bluuebunny/crossref_metadata_2025 huggingface dataset:
Global cataloguing of variations in untranslated regions of viral genome and prediction of key host RNA binding protein-microRNA interactions modulating genome stability in SARS-CoV2
Authors: Mukherjee Moumita , Goswami Srikanta
Published: June 2020

Background

The world is going through the critical phase of COVID-19 pandemic, caused by human coronavirus, SARS-CoV2. Worldwide concerted effort to identify viral genomic changes across different sub-types has identified several strong changes in the coding region. However, there have not been many studies focusing on the variations in the 5’ and 3’ untranslated regions and their consequences. Considering the possible importance of these regions in host mediated regulation of viral RNA genome, we wanted to explore the phenomenon.

Methods

To have an idea of the global changes in 5’ and 3’-UTR sequences, we downloaded 8595 complete and high-coverage SARS-CoV2 genome sequence information from human host in FASTA format from Global Initiative on Sharing All Influenza Data (GISAID) from 15 different geographical regions. Next, we aligned them using Clustal Omega software and investigated the UTR variants. We also looked at the putative host RNA binding protein (RBP) and microRNA binding sites in these regions by ‘RBPmap’ and ‘RNA22 v2’ respectively. Expression status of selected RBPs and microRNAs were checked in lungs tissue.

Results

We identified 28 unique variants in SARS-CoV2 UTR region based on a minimum variant percentage cut-off of 0.5. Along with 241C>T change the important 5’-UTR change identified was 187A>G, while 29734G>C, 29742G>A/T and 29774C>T were the most familiar variants of 3’UTR among most of the continents. Furthermore, we found that despite of the variations in the UTR regions, binding of host RBP to them remains mostly unaltered, which further influenced the functioning of specific miRNAs.

Conclusion

Our results, shows for the first time in SARS-Cov2 infection, a possible cross-talk between host RBPs-miRNAs and viral UTR variants, which ultimately could explain the mechanism of escaping host RNA decay machinery by the virus. The knowledge might be helpful in developing anti-viral compounds in future.
Activity-specificity trade-off gives PI5P4Kβ a nucleotide preference to function as a GTP-sensing kinase
Authors: Takeuchi Koh , Ikeda Yoshiki , Senda Miki , Harada Ayaka , Okuwaki Koji , Fukuzawa Kaori , Nakagawa So , Yu Hongyang , Nagase Lisa , Imai Misaki , Sasaki Mika , Lo YuHua , Sasaki Atsuo T. , Senda Toshiya
Published: June 2020

Most kinases function with ATP. However, contrary to the prevailing dogma, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) utilizes GTP as a primary phosphate donor with a unique binding mode for GTP. Although PI5P4Kβ is evolved from a primordial ATP-utilizing enzyme, PI4P5K, how PI5P4Kβ evolutionarily acquired the GTP preference to function as a cellular GTP sensor remains unclear. In this study, we show that the short nucleotide base-recognition motif, TRNVF, is responsible for the GTP binding of PI5P4Kβ, and also confers onto PI5P4Kβ an unexpected specificity that extends to inosine triphosphate (ITP) and xanthosine triphosphate (XTP). A mutational study with GTP analogues suggests that the extended specificity is an obligatory consequence to the acquisition of GTP-dependent activity. However, as the cellular concentrations of ITP and XTP are typically negligible, PI5P4Kβ can still function as a GTP sensor, suggesting that the cellular physiological conditions leave room for the functional evolution of PI5P4Kβ.
SARS-CoV-2 nucleocapsid protein undergoes liquid-liquid phase separation stimulated by RNA and partitions into phases of human ribonucleoproteins
Authors: Perdikari Theodora Myrto , Murthy Anastasia C. , Ryan Veronica H. , Watters Scott , Naik Mandar T. , Fawzi Nicolas L.
Published: June 2020

Tightly packed complexes of nucleocapsid protein and genomic RNA form the core of viruses and may assemble within viral factories, dynamic compartments formed within the host cells. Here, we examine the possibility that the multivalent RNA-binding nucleocapsid protein (N) from the severe acute respiratory syndrome coronavirus (SARS-CoV-2) compacts RNA via protein-RNA liquid-liquid phase separation (LLPS) and that N interactions with host RNA-binding proteins are mediated by phase separation. To this end, we created a construct expressing recombinant N fused to a N-terminal maltose binding protein tag which helps keep the oligomeric N soluble for purification. Usingin vitrophase separation assays, we find that N is assembly-prone and phase separates avidly. Phase separation is modulated by addition of RNA and changes in pH and is disfavored at high concentrations of salt. Furthermore, N enters intoin vitrophase separated condensates of full-length human hnRNPs (TDP-43, FUS, and hnRNPA2) and their low complexity domains (LCs). However, N partitioning into the LC of FUS, but not TDP-43 or hnRNPA2, requires cleavage of the solubilizing MBP fusion. Hence, LLPS may be an essential mechanism used for SARS-CoV-2 and other RNA viral genome packing and host protein co-opting, functions necessary for viral replication and hence infectivity.
First and broad detection of three typical carbapenemase genes on the surfaces of commercially available spices worldwide and isolation of complete NDM-1 genes from black pepper, cumin, and clove
Authors: Mochizuki Minako , Maeda Sumio
Published: June 2020

