bluuebunny/crossref_metadata_2025 huggingface dataset:
The loss of enzymatic activity of the PHARC associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation
Authors: Singh Shubham , Kamat Siddhesh S.
Published: August 2021

Phagocytosis is an important evolutionary conserved process, essential for clearing pathogens and cellular debris in higher organisms, including humans. This well-orchestrated innate immunological response is intricately regulated by numerous cellular factors, important amongst which, are the immunomodulatory lysophosphatidylserines (lyso-PSs) and the pro-apoptotic oxidized phosphatidylserines (PSs) signaling lipids. Interestingly, in mammals, both these signaling lipids are physiologically regulated by the lipase ABHD12, mutations of which, cause the human neurological disorder PHARC. Despite the biomedical significance of this lipase, detailed mechanistic studies and the specific contribution of ABHD12 to innate processes like phagocytosis remain poorly understood. Here, by immunohistochemical and immunofluorescence approaches, using the murine model of PHARC, we show, that upon an inflammatory stimulus, activated microglial cells in the cerebellum of mice deficient in ABHD12 have an amoeboid morphology, increased soma size, and display heightened phagocytosis activity. We also report that upon an inflammatory stimulus, cerebellar levels of ABHD12 increase to possibly metabolize the heightened oxidized PS levels, temper phagocytosis and in turn control neuroinflammation during oxidative stress. Next, to complement these findings, using biochemical approaches in cultured microglial cells, we show that the pharmacological inhibition and/or genetic deletion of ABHD12 results in increased phagocytic uptake in a fluorescent bead uptake assay. Together, our studies provide compelling evidence that ABHD12 plays an important role in regulating phagocytosis in cerebellar microglial cells, and provides a possible explanation, as to why human PHARC subjects display neuroinflammation and atrophy in the cerebellum.
Evaluation of the stereochemical quality of predicted RNA 3D models in the RNA-Puzzles submissions
Authors: Carrascoza Francisco , Antczak Maciej , Miao Zhichao , Westhof Eric , Szachniuk Marta
Published: August 2021

In silico prediction is a well-established approach to derive a general shape of an RNA molecule based on its sequence or secondary structure. This paper reports an analysis of the stereochemical quality of the RNA three-dimensional models predicted using dedicated computer programs. The stereochemistry of 1,052 RNA 3D structures, including 1,030 models predicted by fully automated and human-guided approaches within 22 RNA-Puzzles challenges and reference structures, is analysed. The evaluation is based on standards of RNA stereochemistry that the Protein Data Bank requires from deposited experimental structures. Deviations from standard bond lengths and angles, planarity or chirality are quantified. A reduction in the number of such deviations should help in the improvement of RNA 3D structure modelling approaches.
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

Neurons 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

Understanding 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

We 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

Neprilysin (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

Bacterial 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

Language 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

Malaysian 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

Objectives

To 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.

Design

Case-crossover study comparing recent (1-14 days after vaccination) with less recent exposure to vaccination among cases of CVT.

Setting

National 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 measure

Primary acute cerebral venous thrombosis

Results

Of 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.

Conclusions

These 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 topic

The 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 adds

All 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

Insulin-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

The 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
Evolution of a putative, host-derived endosymbiont division ring and symbiosis-induced proteome rearrangements in the trypanosomatid Angomonas deanei
Authors: Morales Jorge , Ehret Georg , Poschmann Gereon , Reinicke Tobias , Kröninger Lena , Zanini Davide , Wolters Rebecca , Kalyanaraman Dhevi , Krakovka Michael , Stühler Kai , Nowack Eva C. M.
Published: August 2021

The transformation of endosymbiotic bacteria into genetically integrated organelles was central to eukaryote evolution. During organellogenesis, control over endosymbiont division, proteome composition, and physiology largely shifted from the endosymbiont to the host cell nucleus. However, to understand the order and timing of events underpinning organellogenesis novel model systems are required. The trypanosomatid Angomonas deanei contains a β-proteobacterial endosymbiont that divides synchronously with the host1, contributes essential metabolites to host cell metabolism2-5, and transferred one bacterial gene [encoding an ornithine cyclodeaminase (OCD)] to the nucleus2. However, the molecular mechanisms mediating the intricate host/symbiont interactions are largely unexplored. Here we identified seven nucleus-encoded proteins by protein mass spectrometry that are targeted to the endosymbiont. Expression of fluorescent fusion proteins revealed recruitment of these proteins to specific sites within the endosymbiont including its cytoplasm and a ring-shaped structure surrounding its division site. This structure remarkably resembles in shape and predicted functions mitochondrial and plastid division machineries. The endosymbiotic gene transfer-derived OCD localizes to glycosomes instead of being retargeted to the endosymbiont. Hence, scrutiny of protein re-localization patterns that are induced by endosymbiosis, yielded profound insights into how an endosymbiotic relationship can stabilize and deepen over time far beyond the level of metabolite exchange.
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

