bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dominant role of adult neurogenesis-induced structural heterogeneities in driving plasticity heterogeneity in dentate gyrus granule cells
Authors: Shridhar Sameera , Mishra Poonam , Narayanan Rishikesh 
Published: August 2021

ABSTRACTNeurons and synapses manifest pronounced variability in the amount of plasticity induced by identical activity patterns. The mechanisms underlying such plasticity heterogeneity, implicated in context-specific resource allocation during encoding, have remained unexplored. Here, we employed a systematic, unbiased, and physiologically constrained search to identify the mechanisms behind plasticity heterogeneity in dentate gyrus granule cells. We found that each of intrinsic, synaptic, and structural heterogeneities independently yielded heterogeneous plasticity profiles obtained with two different induction protocols. However, prior predictions about strong relationships between neuronal intrinsic excitability and plasticity emerged only when adult-neurogenesis-induced structural heterogeneities were accounted for. Strikingly, despite the concomitant expression of heterogeneities in structural, synaptic, and intrinsic neuronal properties, similar plasticity profiles were attainable through synergistic interactions among these heterogeneities. Importantly, consequent to strong relationships with intrinsic excitability measurements, we found that synaptic plasticity in the physiological range was achieved in immature cells despite their electrophysiologically-observed weak synaptic strengths. Together, our analyses unveil the dominance of neurogenesis-induced structural heterogeneities in driving plasticity heterogeneity in granule cells. Broadly, these analyses emphasize that the mechanistic origins of and the implications for plasticity heterogeneities need quantitative characterization across brain regions, particularly focusing on context-specific encoding of learned behavior.
BRANEart: identify stability strength and weakness regions in membrane proteins
Authors: Basu Sankar , Assaf Simon S. , Teheux Fabian , Rooman Marianne , Pucci Fabrizio 
Published: August 2021

AbstractUnderstanding the role of stability strengths and weaknesses in proteins is a key objective for rationalizing their dynamical and functional properties such as conformational changes, catalytic activity, and protein-protein and protein-ligand interactions. We present BRANEart, a new, fast and accurate method to evaluate the per-residue contributions to the overall stability of membrane proteins. It is based on an extended set of recently introduced statistical potentials derived from membrane protein structures, which better describe the stability properties of this class of proteins than standard potentials derived from globular proteins. We defined a per-residue membrane propensity index from combinations of these potentials, which can be used to identify residues which strongly contribute to the stability of the transmembrane region or which would, on the contrary, be more stable in extramembrane regions, or vice versa. Large-scale application to membrane and globular proteins sets and application to tests cases show excellent agreement with experimental data. BRANEart thus appears as a useful instrument to analyze in detail the overall stability properties of a target membrane protein, to position it relative to the lipid bilayer, and to rationally modify its biophysical characteristics and function. BRANEart can be freely accessed from http://babylone.3bio.ulb.ac.be/BRANEart.
An isogenic panel of single App knock-in mouse models of Alzheimer’s disease confers differential profiles of β-secretase inhibition and endosomal abnormalities
Authors: Watamura Naoto , Sato Kaori , Shiihashi Gen , Iwasaki Ayami , Kamano Naoko , Takahashi Mika , Sekiguchi Misaki , Yamazaki Naomi , Fujioka Ryo , Nagata Kenichi , Hashimoto Shoko , Saito Takashi , Ohshima Toshio , Saido Takaomi C. , Sasaguri Hiroki 
Published: August 2021