The spread of multidrug-resistant bacteria, particularly those producing carbapenemases, has become a major public health concern. The presence of carbapenemase genes has primarily been reported in clinical samples, whereas the presence of these genes in commercially available foods has insufficiently been studied despite its growing importance. The present study aimed to detect and characterize carbapenemase genes (blaNDM,blaIMP,blaKPC, andblaOXA-48-like) on the surfaces of commercially available spices using PCR to amplify conserved regions of these genes. It was revealed that DNAs of these genes are commonly present (13 genes/29 samples) on spices derived from at least 9 different countries. This is the first detection of any carbapenemase gene on eight spices (black pepper, cumin, clove, cardamom, mustard, caraway, parsley, and rosemary) among these. This is also the first detection of theblaIMPandblaNDMas well as the broad detection of theblaOXA-48-likeon spices. We also isolated complete, functionalblaNDM-1genes from three spices (black pepper, cumin, and clove) up to the present.
Genomic and kinetic analysis of novel Nitrospinae enriched by cell sorting
Authors: Mueller Anna J. , Jung Man-Young , Strachan Cameron R. , Herbold Craig W. , Kirkegaard Rasmus H. , Wagner Michael , Daims Holger
Published: June 2020

Chemolithoautotrophic nitrite-oxidizing bacteria (NOB) are key players in global nitrogen and carbon cycling. Members of the phylum Nitrospinae are the most abundant, known NOB in the oceans. To date, only two closely affiliated Nitrospinae species have been isolated, which are only distantly related to the environmentally abundant uncultured Nitrospinae clades. Here, we applied live cell sorting, activity screening, and subcultivation on marine nitrite-oxidizing enrichments to obtain novel marine Nitrospinae. Two binary cultures were obtained, each containing one Nitrospinae strain and one alphaproteobacterial heterotroph. The Nitrospinae strains represent two new genera, and one strain is more closely related to environmentally abundant Nitrospinae than previously cultured NOB. With an apparent half-saturation constant of 8.7±2.5 µM, this strain has the highest affinity for nitrite among characterized marine NOB, while the other strain (16.2±1.6 µM) andNitrospina gracilis(20.1±2.1 µM) displayed slightly lower nitrite affinities. The new strains andN. gracilisshare core metabolic pathways for nitrite oxidation and CO2fixation but differ remarkably in their genomic repertoires of terminal oxidases, use of organic N sources, alternative energy metabolisms, osmotic stress and phage defense. The new strains, tentatively named “CandidatusNitrohelix vancouverensis” and “CandidatusNitronauta litoralis”, shed light on the niche differentiation and potential ecological roles of Nitrospinae.
Modeling the variability of the electromotor command system of pulse electric fish
Authors: Lareo Ángel , Varona Pablo , Rodríguez Francisco B.
Published: June 2020

Mormyrids, a family of weakly electric fish, use electric pulses for communication and for extracting information from the environment (active electroreception). The electromotor system controls the timing of pulse generation. Ethological studies have described several sequences of pulse intervals (SPIs) which are related to distinct behaviors (e.g. mating or exploratory behaviors). Accelerations, scallops, rasps, and cessations are four SPI patterns reported in these fish, each showing characteristic temporal structures and large variability. This paper presents a computational model of the electromotor command circuit that reproduces SPI patterns as a function of the inputs to the model while keeping the same internal network configuration. The topology of the model is based on a simplified representation of the network with four neuron clusters (nuclei). An initialad hoctuned configuration (S-T) was built to reproduce nucleus characteristics and network topology as described by detailed morphological and electrophysiological studies. Then, a genetic algorithm (GA) was developed and applied to automatically tune the synaptic parameters of the model connectivity. Two different configurations obtained from the GA are presented here: one optimized to a set of synthetic examples of SPI patterns (S-GA) and another configuration adjusted to patterns recorded from freely-behavingGnathonemus Petersiispecimens (R-GA). Robustness analyses to input variability were performed to discard overfitting and assess validity. Results show that the set of SPI patterns are consistently reproduced, both for synthetic data and for recorded data. This model can be used as a tool to test novel hypotheses regarding temporal structure in electrogeneration.
Unravelling the debate on heme effects in COVID-19 infections
Authors: Hopp Marie-Thérèse , Domingo-Fernández Daniel , Gadiya Yojana , Detzel Milena S. , Schmalohr Benjamin F. , Steinbock Francèl , Imhof Diana , Hofmann-Apitius Martin
Published: June 2020