Abstract

Event 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

Aggregation 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
Basolateral Amygdala Represents and Remembers Ethological Events
Authors: Mazuski Cristina , O’Keefe John
Published: August 2021

The basolateral amygdala plays a crucial role in memory consolidation yet the general neural mechanism remains elusive. Basolateral amygdala neurons were recorded from freely-moving rats as they interacted with different ethological stimuli: male or female rats, a moving toy and food. Over 20% of neurons showed highly tuned event-specific responses to a single class of stimuli. Firing persisted in 30% of these responsive cells for minutes after the removal of the eliciting stimulus. Neural information flowed directionally from event-specific neurons to less specific neurons with changes in connection strength after removal of the stimulus. We propose that the basolateral amygdala identifies specific ethological events, with circuit-wide activity driven by the event-specific neurons during and after the termination of those events likely facilitating active short-term memory consolidation.
SmcHD1 underlies the formation of H3K9me3 blocks on the inactive X chromosome in mice
Authors: Ichihara Saya , Nagao Koji , Sakaguchi Takehisa , Obuse Chikashi , Sado Takashi
Published: August 2021

Stable silencing of the inactive X chromosome (Xi) in female mammals is critical for the development of embryos and their postnatal health. SmcHD1 is essential for stable silencing of the Xi, and its functional deficiency results in derepression of many X-inactivated genes. Although SmcHD1 has been suggested to play an important role in the formation of higher order chromatin structure of the Xi, the underlying mechanism is largely obscure. Here we explore the epigenetic state of the Xi in SmcHD1-deficient epiblast stem cells (EpiSCs) and mouse embryonic fibroblasts (MEFs) in comparison with their wild-type counterparts. The results suggest that SmcHD1 underlies the formation of H3K9me3-enriched blocks on the Xi, which, although the importance of H3K9me3 has been largely overlooked in mice, play a critical role in the establishment of the stably silenced state. We propose that the H3K9me3 blocks formed on the Xi facilitate robust heterochromatin formation in combination with H3K27me3, and the substantial loss of H3K9me3 caused by SmcHD1 deficiency leads to aberrant distribution of H3K27me3 on the Xi and derepression of X-inactivated genes.
Genetic coupling of life-history and aerobic performance in Atlantic salmon
Authors: Prokkola Jenni M. , Åsheim Eirik R. , Morozov Sergey , Bangura Paul , Erkinaro Jaakko , Ruokolainen Annukka , Primmer Craig R. , Aykanat Tutku
Published: August 2021

A better understanding of the genetic and phenotypic architecture underlying life-history variation is a longstanding aim in biology. Theories suggest energy metabolism determines life-history variation by modulating resource acquisition and allocation trade-offs, but the genetic underpinnings of the relationship and its dependence on ecological conditions have rarely been demonstrated. The strong genetic determination of age-at-maturity by two unlinked genomic regions (vgll3andsix6) makes Atlantic salmon (Salmo salar) an ideal model to address these questions. Using more than 250 juveniles in common garden conditions, we quantified the covariation between metabolic phenotypes –standard and maximum metabolic rates (SMR and MMR), and aerobic scope (AS) – and the life-history genomic regions and tested if food availability modulates the relationships. We found that the early maturation genotype invgll3was associated with higher MMR and consequently AS. Additionally, MMR exhibited physiological epistasis; it was decreased when late maturation genotypes co-occurred in both genomic regions. Contrary to our expectation, the life-history genotypes had no effects on SMR. Further, food availability had no effect on the genetic covariation, suggesting a lack of genotype-by-environment interactions. Our results provide insights on the key organismal processes that link energy use at the juvenile-stage to age-at-maturity, indicating potential mechanisms by which metabolism and life-history can coevolve.
proovframe: frameshift-correction for long-read (meta)genomics
Authors: Hackl Thomas , Trigodet Florian , Eren A. Murat , Biller Steven J. , Eppley John M. , Luo Elaine , Burger Andrew , DeLong Edward F. , Fischer Matthias G.
Published: August 2021