SUMMARYWe previously developed single App knock-in mouse models of Alzheimer’s disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL- G-F and AppNL-F mice). These models showed the development of amyloid β peptide (Aβ) pathology, neuroinflammation and cognitive impairment with aging. We have now generated App knock-in mice devoid of the Swedish mutations (AppG-F mice) and some additional mutants to address the following two questions: [1] Do the Swedish mutations influence the mode of β-secretase inhibitor action in vivo? [2] Does the quantity of C-terminal fragment of amyloid precursor protein (APP) generated by β-secretase (CTF-β) affect endosomal properties as previously reported as well as other pathological events? Aβ pathology was exhibited by AppG-F mice from 6 to 8 months of age, and was accompanied by microglial and astrocyte activation. We found that a β-secretase inhibitor, verubecestat, inhibited Aβ production in AppG-F mice, but not in AppNL-G-F mice, indicating that the AppG-F mice are more suitable for preclinical studies of β-secretase inhibition given that most AD patients do not carry Swedish mutations. We also found that the quantity of CTF-β generated by various App knock-in mutants failed to correlate with endosomal alterations or enlargement, implying that CTF-β, endosomal abnormalities, or both are unlikely to play a major role in AD pathogenesis. This is the first AD mouse model ever described that recapitulates amyloid pathology in the brain without the presence of Swedish mutations and without relying on the overexpression paradigm. Thus, experimental comparisons between different App knock-in mouse lines will potentially provide new insights into our understanding of the etiology of AD.
Neprilysin-sensitive amyloidogenic Aβ versus IDE-sensitive soluble Aβ: a probable mechanistic cause for sporadic Alzheimer’s disease
Authors: Sasaguri Hiroki , Takamura Risa , Watamura Naoto , Kakiya Naomasa , Ohshima Toshio , Fujioka Ryo , Yamazaki Naomi , Sekiguchi Misaki , Iwata Kaori , Matsuba Yukio , Hashimoto Shoko , Tsubuki Satoshi , Saito Takashi , Iwata Nobuhisa , Saido Takaomi C. 
Published: August 2021

AbstractNeprilysin (NEP) and insulin-degrading enzyme (IDE) are considered the two major catabolic enzymes that degrade amyloid β peptide (Aβ), the primary cause of Alzheimer’s disease (AD). However, their roles in Aβ metabolism in vivo have never been compared in an impartial and side-by-side manner. Here, we crossbred single App knock-in mice with NEP (Mme) KO mice and with IDE (Ide) KO mice to generate double mutants that were analyzed for their biochemical and Aβ pathology properties. We found that NEP is responsible for the metabolism of amyloidogenic insoluble Aβ whereas IDE affects soluble Aβ. A deficiency of NEP, but not of IDE, augmented the formation of Aβ plaques, dystrophic neurites, and astrocytic and microglial activation, all of which are key pathological events in the development of AD. In addition, a deficiency of NEP had no significant impact on the levels of various neuropeptides (somatostatin, substance P, cholecystokinin, and neuropeptide Y), well known to be in vitro substrates for NEP, presumably because NEP is expressed in secretory vesicles and on the presynaptic membranes of excitatory neurons while most if not all neuropeptides are secreted from inhibitory neurons. This argues against the concern that NEP up-regulation for treatment of preclinical AD would reduce the levels of these neuropeptides. These findings indicate that NEP relatively selectively degrades Aβ in the brain. Whereas familial AD (FAD) is unambiguously caused by an increased anabolism of Aβ, and of Aβ 42 and Aβ 43 in particular, the anabolism of Aβ appears unaffected before its deposition in the brain that subsequently leads to the onset of sporadic AD (SAD). These observations thus suggest that NEP-sensitive amyloidogenic Aβ likely plays a primary pathogenic role in the etiology of SAD. Our findings are consistent with the aging-dependent decline of NEP expression in human brain and with recent genome-wide association studies (GWAS) indicating that variants of the gene encoding NEP (MME) are associated with the risk of SAD development. Taken together, our results imply that the aging-associated decrease in NEP expression is a primary cause of SAD and could thus be a target for the treatment of preclinical AD once other factors such as apolipoprotein E genotypes have also been considered.
Coordinately regulated interbacterial antagonism defense pathways constitute a bacterial innate immune system
Authors: Ting See-Yeun , LaCourse Kaitlyn D. , Ledvina Hannah E. , Zhang Rutan , Radey Matthew C. , Kulasekara Hemantha D. , Somavanshi Rahul , Bertolli Savannah K. , Gallagher Larry A. , Kim Jennifer , Penewit Kelsi M. , Salipante Stephen J. , Xu Libin , Peterson S. Brook , Mougous Joseph D. 
Published: August 2021