The SARS-CoV-2 outbreak was recently declared a worldwide pandemic. Infection triggers the respiratory tract disease COVID-19, which is accompanied by serious changes of clinical biomarkers such as hemoglobin and interleukins. The same parameters are altered during hemolysis, which is characterized by an increase in labile heme. We present two approaches that aim at analyzing a potential link between available heme and COVID-19 pathogenesis. Four COVID-19 related proteins, i.e. the host cell proteins ACE2 and TMPRSS2 as well as the viral protein 7a and S protein, were identified as potential heme binders. We also performed a detailed analysis of the common pathways induced by heme and SARS-CoV-2 by superimposition of knowledge graphs covering heme biology and COVID-19 pathophysiology. Herein, focus was laid on inflammatory pathways, and distinct biomarkers as the linking elements. Finally, the results substantially improve our understanding of COVID-19 infections and disease progression of patients with different clinical backgrounds and expand the diagnostic and treatment options.
The plant endoplasmic reticulum is both receptive and responsive to pathogen effectors
Authors: Breeze Emily , Vale Victoria , McLellan Hazel , Godiard Laurence , Grant Murray , Frigerio Lorenzo
Published: June 2020

The endoplasmic reticulum (ER) is the entry point to the secretory pathway and, as such, is critical for adaptive responses to biotic stress, when the demand for de novo synthesis of immunity-related proteins and signalling components increases significantly. Comprised of a network of interconnected tubules and cisternae, the architecture of the ER is highly pleomorphic and dynamic, rapidly remodelling to meet new cellular requirements. During infection with the hemi-biotrophic phytopathogen, Pseudomonas syringae pv. tomato DC3000, the ER in cells immediately adjacent to established bacterial colonies condenses into ‘knot-like’ structures, reminiscent of fenestrated sheets. Based on known temporal dynamics of pathogen effector delivery and initial bacterial multiplication, the timing of these observed morphological changes is rapid and independent of classical elicitor activation of pathogen-triggered immunity. To further investigate a role for ER reconfiguration in suppression of plant immunity we identified a conserved C-terminal tail-anchor domain in a set of pathogen effectors known to localize to the ER and used this protein topology in an in silico screen to identify putative ER-localised effectors within the effectorome of the oomycete Phytophthora infestans. Subsequent characterization of a subset of 15 candidate tail-anchored P. infestans effectors revealed that 11 localised to the ER and/or Golgi. Notably, transient expression of an ER-localised effector from the closely related oomycete, Plasmopara halstedii, reconfigured the ER network, revealing intimate association of labelled ER with perinuclear chloroplasts and clusters of chloroplasts, potentially facilitating retrograde signalling during plant defence.
Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle
Authors: Conceição Mariana , Forcina Laura , Wiklander Oscar P. B. , Gupta Dhanu , Nordin Joel Z. , McClorey Graham , Mäger Imre , Görgens André , Lundin Per , Musarò Antonio , Wood Matthew J. A. , Andaloussi Samir EL , Roberts Thomas C.
Published: June 2020

The cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two different mechanisms, the classical and transsignalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 transsignalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstratingin vivoactivity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.
BoardION: real-time monitoring of Oxford Nanopore Technologies devices
Authors: Bruno Aimeric , Aury Jean-Marc , Engelen Stefan
Published: June 2020

One of the main advantages of the Oxford Nanopore Technology (ONT) is the possibility of sequencing in real time. However, the ONT sequencing interface is not sufficient to explore the quality of sequencing data in depth and existing tools do not take full advantage of real-time data streaming. We present BoardION, an interactive web application, dedicated to sequencing platforms, for real-time monitoring of all ONT sequencing devices (MinION, Mk1C, GridION and PromethION). BoardION allows users to easily explore sequencing metrics and optimize the quantity and the quality of the generated data during the experiment. It also enables the comparison of several flowcells to evaluate the library preparation protocols or the quality of input samples.

Availability

Source code and a Docker image are available athttp://www.genoscope.cns.fr/boardion/

Contact

stefan.engelen@genoscope.cns.fr
Designed peptides as potential fusion inhibitors against SARA-CoV-2 coronavirus infection
Authors: Chen Ke , Bai Shihao , Zou Xin , Hao Jie , Da Lin-tai , Han Ze-Guang
Published: June 2020

Inspired by fusion-inhibitory peptides from heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains from human immuno-deficiency virus type 1 (HIV-1) envelope glycoprotein gp41 and severe acute respiratory syndrome-coronavirus (SARS-CoV) based on viral fusogenic mechanism in the present work, we provided a similar approach to design the synthesized peptides against the entry into host cells of SARA-CoV-2 virus that causes 2019 novel coronavirus disease (COVID-19). These peptides derived from HR1 and HR2 of SARA-CoV-2 spike protein were further tested for their interaction and potential fusion possibility through circular dichroism spectrum. Here we used the peptide COVID-2019-HR1P1 (40 amino acids) as the target, which was derived from HR1 of SARA-CoV-2 spike protein, while the designed peptides including COVID-2019-HR2P1 (37 amino acids), COVID-2019-HR2P2 (32 amino acids) and others derived from HR2 of SARA-CoV-2 were tested for their binding to COVID-2019-HR1P1. Interestingly, results showed that both COVID-2019-HR2P1 and COVID-2019-HR2P2 can form the complex with COVID-2019-HR1P1, respectively. This implied that these designed peptides could play an important role in blocking SARA-CoV-2 entry into mammalian host cells via viral fusogenic mechanism, and thus could be used for preventing SARA-CoV-2 infection.
The impact of viral transport media on PCR assay results for the detection of nucleic acid from SARS-CoV-2 and other viruses
Authors: Kirkland P.D. , Frost M.J.
Published: June 2020

During the 2020 SARS-Cov-2 pandemic, there has been an acute shortage of viral transport medium. Many different products have been used to meet the demands of large-scale diagnostic and surveillance testing. The stability of SARS-Cov-2 RNA was assessed in several commercially produced transport media and an in-house solution. Coronavirus RNA was rapidly destroyed in the commercial transport media though the deleterious effects on intact virus were limited. Similar results were obtained for a Type A influenza virus. There was reduced detection of both virus and nucleic acid when a herpesvirus sample and purified DNA were tested. Collectively these data showed that the commercial viral transport media contained nucleases or similar substances and may seriously compromise diagnostic and epidemiological investigations.

