducted using STATA version 14.0 and Review Manager version 5.3 softwares. We calculated the weighted mean differences(WMD) to analyze the change of ocular axial length (AL) between orthokeratology combined with 0.01% atropine (OKA) and orthokeratology (OA) alone. The Cochran’ s Q-statistic and I2 test were used to evaluate potential heterogeneity between studies. To evaluate the influence of single studies on the overall estimate, a sensitivity analysis was performed. We also performed sub group and meta-regression analyses to investigate potential sources of heterogeneity. We conducted Begger’ s funnel plots and Egger’ s linear regression tests to investigate publication bias.ResultsNine studies that met all inclusion criteria were included in this meta-analysis. A total of 191 children in OKA group and 196 children in OK group were assessed. The pooled summary WMD of AL change was -0.90(95%CI=-1.25∼-0.55) with statistical significance(t=-5.03, p<0.01), which indicated there was obvious difference between OKA and OK in myopic children. Subgroup analysis also showed that OKA treatment resulted in significantly less axial elongation compared to OK treatment alone according to SER. We found no evidence for publication bias.ConclusionsOur meta-analysis indicates 0.01% atropine atropine is effective in slowing axial elongation in myopia children with orthokeratology.
Transcriptomic analysis of astaxanthin hyper-producing Coelastrum sp. mutant obtained by chemical mutagenesis
Authors: Tharek Ameerah , Mohamad Shaza Eva , Suzuki Iwane , Iwamoto Koji , Hara Hirofumi , Yoshizaki Shinji , Jamaluddin Haryati , Salleh Madihah Md , Yahya Adibah 
Published: August 2021

AbstractA newly isolated green microalga, Coelastrum sp. has the capability to produce and accumulate astaxanthin under various stress conditions. At present, a mutant G1-C1 of Coelastrum sp. obtained through chemical mutagenesis using ethyl methane sulfonate displayed an improvement in astaxanthin accumulation, which was 2-fold higher than that of the wild-type. However, lack of genomic information limits the understanding of the molecular mechanism that leads to a high level of astaxanthin in the mutant G1-C1. In this study, transcriptome sequencing was performed to compare the transcriptome of astaxanthin hyper-producing mutant G1-C1 and wild-type of Coelastrum sp. with respect to astaxanthin biosynthesis. This is to clarify why the mutant produced higher astaxanthin yield compared to the wild-type strain. Based on the transcriptomic analysis, the differentially expressed genes involved in astaxanthin biosynthesis were significantly upregulated in the mutant G1-C1 of Coelastrum sp. Genes coding phytoene synthase, phytoene desaturase, ζ-carotene desaturase, and lycopene β-cyclase involved in β-carotene biosynthesis in the mutant cells were upregulated by 10-, 9.2-, 8.4-, and 8.7-fold, respectively. Genes coding beta-carotene ketolase and beta-carotene 3-hydroxylase involved in converting β-carotene into astaxanthin were upregulated by 7.8- and 8.0-fold, respectively. In contrast, the lycopene ε-cyclase gene was downregulated by 9.7-fold in mutant G1-C1. Together, these results contribute to higher astaxanthin accumulation in mutant G1-C1. Overall, the data in this study provided molecular insight for a better understanding of the differences in astaxanthin biosynthesis between the wild-type and mutant G1-C1 strains.
Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 Delta variant
Authors: Zhang Jun , Xiao Tianshu , Cai Yongfei , Lavine Christy L. , Peng Hanqin , Zhu Haisun , Anand Krishna , Tong Pei , Gautam Avneesh , Mayer Megan L. , Walsh Richard M. , Rits-Volloch Sophia , Wesemann Duane R. , Yang Wei , Seaman Michael S. , Lu Jianming , Chen Bing 
Published: August 2021

AbstractThe Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outcompeted previously prevalent variants and become a dominant strain worldwide. We report here structure, function and antigenicity of its full-length spike (S) trimer in comparison with those of other variants, including Gamma, Kappa, and previously characterized Alpha and Beta. Delta S can fuse membranes more efficiently at low levels of cellular receptor ACE2 and its pseudotyped viruses infect target cells substantially faster than all other variants tested, possibly accounting for its heightened transmissibility. Mutations of each variant rearrange the antigenic surface of the N-terminal domain of the S protein in a unique way, but only cause local changes in the receptor-binding domain, consistent with greater resistance particular to neutralizing antibodies. These results advance our molecular understanding of distinct properties of these viruses and may guide intervention strategies.
Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions
Authors: Song Aixin , Hazlett Zachary , Abeykoon Dulith , Dortch Jeremy , Dillon Andrew , Curtiss Justin , Martinez Sarah Bollinger , Hill Christopher P. , Yu Clinton , Huang Lan , Fushman David , Cohen Robert E. , Yao Tingting 
Published: August 2021