AbstractBacterial survival is fraught with antagonism, including that deriving from viruses and competing bacterial cells1–3 4. It is now appreciated that bacteria mount complex antiviral responses; however, whether a coordinated defense against bacterial threats is undertaken is not well understood. Previously we showed thatPseudomonas aeruginosapossess a danger sensing pathway that is a critical fitness determinant during competition against other bacteria5, 6. Here, we conducted genome-wide screens inP. aeruginosathat reveal three conserved and widespread interbacterial antagonism resistance clusters (arc1-3). We find that althougharc1-3are coordinately activated by the Gac/Rsm danger sensing system, they function independently and provide idiosyncratic defense capabilities, distinguishing them from general stress response pathways. Our findings demonstrate that Arc3 family proteins provide specific protection against phospholipase toxins by preventing the accumulation of lysophospholipids in a manner distinct from previously characterized membrane repair systems. These findings liken the response ofP. aeruginosato bacterial threats to that of eukaryotic innate immunity, wherein threat detection leads to the activation of specialized defense systems.
Correlation analysis among single nucleotide polymorphisms in thirteen language genes and culture/education parameters from twenty-six countries
Authors: Sun Bo , Guo Changlu , Zhang Zhizhou 
Published: August 2021

AbstractLanguage is a vital feature of any human culture, but whether language gene polymorphisms have meaningful correlations with some cultural characteristics during the long-run evolution of human languages largely remains obscure (uninvestigated). This study would be an endeavor example to find evidences for the above question’s answer. In this study, the collected basic data include 13 language genes and their randomly selected 111 single nucleotide polymorphisms (SNPs), SNP profiles, 29 culture/education parameters, and estimated cultural context values for 26 representative countries. In order to undertake principal component analysis (PCA) for correlation search, SNP genotypes, cultural context and all other culture/education parameters have to be quantitatively represented into numerical values. Based on the above conditions, this study obtained its preliminary results, the main points of which contain: (1) The 111 SNPs contain several clusters of correlational groups with positive and negative correlations with each other; (2) Low cultural context level significantly influences the correlational patterns among 111 SNPs in the principal component analysis diagram; and (3) Among 29 culture/education parameters, several basic characteristics of a language (the numbers of alphabet, vowel, consonant and dialect) demonstrate least correlations with 111 SNPs of 13 language genes.
Identification of MIRNA-MRNA-HUB Gene Network Prediction in Squamous Cell Lung Carcinoma Via Starbase Server and Insilico Analysis of Hub Genes
Authors: Kalaiselven Ashwini , Swaminathan Venkataramanan 
Published: August 2021

ABSTRACTMalaysian has suffered from lung cancer, accounting for around 10% of all cancers reported in 2021. Prioritization of early diagnosis and natural treatments of lung cancer patients is crucial to improve their survival rate.The aim of this study is to identify the miRNA-mRNA and potential hub gene corresponding to lung carcinoma and natural drugs candidates to inhibit progression of lung cancer via insilico approaches.GSE176348,GSE85841 and GSE164750 gene expression profiles were retrieved from NCBI and GEO2R analysis was carried out accordingly to principal standard p<0.05 and logFC>1 to identify up-regulated and down-regulated genes from the datasets. Protein-protein interaction analysis of up-regulated and down-regulated genes was performed in Cytoscape software and top 10 hub genes were observed by cytohubba tools plugin in Cytoscape.Next, Biological Process (BP), cellular component (CC), molecular function (MF) of top 10 up regulated and down regulated hub genes were observed via DAVID server. The survival curves of top 10 up and down regulated hub genes were constructed by the Kaplan-Meier plotter and the expression level of hub genes in lung cancer tissues and normal tissues analyzed via GEPIA2 online database. IMPPAT: Indian Medicinal Plants, Phytochemistry And Therapeutics database was utilized for selection of potential natural drug candidates for lung cancer and ADME test was carried out on the selected drug compounds.To identify the most promising drug candidates,the hub genes were docked with respective natural drugs candidates via Swiss Dock online tool.Finally, The Encyclopedia of RNA Interactomes (ENCORI) database was used to study the MIRNA-MRNA network of targeted hub genes.In summary,this study is helpful in discovery of miRNAs-mRNA and analysis of natural drug candidates to inhibit lung carcinoma.
Association of cerebral venous thrombosis with recent COVID-19 vaccination: case-crossover study using ascertainment through neuroimaging in Scotland
Authors: McKeigue Paul M , Burgul Raj , Bishop Jen , Robertson Chris , McMenamin Jim , O’Leary Maureen , McAllister David A , Colhoun Helen M 
Published: August 2021