Recommendations to include foetal bovine serum as a source of protein to enhance the stabilising properties of viral transport media are contraindicated. Almost all commercial batches of foetal bovine serum contain pestiviruses and at times other bovine viruses. In addition to the potential for there to be nucleases in the transport medium, the presence of these viruses and other extraneous nucleic acid in samples may compromise the interpretation of sequence data. The inclusion of foetal bovine serum presents a biosecurity risk for the movement of animal pathogens and renders these transport media unsuitable for animal disease diagnostic applications. While these transport media may be suitable for virus culture purposes, there could be misleading results if used for nucleic acid-based tests. Therefore, these products should be evaluated to ensure fitness for purpose.
Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans
Authors: Fatumo Segun , Chikowore Tinashe , Kalyesubula Robert , Nsubuga Rebecca N , Asiki Gershim , Nashiru Oyekanmi , Seeley Janet , Crampin Amelia C , Nitsch Dorothea , Smeeth Liam , Kaleebu Pontiano , Nyirenda Moffat , Burgess Stephen , Franceschini Nora , Morris Andrew P , Tomlinson Laurie , Newton Robert
Published: June 2020

Genome-wide association studies (GWAS) for kidney function have uncovered hundreds of risk loci, primarily in populations of European ancestry. We conducted the first GWAS of estimated glomerular filtration rate (eGFR) in Africa in 3288 Ugandans and replicated the findings in 8224 African Americans. We identified two loci associated with eGFR at genome-wide significance (p<5×10−8). The most significantly associated variant (rs2433603, p=2.4×10−9) inGATMwas distinct from previously reported signals. A second association signal mapping nearHBB(rs141845179, p=3.0×10−8) was not significant after conditioning on a previously reported SNP (rs334) for eGFR. However, fine-mapping analyses highlighted rs141845179 to be the most likely causal variant at the HBB locus (posterior probability of 0.61). A trans-ethnic GRS of eGFR constructed from previously reported lead SNPs was not predictive into the Ugandan population, indicating that additional large-scale efforts in Africa are necessary to gain further insight into the genetic architecture of kidney disease.
Comparative analysis of non structural protein 1 of SARS-CoV2 with SARS-CoV1 and MERS-CoV: An in silicostudy
Authors: Chaudhuri Ankur
Published: June 2020

The recently emerged SARS-CoV2 caused a major pandemic of coronavirus disease (COVID-19). Non structural protein 1 (nsp1) is found in all beta coronavirus that causes several severe respiratory diseases. This protein is considered as a virulence factor and has an important role in pathogenesis. This study aims to elucidate the structural conformations of non structural protein 1 (nsp1), prediction of epitope sites and identification of important residues for targeted therapy against COVID-19. In this study, molecular modelling coupled with molecular dynamics simulations were performed to analyse the conformational change of nsp1 of SARS-CoV1, SARS-CoV2 and MERS-CoV at molecular level. Principal component analysis escorted by free energy landscape revealed that SARS-CoV2 nsp1 protein shows greater flexibility, compared to SARS-CoV1 and MERS-CoV nsp1. From the sequence alignment, it was observed that 28 mutations are present in SERS-CoV2 nsp1 protein compared to SERS-CoV1 nsp1. Several B-cell and T-cell epitopes were identified by immunoinformatics approach. SARS-CoV2 nsp1 protein binds with the interface region of the palm and finger domain of POLA1 by using hydrogen bond and salt bridge interactions. These findings can be used to develop therapeutics specific against COVID-19.
SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis inp27null mice
Authors: Moncho-Amor Veronica , Chakravarty Probir , Galichet Christophe , Matheu Ander , Lovell-Badge Robin , Rizzoti Karine
Published: June 2020