Long-read sequencing technologies hold big promises for the genomic analysis of complex samples such as microbial communities. Yet, despite improving accuracy, basic gene prediction on long-read data is still often impaired by frameshifts resulting from small indels. Consensus polishing using either complementary short reads or to a lesser extent the long reads themselves can mitigate this effect but requires universally high sequencing depth, which is difficult to achieve in complex samples where the majority of community members are rare. Here we present proovframe, a software implementing an alternative approach to overcome frameshift errors in long-read assemblies and raw long reads. We utilize protein-to-nucleotide alignments against reference databases to pinpoint indels in contigs or reads and correct them by deleting or inserting 1-2 bases, thereby conservatively restoring reading-frame fidelity in aligned regions. Using simulated and real-world benchmark data we show that proovframe performs comparably to short-read-based polishing on assembled data, works well with remote protein homologs, and can even be applied to raw reads directly. Together, our results demonstrate that protein-guided frameshift correction significantly improves the analyzability of long-read data both in combination with and as an alternative to common polishing strategies. Proovframe is available from https://github.com/thackl/proovframe.
Cargo genes of Tn7-like transposons comprise an enormous diversity of defense systems, mobile genetic elements and antibiotic resistance genes
Authors: Benler Sean , Faure Guilhem , Tran Han-Altae , Shmakov Sergey , Zheng Feng , Koonin Eugene
Published: August 2021

Transposition is a major mechanism of horizontal gene mobility in prokaryotes. However, exploration of the genes mobilized by transposons (cargo) is hampered by the difficulty in delineating integrated transposons from their surrounding genetic context. Here, we present a computational approach that allowed us to identify the boundaries of 6,549 Tn7-like transposons at base pair resolution. We found that 96% of these transposons carry at least one cargo gene. Delineation of distinct communities in a gene-sharing network demonstrates how transposons function as a conduit of genes between phylogenetically distant hosts. Comparative analysis of the cargo genes reveals significant enrichment of mobile genetic elements (MGEs) nested within Tn7-like transposons, such as insertion sequences and toxin-antitoxin modules, genes involved in recombination and anti-MGE defense, and in antibiotic resistance. More unexpectedly, cargo also includes genes encoding central carbon metabolism enzymes. Twenty- two Tn7-like transposons carry both an anti-MGE defense system and antibiotic resistance genes, illustrating how bacteria can overcome these combined pressures upon acquisition of a single transposon. This work substantially expands the distribution of Tn7-like transposons, defines their evolutionary relationships and provides a large-scale functional classification of prokaryotic genes mobilized by transposition.

Significance

Transposons are major vehicles of horizontal gene transfer that, in addition to genes directly involved in transposition, carry cargo genes. However, characterization of these genes is hampered by the difficulty of identification of transposon boundaries. We developed a computational approach for detecting transposon ends and applied it to perform a comprehensive census of the cargo genes of Tn7-like transposons, a large class of bacterial mobile genetic elements (MGE), many of which employ a unique, CRISPR-mediated mechanism of site- specific transposition. The cargo genes encompass a striking diversity of MGE, defense and antibiotic resistance systems. Unexpectedly, we also identified cargo genes encoding metabolic enzymes. Thus, Tn7-like transposons mobilize a vast repertoire of genes that can have multiple effects on the host bacteria.
OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway
Authors: Farré Jean-Claude , Carolino Krypton , Devanneaux Lou , Subramani Suresh
Published: August 2021

How environmental cues influence peroxisome proliferation, particularly through other organelles, remains largely unknown. Yeast peroxisomes metabolize all fatty acids (FA), and methylotrophic yeasts also metabolize methanol. NADH and acetyl-CoA, the products of these pathways enter mitochondria for ATP production, and for anabolic reactions. During the metabolism of FA and/or methanol, the mitochondrial oxidative phosphorylation (OXPHOS) pathway accepts NADH for ATP production and maintains cellular redox balance. Remarkably, peroxisome proliferation inPichia pastoriswas abolished in NADH shuttling and OXPHOS mutants affecting complex I or III, or by the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), indicating ATP depletion causes the phenotype. We show that mitochondrial OXPHOS deficiency inhibits the expression of several peroxisomal proteins implicated in FA and methanol metabolism, as well as in peroxisome division and proliferation. These genes are regulated by the Snf1 complex (SNF1), a pathway generally activated by high AMP and low ATP. Consistent with this mechanism, in OXPHOS mutants, Snf1 is activated by phosphorylation, but Gal83, its interacting subunit, fails to translocate to the nucleus. Phenotypic defects in peroxisome proliferation observed in the OXPHOS mutants, and phenocopied by theΔgal83mutant, were rescued by deletion of three transcriptional repressor genes (MIG1,MIG2andNRG1) controlled by SNF1 signaling. We uncovered here the mechanism by which peroxisomal and mitochondrial metabolites influence redox and energy metabolism, while also influencing peroxisome biogenesis and proliferation, thereby exemplifying interorganellar communication and interplay involving peroxisomes, mitochondria, cytosol and the nucleus. We discuss the physiological relevance of this work in view of human OXPHOS deficiencies.
Deep immune profiling of the maternal-fetal interface with mild SARS-CoV-2 infection
Authors: Sureshchandra Suhas , Zulu Michael Z , Doratt Brianna , Jankeel Allen , Tifrea Delia , Edwards Robert , Rincon Monica , Marshall Nicole E. , Messaoudi Ilhem
Published: August 2021