AbstractUCH37, also known as UCHL5, is a highly conserved deubiquitinating enzyme (DUB) that associates with the 26S proteasome. Recently it was reported that UCH37 activity is stimulated by branched ubiquitin chain architectures. To understand how UCH37 achieves its unique debranching specificity, we performed biochemical and NMR structural analyses and found that UCH37 is activated by contacts with the hydrophobic patches of both distal ubiquitins that emanate from a branched ubiquitin. In addition, RPN13, which recruits UCH37 to the proteasome, further enhances branched-chain specificity by restricting linear ubiquitin chains from having access to the UCH37 active site. In cultured human cells under conditions of proteolytic stress, we show that substrate clearance by the proteasome is promoted by both binding and deubiquitination of branched polyubiquitin by UCH37. Proteasomes containing UCH37(C88A), which is catalytically inactive, aberrantly retain polyubiquitinated species as well as the RAD23B substrate shuttle factor, suggesting a defect in recycling of the proteasome. These findings provide a foundation to understand how proteasome degradation of substrates modified by a unique ubiquitin chain architecture is aided by a DUB.
Integrated experimental-computational analysis of a liver-islet microphysiological system for human-centric diabetes research
Authors: Casas Belén , Vilén Liisa , Bauer Sophie , Kanebratt Kajsa , Huldt Charlotte Wennberg , Magnusson Lisa , Marx Uwe , Andersson Tommy B. , Gennemark Peter , Cedersund Gunnar 
Published: August 2021

AbstractMicrophysiological systems (MPS) are powerful tools for emulating human physiology and replicating disease progression in vitro. MPS could be better predictors of human outcome than current animal models, but mechanistic interpretation and in vivo extrapolation of the experimental results remain significant challenges. Here, we address these challenges using an integrated experimental-computational approach. This approach allows for in silico representation and predictions of glucose metabolism in a previously reported MPS with two organ compartments (liver and pancreas) connected in a closed loop with circulating medium. We developed a computational model describing glucose metabolism over 15 days of culture in the MPS. The model was calibrated on an experiment-specific basis using data from seven experiments, where single-liver or liver-islet cultures were exposed to both normal and hyperglycemic conditions resembling high blood glucose levels in diabetes. The calibrated models reproduced the fast (i.e. hourly) variations in glucose and insulin observed in the MPS experiments, as well as the long-term (i.e. over weeks) decline in both glucose tolerance and insulin secretion. We also investigated the behavior of the system under hypoglycemia by simulating this condition in silico, and the model could correctly predict the glucose and insulin responses measured in new MPS experiments. Last, we used the computational model to translate the experimental results to humans, showing good agreement with published data of the glucose response to a meal in healthy subjects. The integrated experimental-computational framework opens new avenues for future investigations toward disease mechanisms and the development of new therapies for metabolic disorders.
Multiple parasitism promotes facultative host acceptance of cuckoo eggs and rejection of cuckoo chicks
Authors: Noh Hee-Jin , Gloag Ros , Langmore Naomi E. 
Published: August 2021

AbstractMany hosts of brood parasitic cuckoos reject foreign eggs from the nest. Yet where nests commonly receive more than one cuckoo egg, hosts might benefit by instead accepting parasite eggs. This is because cuckoos remove an egg from the nest before adding their own, and keeping cuckoo eggs in the nest reduces the odds that further host eggs are removed by subsequent cuckoos. This ‘clutch dilution effect’ has been proposed as a precondition for the evolution of cuckoo nestling eviction by hosts, but no previous studies have tested this in a host that rejects cuckoo nestlings. We tested the clutch dilution hypothesis in large-billed gerygones (Gerygone magnirostris), which are multiply parasitized by little bronze-cuckoos (Chalcites minutillus). Gerygones evict cuckoo nestlings but accept cuckoo eggs. Consistent with multiple parasitism favouring egg acceptance, we found gerygone egg survival was higher under scenarios of cuckoo egg acceptance than rejection. Yet gerygones were also flexible in their egg acceptance, with 35% abandoning cuckoo-egg-only clutches. This novel demonstration of adaptive clutch dilution suggests that multiple parasitism can favour a facultative response to brood parasite eggs, whereby hosts accept or reject parasite eggs depending on clutch composition.
Myostatin is a negative regulator of adult neurogenesis in zebrafish
Authors: Saraswathy Vishnu Muraleedharan , Zhou Lili , Burris Brooke , Dogra Deepika , Reischauer Sven , Mokalled Mayssa H. 
Published: August 2021