Loss of P27 predominantly results in development of murine pituitary intermediate lobe (IL) tumours. We previously showed that the pleiotropic protein P27 can drive repression of the transcription factorSox2. This interaction plays an important role during development ofp27-/-IL tumours because loss of one copy ofSox2diminishes tumorigenesis. Here, we have explored the cellular origin and mechanisms underlying melanotroph tumorigenesis inp27-/-IL. We show that IL hyperplasia is associated with reduced cellular differentiation, while levels of SOX2 increase in both stem cells (SC) and melanotrophs. Using loss-of-function and lineage tracing approaches, we demonstrate that SOX2 is required cell-autonomously inp27-/-melanotrophs and SCs for tumorigenesis. This is supported by studies deleting theSox2regulatory region 2 (Srr2), which is the target of P27 repressive action. Single cell transcriptomic analysis reveals that activation of a SOX2-dependent MAPK pathway in SCs is important forp27-/-tumorigenesis. Our data highlight different roles of SOX2 following loss ofp27, according to the cellular context. Furthermore, we uncover a tumor-promoting function for SCs, which is SOX2-dependant. In conclusion, our results imply that targeting SCs, in addition to tumour cells themselves, may represent an efficient anti-tumoral strategy in certain contexts.
Lipid suppressed and tissue-fraction corrected metabolic distributions in human central brain structures using 2D1H Magnetic Resonance Spectroscopic Imaging at 7 tesla
Authors: Bhogal Alex A. , Broeders Tommy A.A. , Morsinkhof Lisan , Edens Mirte , Nassirpour Sahar , Chang Paul , Klomp Dennis , Vinkers Christiaan H. , Wijnen Jannie P.
Published: June 2020

Magnetic resonance spectroscopic imaging (MRSI) has the potential to add a layer of understanding of the neurobiological mechanisms underlying brain diseases, disease progression, and treatment efficacy. Limitations related to metabolite fitting of low SNR data, signal variations due to partial volume effects, acquisition and extra-cranial lipid artefacts, along with clinically relevant aspects such as scan-time constraints, are among the factors that hinder the widespread implementation ofin vivoMRSI. The aim of this work was to address these factors and to develop an acquisition, reconstruction and post-processing pipeline to derive lipid suppressed metabolite values based on Free Induction Decay (FID-MRSI) measurements made using a 7 tesla MR scanner. Anatomical images were used to perform high-resolution (1mm3) partial-volume correction to account for grey matter, white matter and cerebral-spinal fluid signal contributions. Implementation of automatic quality control thresholds and normalization of metabolic maps from 23 subjects to the MNI standard atlas facilitated the creation of high-resolution average metabolite maps of several clinically relevant metabolites in central brain regions, while accounting for macromolecular distributions. Reported metabolite values include glutamate, choline, (phospo)creatine, myo-inositol, glutathione, N-acetyl aspartyl glutamate(and glutamine) and N-acetyl aspartate. MNI-registered average metabolite maps facilitate group-based analysis; thus offering the possibility to mitigate uncertainty in variable MRSI.
Biased Auditory Nerve Central Synaptopathy Exacerbates Age-related Hearing Loss
Authors: Wang Meijian , Zhang Chuangeng , Lin Shengyin , Wang Yong , Seicol Benjamin J. , Ariss Robert W. , Xie Ruili
Published: June 2020

Sound information is transmitted from the cochlea to the brain by different subtypes of spiral ganglion neurons (SGN), which show varying degrees of vulnerbility under pathological conditions. It remains unclear how information from these SGNs reassemble among target neurons in the cochlear nucleus (CN) at the auditory nerve (AN) central synapses, and how different synapses change during hearing loss. Combining immunohistochemistry with electrophysiology, we investigated the giant endbulb of Held synapses and their postsynaptic bushy neurons in mice under normal hearing and age-related hearing loss (ARHL). We found that calretinin-expressing and non-calretinin-expressing endbulbs converge at continuously different ratios onto bushy neurons with varying physiological properties. Endbulbs degenerate during ARHL, and the degeneration is more severe in non-calretinin-expressing synapses, which correlates with a gradual decrease in neuronal subpopulation predominantly innervated by these inputs. Our findings suggest that biased AN central synaptopathy and shifted CN neuronal composition underlie reduced auditory input and altered central auditory processing during ARHL.
Reverse-engineering Recurrent Neural Network solutions to a hierarchical inference task for mice
Authors: Schaeffer Rylan , Khona Mikail , Meshulam Leenoy ,   International Brain Laboratory, Fiete Ila Rani
Published: June 2020

We study how recurrent neural networks (RNNs) solve a hierarchical inference task involving two latent variables and disparate timescales separated by 1-2 orders of magnitude. The task is of interest to the International Brain Laboratory, a global collaboration of experimental and theoretical neuroscientists studying how the mammalian brain generates behavior. We make four discoveries. First, RNNs learn behavior that is quantitatively similar to ideal Bayesian baselines. Second, RNNs perform inference by learning a two-dimensional subspace defining beliefs about the latent variables. Third, the geometry of RNN dynamics reflects an induced coupling between the two separate inference processes necessary to solve the task. Fourth, we perform model compression through a novel form of knowledge distillation on hidden representations – Representations and Dynamics Distillation (RADD)– to reduce the RNN dynamics to a low-dimensional, highly interpretable model. This technique promises a useful tool for interpretability of high dimensional nonlinear dynamical systems. Altogether, this work yields predictions to guide exploration and analysis of mouse neural data and circuity.
How does it feel to be on psilocybin? Dose-response relationships of subjective experiences in humans
Authors: Hirschfeld Tim , Schmidt Timo Torsten
Published: June 2020