Pregnant women are an at-risk group for severe COVID-19, though the majority experience mild/asymptomatic disease. Although severe COVID-19 has been shown to be associated with immune activation at the maternal-fetal interface even in the absence of active viral replication, the immune response to asymptomatic/mild COVID-19 remains unknown. Here, we assessed immunological adaptations in both blood and term decidua from 9 SARS-exposed pregnant women with asymptomatic/mild disease and 15 pregnant SARS-naive women. In addition to selective loss of tissue-resident decidual macrophages, we report attenuation of antigen presentation and type I IFN signaling but upregulation of inflammatory cytokines and chemokines in blood monocyte derived decidual macrophages. On the other hand, infection was associated with remodeling of the T cell compartment with increased frequencies of activated CD69+ tissue-resident T cells and decreased abundance of Tregs. Interestingly, frequencies of cytotoxic CD4 and CD8 T cells increased only in the blood, while CD8 effector memory T cells were expanded in the decidua. In contrast to decidual macrophages, signatures of type I IFN signaling were increased in decidual T cells. Finally, T cell receptor diversity was significantly reduced with infection in both compartments, albeit to a much greater extent in the blood. The resulting aberrant immune activation in the placenta, even with asymptomatic disease may alter the exquisitely sensitive developing fetal immune system, leading to long-term adverse outcomes for offspring.
Water Pollution and Administrative Division Adjustments: A Quasi-natural Experiment in Chaohu Lake of China
Authors: Li Jing , Liu Di , Cai Mengyuan
Published: August 2021

The adjustment of administrative divisions introduces a series of uncertain impacts on the social and economic development in the administrative region. Previous studies focused more on the economic effects of the adjustment of administrative divisions, while, in this paper, we also take environmental effects into consideration. The administrative division adjustment for Chaohu Lake is used as a quasi-natural experiment to explore the influence of the adjustment on pollution control. The synthetic control method is used in this study to access the effect of administrative division adjustment on the water quality indicators of Chaohu Lake and its internal mechanism. Some conclusions are as follows. First, after the administrative division adjustment, some water quality indicators, such as ammonia nitrogen, have indeed been alleviated; however, other major pollution indicators, such as chemical oxygen demand and dissolved oxygen, have deteriorated to varying degrees. Second, the results also reveal that improper development ideas, industrial excessive expansion, and the swing of economic growth and environmental goals are problems after the adjustment. Returning to the original intention of adjustment, rationalizing the Chaohu Lake management system and designing a sound and feasible accountability mechanism are fundamental measures to reduce pollution.
Structure-based design of antisense oligonucleotides that inhibit SARS-CoV-2 replication
Authors: Li Yan , Garcia Gustavo , Arumugaswami Vaithilingaraja , Guo Feng
Published: August 2021

Antisense oligonucleotides (ASOs) are an emerging class of drugs that target RNAs. Current ASO designs strictly follow the rule of Watson-Crick base pairing along target sequences. However, RNAs often fold into structures that interfere with ASO hybridization. Here we developed a structure-based ASO design method and applied it to target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our method makes sure that ASO binding is compatible with target structures in three-dimensional (3D) space by employing structural design templates. These 3D-ASOs recognize the shapes and hydrogen bonding patterns of targets via tertiary interactions, achieving enhanced affinity and specificity. We designed 3D-ASOs that bind to the frameshift stimulation element and transcription regulatory sequence of SARS-CoV-2 and identified lead ASOs that strongly inhibit viral replication in human cells. We further optimized the lead sequences and characterized structure-activity relationship. The 3D-ASO technology helps fight coronavirus disease-2019 and is broadly applicable to ASO drug development.
Multi-organ analysis of low-level somatic mosaicism reveals stage- and tissue-specific mutational features in human development
Authors: Son Hyeonju , Kim Ja Hye , Kim Il Bin , Kim Myeong-Heui , Sim Nam Suk , Kim Dong-Seok , Lee Junehawk , Lee Jeong Ho , Kim Sangwoo
Published: August 2021