ABSTRACTIntrinsic and extrinsic inhibition of axonal and neuronal regeneration obstruct spinal cord (SC) repair in mammals. In contrast, adult zebrafish achieve functional recovery after SC damage. While studies of innate SC regeneration have focused on axon regrowth as a primary repair mechanism, how local neurogenesis impacts functional recovery is unknown. We uncovered dynamic expression ofmyostatin b(mstnb) in a niche of dorsal ependymal progenitors after complete SC transection in zebrafish. Genetic loss-of-function inmstnbimpaired functional recovery, although glial and axonal bridging across the lesion were unaffected. Using a series of transgenic reporter lines, we quantified the numbers of stem, progenitor, and neuronal cells in the absence ofmstnb. We found neural stem cell proliferation was reduced, while newborn neurons were increased inmstnbnull tissues, suggestingmstnbis a negative regulator of neurogenesis. Molecularly, neuron differentiation genes were upregulated, while the neural stem cell maintenance genefgf1bwas downregulated inmstnbmutants. Finally, we show that human FGF1 treatment rescued neuronal gene expression inmstnbmutants. These studies uncover unanticipated neurogenic functions formstnbin adult zebrafish, and establish the importance of local neurogenesis for functional SC repair.
ROS signalling requires uninterrupted electron flow and is lost during ageing in flies
Authors: Graham Charlotte , Stefanatos Rhoda , Yek Angeline E.H. , Spriggs Ruth V. , Loh Samantha H.Y. , Uribe Alejandro Huerta , Zhang Tong , Martins L. Miguel , Maddocks Oliver D.K. , Scialo Filippo , Sanz Alberto 
Published: August 2021

AbstractMitochondrial Reactive Oxygen Species (mtROS) are cellular messengers essential for cellular homeostasis. In response to stress, reverse electron transport (RET) by respiratory complex I generates high levels of mtROS. Suppression of ROS produced via RET (ROS-RET) reduces survival under stress, while activation of ROS-RET extends lifespan in basal conditions. Here, we demonstrate that ROS-RET signalling requires increased electron entry and uninterrupted electron flow through the electron transport chain (ETC). We found that ROS-RET is abolished in old fruit flies where electron flux is reduced. Instead, mitochondria in aged flies produce consistently high levels of mtROS. Finally, we demonstrate that in young flies reduction of electron exit from the ETC, but not electron entry, phenocopies mtROS generation observed in old individuals. Our results define the mechanism by which ROS signalling is lost during ageing.HighlightsROS-RET signalling requires an uninterrupted flow of electrons through the ETC.ROS-RET signalling fails during ageing, with mitochondria producing persistently high levels of ROS.Interruption of ROS-RET signalling compromises stress adaptation in old flies.Reducing electron exit suppresses ROS-RET signalling and phenocopies ROS production observed in old mitochondria.
Synthesis and structures of three new pyridine-containing oxazoline ligands of complexes for asymmetric catalysis
Authors: Wolińska Ewa , Wysocki Waldemar , Branowska Danuta , Karczmarzyk Zbigniew 
Published: August 2021

Three new chiral pyridine-containing oxazoline derivatives with fluorine and perfluoromethyl groups, namely, 2-({2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C21H16F3N3O, 2-({5-fluoro-2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C18H17F4N3O, and 2-({2-[(3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C22H16F3N3O, as chiral ligands in metal-catalysed asymmetric reactions, were synthesized and characterized by spectral and X-ray diffraction methods. The conformation of the molecules is influenced by strong N—H...N hydrogen bonding and weak C—H...X(X = O and N) interactions. There are no intermolecular hydrogen bonds in the crystal structures of the analysed compounds. Hirshfeld surface analysis showed that the H...H contacts constitute a high percentage of the intermolecular interactions. The conformational analysis was performed by theoretical calculations using the density functional theory (DFT) method. The mechanism of complex formation in terms of the electron-withdrawing effect of the substituents on the oxazoline ring and the ligand conformation is discussed.