Psilocybin is the active component of magic mushrooms and is well known for its psychoactive properties. Different questionnaires have been developed to systematically quantify altered states of consciousness induced by psychoactive drugs. The aim of this study was to obtain the dose-response relationships of the subjective experiences induced by psilocybin in healthy study participants. For this purpose, we applied a linear meta-regression approach on questionnaire ratings after oral administration of psilocybin in a controlled setting. Data was obtained from The Altered States Database, which contains psychometric data extracted from peer-reviewed articles published in MEDLINE-listed journals that used standardized and validated questionnaires. Our meta-analysis included data of the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire (MEQ30), and the Hallucinogen Rating Scale (HRS). We used the Robust Variance Estimation Framework to obtain linear dose-response relationship estimates for each dimension of the given questionnaires. Ratings on most dimensions and subscales of the included questionnaires correlated positively with dose. Since subjective experiences are not only determined by dose, but also by individual differences and environmental factors, our results do not necessarily generalize to recreational use, as our analyses are based on data from controlled laboratory experiments. The paper at hand could serve as a general literature citation for the use of psilocybin in experimental and clinical research, especially for the comparison of expected and observed subjective drug experiences.
Understanding the role of apolipoproteinA-I in atherosclerosis. Post-translational modifications synergize dysfunction?
Authors: Ludovico Ivo Díaz , Gisonno Romina A. , Gonzalez Marina C. , Garda Horacio A. , Ramella Nahuel A. , Tricerri M. Alejandra
Published: June 2020

Background

The identification of dysfunctional human apolipoprotein A-I (apoA-I) in atherosclerotic plaques suggests that protein structure and function may be hampered under a chronic pro inflammatory scenario. Moreover, the fact that natural mutants of this protein elicit severe cardiovascular diseases (CVD) strongly indicates that the native folding could shift due to the mutation, yielding a structure more prone to misfold or misfunction. To understand the events that determine the failure of apoA-I structural flexibility to fulfill its protective role, we took advantage of the study of a natural variant with a deletion of the residue lysine 107 (K107del) associated with atherosclerosis.

Methods

Biophysical approaches, such as electrophoresis, fluorescence and spectroscopy were used to characterize proteins structure and function, either in the native conformation or under oxidation or intramolecular crosslinking.

Results

K107del structure was more flexible than the protein with the native sequence (Wt) but interactions with artificial membranes were preserved. Instead, structural restrictions by intramolecular crosslinking impaired the Wt and K107del lipid solubilization function. In addition, controlled oxidation decreased the yield of the native dimer conformation for both variants.

Conclusions

We conclude that even though mutations may alter protein structure and spatial arrangement, the highly flexible conformation compensates the mild shift from the native folding. Instead, post translational apoA-I modifications (probably chronic and progressive) are required to raise a protein conformation with significant loss of function and increased aggregation tendency.

General Significance

The results learnt from this variant strength a close association between amyloidosis and atherosclerosis.

Graphical abstract

Highlights

-Oxidation is clue to induce protein misfolding

-Natural mutation does not seem critical as a sole reason to determine pathogenicity

-Atherosclerosis and amyloidosis are closely related

-Intramolecular crosslinking restrains protein flexibility and function
Combining small-molecule bioconjugation and hydrogen-deuterium exchange mass spectrometry (HDX-MS) to expose allostery: the case of human cytochrome P450 3A4
Authors: Ducharme Julie , Thibodeaux Christopher J. , Auclair Karine
Published: June 2020

We report herein a novel approach to study allostery which combines the use of carefully selected bioconjugates and hydrogen-deuterium exchange mass spectrometry (HDX-MS). The utility of our method is demonstrated using human cytochrome P450 3A4 (CYP3A4). CYP3A4 is arguably the most important drug-metabolizing enzyme, and as such, is involved in numerous drug interactions. Diverse allosteric ligand effects have been reported for this enzyme, yet the structural mechanism of these phenomena remain poorly understood. We have described different CYP3A4-effector bioconjugates, some of which mimic the allosteric effect of positive effectors on CYP3A4, while others show activity enhancement even though the label does not occupy the allosteric pocket (agonistic), or do not show activation while still blocking the allosteric site (antagonistic). These bioonjugates were studied here by HDX-MS, which enabled us to better define the position of the allosteric site, and to identify important regions involved in CYP3A4 activation.
Michigan ZoomIN: validating crowd-sourcing to identify mammals from camera surveys
Authors: Gadsden Gabriel I. , Malhotra Rumaan , Schell Justin , Carey Tiffany , Harris Nyeema C.
Published: June 2020

