bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms and functions of respiration-driven gamma oscillations in the primary olfactory cortex
Authors: González Joaquín , Torterolo Pablo , Tort Adriano BL
Published: May 2022

Gamma oscillations are believed to underlie cognitive processes by shaping the formation of transient neuronal partnerships on a millisecond scale. These oscillations are coupled to the phase of breathing cycles in several brain areas, possibly reflecting local computations driven by sensory inputs sampled at each breath. Here, we investigated the mechanisms and functions of gamma oscillations in the piriform (olfactory) cortex of awake mice to understand their dependence on breathing and how they relate to local spiking activity. Mechanistically, we find that respiration drives gamma oscillations in the piriform cortex, which correlate with local feedback inhibition and result from recurrent connections between local excitatory and inhibitory neuronal populations. Moreover, respiration-driven gamma oscillations are triggered by the activation of mitral/tufted cells in the olfactory bulb and are abolished during ketamine/xylazine anesthesia. Functionally, we demonstrate that they locally segregate neuronal assemblies through a winner-take-all computation leading to sparse odor coding during each breathing cycle. Our results shed new light on the mechanisms of gamma oscillations, bridging computation, cognition and physiology.
LRRK2 Phosphorylates Neuronal Elav RNA-Binding Proteins to Regulate Phenotypes Relevant to Parkinson’s Disease
Authors: Pastic Alyssa , Negeri Olanta , Ravel-Chapuis Aymeric , Savard Alexandre , Trung My Tran , Palidwor Gareth , Guo Huishan , Marcogliese Paul , Taylor James A. , Okano Hideyuki , Trinkle-Mulcahy Laura , Jasmin Bernard J. , Park David , Gibbings Derrick
Published: May 2022

Parkinson’s disease (PD) is characterized by accumulation of α-synuclein and the loss of dopaminergic neurons. Mutations which cause an increase in the kinase activity of Leucine-Rich-Repeat Kinase-2 (LRRK2) are a major inherited cause of PD. Research continues to determine which targets LRRK2 phosphorylates to cause disease. Polymorphisms in the locus of ELAVL4, an RNA-binding protein are a risk-factor for Parkinson’s disease and an ELAV family member was identified in Drosophila as required for pathology instigated by human mutant LRRK2. We discovered that three neuronal ELAVs including ELAVL4 (also known as HuD) are phosphorylated by LRRK2. This controls binding of neuronal ELAVs to mRNA and their post- transcriptional regulation of mRNA abundance and splicing in neuronal cell lines and the mouse midbrain. LRRK2 G2019S functionally inhibits neuronal ELAVs effects on mRNA abundance, while enhancing their effects on mRNA splicing. The combination of LRRK2 G2019S and ELAVL4-/- causes accumulation of LRRK2 and α-synuclein, loss of dopaminergic neurons and motor deficits. Targets of neuronal ELAVs are also selectively misregulated in cells and tissues of PD patients. Together, this suggests that misregulation of neuronal ELAVs, triggered by LRRK2 mutations may contribute to the characteristic pathology of Parkinson’s disease.

Brief Summary

LRRK2, a kinase linked to Parkinson’s disease, phosphorylates the neuronal ELAV RNA-binding proteins to aggravate key hallmarks of Parkinson’s disease including accumulation of α-synuclein and motor deficits in mice.
The bHLH transcription factor MpHYPNOS regulates gemma dormancy in the liverwort Marchantia polymorpha
Authors: Kato Hirotaka , Yoshimura Nami , Yoshikawa Mikako , Matsuura Hideyuki , Takahashi Kosaku , Takezawa Daisuke , Furuya Tomoyuki , Kondo Yuki , Fukaki Hidehiro , Mimura Tetsuro , Ishizaki Kimitsune
Published: May 2022

Dormancy is a key process employed by land plants to adapt to harsh terrestrial environments. The liverwort Marchantia polymorpha produces dormant propagules called gemmae for asexual reproduction. The plant hormone abscisic acid (ABA) plays important roles in regulating dormancy in both the seeds of flowering plants and the gemmae of M. polymorpha.