AbstractObjectivesTo investigate the association of primary acute cerebral venous thrombosis (CVT) with COVID-19 vaccination through complete ascertainment of all diagnosed CVT in the population of Scotland.DesignCase-crossover study comparing recent (1-14 days after vaccination) with less recent exposure to vaccination among cases of CVT.SettingNational data for Scotland from 1 December 2020, with diagnosed CVT case ascertainment through neuroimaging studies up to 17 May 2021 and diagnostic coding of hospital discharges up to 28 April 2021 and with linkage to vaccination records.Main outcome measurePrimary acute cerebral venous thrombosisResultsOf 50 primary acute CVT cases, 29 were ascertained only from neuroimaging studies, 2 were ascertained only from hospital discharges, and 19 were ascertained from both sources. Of these 50 cases, 14 had received the Astra-Zeneca ChAdOx1 vaccine and 3 the Pfizer BNT162b2 vaccine. The incidence of CVT per million doses in the first 14 days after vaccination was 2.2 (95% credible interval 0.9 to 4.1) for ChAdOx1 and 1 (95% credible interval 0.1 to 2.9) for BNT162b2. The rate ratio for CVT associated with exposure to ChAdOx1 in the first 14 days compared with exposure 15-84 days after vaccination was 3.2 (95% credible interval 1.1 to 9.5). The 95% credible interval for the rate ratio associated with recent versus less recent exposure to BNT162b2 (0.6 to 95.8) was too wide for useful inference.ConclusionsThese findings support a causal association between CVT and the AstraZeneca vaccine. The absolute risk of post-vaccination CVT in this population-wide study in Scotland was lower than has been reported for populations in Scandinavia and Germany; the explanation for this is not clear.What is already known on this topicThe risk of cerebral venous thrombosis (CVT) within 28 days of receiving the AstraZeneca ChAdOx1 vaccine has been estimated as 18 to 25 per million doses in Germany and Scandinavia, but only 5 per million doses in the UK based on the Yellow Card reporting scheme. Risk estimates based on adverse event reporting systems are subject to under-ascertainment and other biases.What this study addsAll diagnosed cases of CVT in Scotland were ascertained by searching neuroimaging studies from December 2020 to May 2021 and linked to national vaccination records. The risk of CVT within 28 days of vaccination with ChAdOx1 was estimated as 3.5 per million doses with an upper bound of 6 per million doses, against a background incidence of about 12 per million adults per year. This indicates that the Yellow Card system has not seriously underestimated the risk in the UK; the explanation for higher risk in other European countries is not clear.
Insulin Signaling Attenuates GLUT4 Endocytosis in Muscle Cells via GSK3α-Dyn2-Bin1 Interplay
Authors: Laiman Jessica , Loh Julie , Tang Wei-Chun , Chuang Mei-Chun , Chen Bi-Chang , Chang Yi-Cheng , Chuang Lee-Ming , Liu Ya-Wen 
Published: August 2021

AbstractInsulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane of skeletal muscle is critical for postprandial glucose uptake; however, whether the internalization of GLUT4 into cells is also regulated by insulin signaling remains unclear. Here, we discover that the activity of dynamin-2 (Dyn2), pivotal GTPase catalyzing GLUT4 internalization, is regulated by insulin signaling in muscle cells. The membrane fission activity of Dyn2 is inhibited in muscle cells through binding with the SH3 domain-containing protein Bin1. Phosphorylation of Serine848 on Dyn2 by GSK3α or the mutations of Bin1-SH3 in patients with centronuclear myopathy, elevate the activity of Dyn2 due to reduced binding affinity toward Bin1. The augmented Dyn2 fission activity in muscle cells leads to GLUT4 internalization and Bin1-tubule vesiculation. Together, our findings reveal a new role of insulin signaling in glucose metabolism and muscle physiology via attenuating Dyn2 activity thus regulating GLUT4 endocytosis in muscle cell.
A small protein, derived from an alternative 53BP1 promoter transcript and expressed via translational reinitiation on an internal overlapping ORF, modulates proteasome activity
Authors: Angela Inchingolo Marta , Maxime Adamczewski , Tom Humphreys , Pascale Jaquier-Gubler , Alphonsus Curran Joseph 
Published: August 2021