Camera trap studies have become a popular medium to assess many ecological phenomena including population dynamics, patterns of biodiversity, and monitoring of endangered species. In conjunction with the benefit to scientists, camera traps present an unprecedented opportunity to involve the public in scientific research via image classifications. However, this engagement strategy comes with a myriad of complications. Volunteers vary in their familiarity with wildlife, and thus, the accuracy of user-derived classifications may be biased by the commonness or popularity of species and user-experience. From an extensive multi-site camera trap study across Michigan U.S.A, images were compiled and identified through a public science platform calledMichigan ZoomIN. We aggregated responses from 15 independent users per image using multiple consensus methods to assess accuracy by comparing to species identification completed by wildlife experts. We also evaluated how different factors including consensus algorithms, study area, wildlife species, user support, and camera type influenced the accuracy of user-derived classifications. Overall accuracy of user-derived classification was 97%; although, several canid (e.g.,Canis lupus, Vulpes vulpes) and mustelid (e.g.,Neovison vison) species were repeatedly difficult to identify by users and had lower accuracy. When validating user-derived classification, we found that study area, consensus method, and user support best explained accuracy. To continue to overcome stigma associated with data from untrained participants, we demonstrated their value by showing the accuracy from volunteers was comparable to experts when classifying North American mammals. Our hierarchical workflow that integrated multiple consensus methods lead to more image classifications without extensive training and even when the expertise of the volunteer was unknown. Ultimately, adopting such an approach can harness broader participation, expedite future camera trap data synthesis, and improve allocation of resources by scholars to enhance performance of public participants and increase accuracy of user-derived data.
Temporal refuges differ between anthropogenic and natural top down pressures in a subordinate carnivore
Authors: Malhotra Rumaan , Lima Samantha , Harris Nyeema C.
Published: June 2020

Apex predators structure communities through consumptive and non-consumptive pathways. In the carnivore guild, this can result in a within-guild cascade through the suppression of mesocarnivores. As the top-down influences of apex predators wane due to human-driven declines, landscape level anthropogenic pressures are rising. Human impacts can be analogous to apex predators in that humans can drive increased mortality in both prey species and carnivores, and impact communities through indirect fear effects and food subsidies. Here, we evaluate whether anthropogenic top-down pressures can structure communities in a similar manner as apex predators in shaping the interactions of mesocarnivores. Specifically, we expect anthropogenic forces to induce comparable effects as occurrence of apex predators in driving spatiotemporal partitioning between two mesocarnivores. Using multiple camera-trap surveys, we compared the temporal response of a small carnivore, the raccoon (Procyon lotor), to the larger coyote (Canis latrans)at four sites across Michigan that represented opposing gradients of pressure from humans and apex predators. Contrary to our expectations, we found that raccoons shifted their activity pattern in response to coyotes at sites with higher anthropogenic pressures and exhibited no temporal response at sites with apex predators. Temporal shifts were characterized by raccoons being more diurnal in areas of high coyote activity. We conclude that despite superficial similarities, anthropogenic forces do not replace the function of native apex predators in structuring the mesocarnivore guild. As such, an intact and functioning native predator guild remains necessary to preserve spatiotemporal community structure, in natural and disturbed systems alike.
Harmonization of L1CAM Expression Facilitates Axon Outgrowth and Guidance of a Motor Neuron
Authors: Sherry Tessa , Nicholas Hannah R. , Pocock Roger
Published: June 2020

Brain development requires precise regulation of axon outgrowth, guidance and termination by multiple signaling and adhesion molecules. How the expression of these neurodevelopmental regulators is transcriptionally controlled is poorly understood. TheCaenorhabditis elegansSMD motor neurons terminate axon outgrowth upon sexual maturity and partially retract their axons during early adulthood. Here we show that C-Terminal Binding Protein-1 (CTBP-1), a transcriptional corepressor, is required for correct SMD axonal development. Loss of CTBP-1 causes multiple defects in SMD axon development: premature outgrowth, defective guidance, delayed termination and absence of retraction. CTBP-1 controls SMD axon development by repressing the expression of SAX-7 – a L1 cell adhesion molecule (L1CAM). CTBP-1-regulated repression is crucial as deregulated SAX-7/L1CAM causes aberrant SMD axons. We found that axonal defects caused by SAX-7/L1CAM misexpression are dependent on a distinct L1CAM, called LAD-2, which itself plays a parallel role in SMD axon guidance. Our results reveal that harmonization of L1CAM expression controls the development and maturation of a single neuron.
Defining Relictual Biodiversity: Conservation Units in Speckled Dace (Cyprinidae:Rhinichthys osculus) of the Greater Death Valley Ecosystem
Authors: Mussmann Steven M. , Douglas Marlis R. , Oakey David D. , Douglas Michael E.
Published: June 2020

The tips in the tree of life serve as foci for conservation and management, yet clear delimitations are masked by inherent variance at the species-population interface. Analyses using thousands of nuclear loci can potentially sort inconsistencies, yet standard categories applied to this parsing are themselves potentially conflicting and/or subjective [e.g., DPS (distinct population segments); DUs (Diagnosable Units-Canada); MUs (management units); SSP (subspecies); Evolutionarily Significant Units (ESUs)]. One potential solution for consistent categorization is to create a comparative framework by accumulating statistical results from independent studies and evaluating congruence among data sets. Our study illustrates this approach in speckled dace (Cyprinidae:Rhinichthys osculus) endemic to two basins (Owens and Amargosa) in the Death Valley ecosystem (DVE). These fish persist in the Mojave Desert as isolated Pleistocene-relicts and are of conservation concern, but lack formal taxonomic descriptions/designations. Double-digest RAD (ddRAD) methods identified 14,355 SNP loci across 10 populations (N=140). Species delimitation analyses [multispecies coalescent (MSC) and unsupervised machine learning (UML)] delineated four putative ESUs.FSToutlier loci (N=106) were juxtaposed to uncover the potential for localized adaptations. We detected one hybrid population that resulted from upstream reconnection of habitat following contemporary pluvial periods, whereas remaining populations represent relics of ancient tectonism within geographically-isolated springs and groundwater-fed streams. Our study offers three salient conclusions: A blueprint for a multi-faceted delimitation of conservation units; a proposed mechanism by which criteria for intraspecific biodiversity can be potentially standardized; and a strong argument for the proactive management of critically-endangered DVE fishes.
Neuroprotective effects of motherhood on brain function in late-life: a resting state fMRI study
Authors: Orchard Edwina R , Ward Phillip GD , Chopra Sidhant , Storey Elsdon , Egan Gary F , Jamadar Sharna D
Published: June 2020