Most somatic mutations arising during normal development present as low-level in single or multiple tissues depending on the developmental stage and affected organs1-4. However, it remains unclear how the human developmental stages or mutation-carrying organs affect somatic mutations’ features. Here, we performed a systemic and comprehensive analysis of low-level somatic mutations using deep whole-exome sequencing (WES; average read depth: ∼500×) of 498 multiple organ tissues with matched controls from 190 individuals. We found that early-stage mutations shared between multiple organs are lower in number but showed higher allele frequencies than late-stage mutations [0.54 vs. 5.83 variants per individual: 6.17% vs. 1.5% variant allele frequency (VAF)] along with less nonsynonymous mutations and lower functional impacts. Additionally, early- and late-stage mutations had unique mutational signatures distinct from tumor-originate mutations. Compared with early-stage mutations presenting a clock-like signature across all studied organs or tissues, late-stage mutations show organ, tissue, and cell-type specificity in mutation count, VAFs, and mutational signatures. In particular, analysis of brain somatic mutations shows bimodal occurrence and temporal-lobe-specific mutational signatures. These findings provide new insight into the features of somatic mosaicisms dependent on developmental stages and brain regions.
Mechanisms of targeted therapy resistance in a pediatric glioma driven by ETV6-NTRK3 fusion
Authors: Keddy Clare , Neff Tanaya , Huan Jianya , Nickerson Joshua P. , Beach Catherine Z. , Akkari Yassmine , Ji Jianling , Moore Stephen , Nazemi Kellie J. , Corless Christopher L. , Beadling Carol , Woltjer Randy , Cho Yoon-Jae , Wood Matthew D. , Davare Monika A.
Published: August 2021

Chromosomal rearrangements of the NTRK genes generate kinase fusions that are targetable oncogenic drivers in diverse adult and pediatric malignancies. Despite robust clinical response to targeted NTRK inhibition, the emergence of therapeutic resistance poses a formidable clinical challenge. Here we report the characterization of an ETV6-NTRK3 fusion–driven pediatric glioma that progressed through NTRK-targeted treatments with entrectinib and selitrectinib. Genetic analysis of multifocal recurrent/resistant lesions identified a previously uncharacterized NTRK3 p.G623A and a known p.G623E resistance mutation, in addition to other alterations of potential pathogenic impact. Functional studies using heterologous reconstitution model systems and patient-derived tumor cell lines establish that NTRK3G623A and NTRK3G623E mutated kinases exhibit reduced sensitivity to entrectinib and selitrectinib, as well as other NTRK inhibitors tested herein. In summary, this genetic analysis of multifocal recurrent/resistant glioma driven by ETV6-NTRK3 fusion captured a cross section of resistance-associated alterations that, based on in vitro analysis, likely contributed to resistance to targeted therapy and disease progression.
Development of cost-effective shock tube based on experimental and numerical analysis
Authors: Thaloor Ramesh Praveenkumar , Kengaiah Vijayaraja , Gutema Endalkachew Mosisa , Velusamy Prabu , Balamoorthy Dhivya
Published: August 2021

Purpose

The purpose of the study is to design economical shock tube. It is an instrument used for experimental investigations not only related to shock phenomena but also for the behavior of the material when it is subjected to high-speed flow. The material used here in this shock tube is stainless steel ss304 and aluminum. A shock tube consists of two sections, namely, the driver and the driven. The gas in the driven and driver is filled with atmospheric air and nitrogen, respectively, under the predominant condition.

Design/methodology/approach

The focus of the study is on the design and fabrication of shock tubes. a shock tube is a research tool to make an aerodynamic test in the presence of high pressure and temperature by generating moving normal shock waves under controlled conditions.

Findings

The main necessity for instrumentation in the shock tube experiment is to know the velocity of the moving shock wave from which the other parameters can be calculated. the pressure transducers are located in the shock tube in various locations to measure aerodynamic parameters in terms of pressure.

Originality/value

The main objective of this project work is to make an experimental setup to produce supersonic velocity with the readily available material in the market in a highly safe manner.