ABSTRACTThe complexity of the metazoan proteome is significantly increased by the expression of small proteins (<100 aas) derived from smORFs within lncRNAs, uORFs, 3’ UTRs and, more rarely, reading frames overlapping the CDS. These smORF encoded proteins (SEPs) can have diverse roles, ranging from the regulation of cellular physiological to essential developmental functions. We report the characterisation of a new member of this protein family, SEP53BP1, derived from a small internal ORF that overlaps the CDS that encodes 53BP1. Its expression is coupled to the utilisation of an alternative, cell-type specific, promoter coupled to translational reinitiation events mediated by a uORF in the alternative 5’ TL of the mRNA. The uORF-mediated initiation at the internal AUG53BP1 is conserved in metazoan species ranging from human to zebrafish. As such, it couples SEP53BP1 expression to the integrated stress response (ISR). We demonstrate that one function of this protein is to interact with, and stimulate, the activity of the 26S proteasome. As such, it opens the door to new approaches in the treatment of clinical conditions that arise due to the accumulation of toxic intracellular protein aggregates
Electrophysiological Markers of Fairness and Selfishness Revealed by a Combination of Dictator and Ultimatum Games
Authors: Miraghaie Ali M. , Villa Alessandro E. P. , Khosrowabadi Reza , Pouretemad Hamidreza , Mazaheri Mohammad A. , Lintas Alessandra 
Published: August 2021

AbstractEvent Related Potentials (ERPs) were recorded from 39 participants who played the role of Allocators in a Dictator Game (DG) and Responders in an Ultimatum Game (UG). Most participants expressed very low levels of altruistic decision making, and two homogeneous groups could be identified, one formed by fair (N= 10) individuals and another by selfish (N= 8) individuals. At fronto-central cortical sites, the ERP early negativity (N1) was reduced in selfish participants with a latency about 10 ms earlier than in fair participants. In fair DG players, the features of the subsequent positive wave P2 suggested that more cognitive resources were required when they allocated the least gains to the other party. P2 latency and amplitude in the selfish group supported the hypothesis that these participants tended to maximize their profit, as expected by a rationalHomo economicus. During UG, we observed that a medial frontal negativity (MFN) occurred earlier and with greater amplitude when selfish participants rejected less favorable endowment shares. In this case, all players received zero payoffs, which showed that MFN in selfish participants was associated with a spiteful punishment. At posterior-parietal sites we found that the greater the selfishness, the greater the amplitude of the late positive component (LPC). Our results bring new evidence to the existence of specific somatic markers associated with the activation of distinct cerebral circuits by the evaluation of fair and unfair proposals in participants characterized by different expressions of perceived fairness, thus suggesting that particular brain dynamics could be associated with moral decisions.
Exploring ensemble structures of Alzheimer’s amyloid β (1-42) monomer using linear regression for the MD simulation and NMR chemical shift
Authors: Yang Wonjin , Kim Beom Soo , Lin Yuxi , Ito Dai , Kim Jin Hae , Lee Young-Ho , Yu Wookyung 
Published: August 2021

AbstractAggregation of intrinsically disordered amyloid β (Aβ) is a hallmark of Alzheimer’s disease. Although complex aggregation mechanisms have been increasingly revealed, structural ensembles of Aβ monomers with heterogeneous and transient properties still hamper detailed experimental accesses to early events of amyloidogenesis. We herein developed a new mathematical tool based on multiple linear regression to obtain the reasonable ensemble structures of Aβ monomer by using the solution nuclear magnetic resonance (NMR) and molecular dynamics simulation data. Our approach provided the best-fit ensemble to two-dimensional NMR chemical shifts, also consistent with circular dichroism and dynamic light scattering analyses. The major monomeric structures of Aβ including β-sheets in both terminal and central hydrophobic core regions and the minor partially-helical structures suggested initial structure-based explanation on possible mechanisms of early molecular association and nucleation for amyloid generation. A wide-spectrum application of the current approach was also indicated by showing a successful utilization for ensemble structures of folded proteins. We propose that multiple linear regression in combination to experimental results will be highly promising for studies on protein misfolding diseases and functions by providing a convincing template structure.Graphic abstract