The maternal brain undergoes structural and functional plasticity during pregnancy and the postpartum period. Little is known about functional plasticity outside caregiving-specific contexts, and whether changes persist across the lifespan. Structural neuroimaging studies suggest that parenthood may confer a protective effect against the ageing process, however it is unknown whether parenthood is associated with functional brain differences in late-life. We examined the relationship between resting state functional connectivity and number of children parented in 220 healthy older females (73.82±3.53years) and 252 healthy older males (73.95±3.50years). We compared patterns of resting state functional connectivity with three different models of age-related functional change to assess whether these effects may be functionally neuroprotective for the ageing human parental brain. No relationship between functional connectivity and number of children was obtained for males. For females, we found widespread decreasing functional connectivity with increasing number of children parented, with increased segregation between networks, decreased connectivity between hemispheres, and decreased connectivity between anterior and posterior regions. The patterns of functional connectivity related to the number of children an older woman has parented were in the opposite direction to those usually associated with age-related cognitive decline, suggesting that motherhood may be beneficial for brain function in late-life.
Single Cell-type Integrative Network Modeling Identified Novel Microglial-specific Targets for the Phagosome in Alzheimer’s disease
Authors: Patel Kruti Rajan , Zhu Kuixi , Henrion Marc Y.R. , Beckmann Noam D. , Moein Sara , Alamprese Melissa L. , Allen Mariet , Wang Xue , Chan Gail , Pertel Thomas , Nejad Parham , Reddy Joseph S. , Carrasquillo Minerva M. , Bennett David A , Ertekin-Taner Nilüfer , De Jager Philip L. , Schadt Eric E. , Bradshaw Elizabeth M. , Chang Rui
Published: June 2020

Late-Onset Alzheimer’s Disease (LOAD) results from a complex pathological process influenced by genetic variation, aging and environment factors. Genetic susceptibility factors indicate that myeloid cells such as microglia play a significant role in the onset of LOAD. Here, we developed a computational systems biology approach to construct probabilistic causal and predictive network models of genetic regulatory programs of microglial cells under LOAD diagnosis by integrating two independent brain transcriptome and genome-wide genotype datasets from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and Mayo Clinic (MAYO) studies in the AMP-AD consortium. From this network model, we identified and replicated novel microglial-specific master regulators predicted to modulate network states associated with LOAD. We experimentally validated three microglial master regulators (FCER1G,HCKandLAPTM5) in primary human microglia-like cells (MDMi) by demonstrating the molecular impact these master regulators have on modulating downstream genomic targets identified by our top-down/bottom-up method and the causal relations among the three key drivers. These master regulators are involved in phagocytosis, a process associated with LOAD. Thus, we propose three new master regulator (key driver) genes that emerged from our network analyses as robust candidates for further evaluation in LOAD therapeutic development efforts.
Beyond olfactory cortex – severity of post-traumatic olfactory loss is associated with response to odors in frontal-parietal-insular networks
Authors: Pellegrino Robert , Farruggia Michael C. , Small Dana M. , Veldhuizen Maria G.
Published: June 2020

Olfactory impairment after trauma is associated with changes in olfactory cortex, including decreased gray matter density and decreased response to odors. Much less is known about the role of other cortical areas in olfactory impairment. We used fMRI in a sample of 63 participants, consisting of 25 with post-traumatic functional anosmia, 16 with post-traumatic hyposmia, and 22 healthy controls with normosmia to investigate whole brain response to odors. Similar neural responses were observed across the groups to odor versus odorless stimuli in the primary olfactory areas in piriform cortex, whereas response in the frontal operculum and anterior insula (fO/al) increased with olfactory function (normosmia > hyposmia > functional anosmia). Unexpectedly, a negative association was observed between response and olfactory function in the mediodorsal thalamus (mdT), ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (pCC). Finally, connectivity within a network consisting of vmPFC, fO, and pCC could be used to successfully classify participants as having functional anosmia or normosmia. We conclude that, at the neural level, olfactory impairment due to head trauma is best characterized by heightened responses and differential connectivity in higher-order areas beyond olfactory cortex.

Significance Statement

Olfactory impairment affects a quarter of the population, with subjective complaints usually confirmed with psychophysical measurements. Here, we demonstrate that the degree of olfactory impairment can also be categorized using neural responses to odors. Remarkably, regions with neural responses that were predictive usually showed an increase in response to odors with degree of impairment, rather than a reduction, as might be expected. Further, predictive cortical regions were not isolated to canonical olfactory areas.