Based on previous transcriptome analysis, we identified the basic helix-loop-helix transcription factor MpHYPNOS (MpHYP) as a key regulator of gemma dormancy.

Knock-out mutants of MpHYP showed much higher germination rates of gemmae in gemma cups than ABA-related mutants, while the growth and development of these mutants resembled that of the wild type. Transient induction of MpHYP caused irreversible growth arrest of gemmae and thalli. Transcriptome and RT-qPCR analyses revealed that MpHYP represses the expression of cell cycle–related genes and induces ABA biosynthesis and ABA-responsive genes. Indeed, ABA levels increased in MpHYP overexpression lines and decreased in Mphyp knock-out lines. However, the growth arrest caused by MpHYP overexpression was not suppressed by a mutation in an ABA receptor gene.

These findings suggest that MpHYP regulates gemma dormancy and thallus growth mainly through the ABA-independent pathway, providing clues about ABA-dependent and independent regulation of dormancy in land plants.
Exploiting threonine sidechains as molecular switches to modulate the fluorescence of genetically encoded biosensors
Authors: Leong Lee Min , Shin Sang Chul , Rhee Jun Kyu , Kim Heejung , Seong Jihye , Woo Junhyuk , Han Kyungreem , Storace Douglas , Baker Bradley J.
Published: May 2022

Rapid and reproducible optical transitions of a fluorescent protein (FP) can be achieved with a Genetically Encoded Voltage Indicator (GEVI) via manipulation of the membrane potential. These transitions revealed novel effects of internal mutations near the chromophore that would not be detected under steady state conditions. Mutating an internal threonine (T203) affected the speed of the voltage-dependent fluorescence transition suggesting a conformational change inside the protein. These optical transitions also demonstrated interplay between internal and externally oriented sidechains of the β-can structure. Replacing the steric hindrance of a phenylalanine near the chromophore with threonine (F165T) did not alter the resting fluorescence but resulted in a more complex fluorescent transition providing evidence for a flexible chromophore undergoing conformational changes. F165T orientation was influenced by the flanking external amino acids at positions 164 and 166 with 164F/165T/166T exacerbating the complexity of the voltage-dependent transition while 164T/165T/166F reduced the flexibility of the chromophore resembling the transition pattern of the original F165 version. Alphafold predictions reveal a threonine switch with different orientations of the F165T internal side chain depending on the direction of the offset in polarity at external positions 164 and 166. The crystal structures of the pH-sensitive FP, Super Ecliptic pHluorin and two derivatives solved in varying pH conditions also indicate interactions between the external protein surface and the internal environment providing another example of a threonine switch near the chromophore at T203. This ability to orient internal sidechains has led to the development of a novel GEVI that gets brighter upon depolarization of the plasma membrane, works at low light levels, is less susceptible to physiological pH, and provides in vivo signals. These observations affecting fluorescent transitions should also prove valuable to the development of any FP-based biosensor.
Flavivirus prM interacts with MDA5 and MAVS to inhibit RLR antiviral signaling
Authors: Sui Liyan , Zhao Yinghua , Wang Wenfang , Chi Hongmiao , Tian Tian , Wu Ping , Zhang Jinlong , Zhao Yicheng , Wei Zheng-Kai , Hou Zhijun , Zhou Guoqiang , Wang Guoqing , Wang Zedong , Liu Quan
Published: May 2022

Vector-borne flaviviruses, including tick-borne encephalitis virus (TBEV), Zika virus (ZIKA), West Nile virus (WNV), yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), pose a growing threat to public health worldwide, and have evolved complex mechanisms to overcome host antiviral innate immunity. However, the underlying mechanisms of flavivirus structural proteins to evade host immune response remain elusive. Here we show that TBEV structural proteins, including pre-membrane (prM), envelope, and capsid proteins, could inhibit type I interferon (IFN-I) production. Mechanically, TBEV prM interacted with both MDA5 and MAVS and interfered with the formation of MDA5-MAVS complex, thereby impeded the nuclear translocation and dimerization of IRF3 to inhibit RLR antiviral signaling. ZIKA and WNV prM was also demonstrated to interact with both MDA5 and MAVS, while dengue virus serotype 2 (DENV2) and YFV prM associated only with MDA5 or MAVS to suppress IFN-I production. In contrast, JEV prM could not suppress IFN-I production. Overexpression of TBEV and ZIKA prM significantly promoted the replication of Sendai virus. Our findings reveal the immune evasion mechanisms of flavivirus prM, which may contribute to understanding flavivirus pathogenicity, therapeutic intervention and vaccine development.

Author Summary

All flaviviruses must overcome the antiviral innate immunity to infect vertebrate host. The non-structural proteins of flaviviruses are mainly responsible for viral replication and host innate immune escape, and the structural proteins are involved in the virus assembly, which are potential targets for prevention and treatment of flaviviral infections. Whether flavivirus structural proteins participate in host innate immune escape remains to be determined. Here, we found that tick-borne encephalitis virus structural proteins precursor membrane (prM), capsid, and envelope proteins can antagonize type I interferon production, in which prM interacts with both MDA5 and MAVS to inhibit RLR antiviral signaling. Additionally, Zika virus and West Nile virus prMs also interact with both MDA5 and MAVS, while dengue virus serotype 2 and yellow fever virus prMs associate only with MDA5 or MAVS to suppress type I interferon production. In contrast, Japanese encephalitis virus prM cannot antagonize type I interferon production. Our findings reveal that flavivirus prM inhibits type I interferon production via interacting with MDA5 and/or MAVS in a species-dependent manner, which may contribute to understanding flavivirus pathogenicity, therapeutic intervention, and vaccine development.
CircEML1 facilitates the steroid synthesis in follicular granulosa cells of chicken through sponging gga-miR-449a to release IGF2BP3 expression
Authors: Li Jing , Si Sujin , Wu Xing , Zhang Zihao , Li Chong , Tao Yiqing , Yang Pengkun , Li Donghua , Li Guoxi , Liu Xiaojun , Tian Yadong , Kang Xiangtao
Published: May 2022

Non-coding RNAs (ncRNAs) induced competing endogenous RNAs (ceRNA) play crucial roles in various biological process by regulating target gene expression. However, the studies of ceRNA networks in the regulation of ovarian ovulation process of chicken remains deficient compared to that in mammals. In the present study, it was revealed that circEML1 was differential expressed in hen’s ovarian tissue at different ages (15W, 20W, 30W and 68W) and identified as a loop structure from EML1 pre-mRNA, which promoted the expressions of CYP19A1 and StAR and the production of E2 and P4 in follicular granulosa cells (GCs) using qRT-PCR and ELISA. Furthermore, circEML1 was proved to serve as a sponge of gga-miR-449a to participate in the steroidogenesis using the dual luciferase reporter, RNA FISH assays, qRT-PCR and ELISA assays. In addition, we evaluated several potential target genes of gga-miR-449a and found that IGF2BP3 was targeted by gga-miR-449a and promoted steroidogenesis and E2/P4 secretions in GCs, which may act the regulatory role via mTOR/p38MAPK pathways. Meanwhile, we implemented a rescue experiment and demonstrated that gga-miR-449a reversed the promoting role of circEML1 on IGF2BP3 expression and steroidogenesis. Eventually, this study suggested that circEML1/gga-miR-449a/IGF2BP3 axis exerted an important role in the regulation of steroidogenesis and steroid hormones’ production possibly through mTOR/p38MAPK pathways in follicular GCs of chicken and may contribute a better understanding of ceRNA network in the modulatory mechanism of hen’s ovarian development and ovulation cycle.
Sequences and proteins that influence mRNA processing in Trypanosoma brucei: evolutionary conservation of SR-domain and PTB protein functions
Authors: Waithaka Albina , Maiakovska Olena , Grimm Dirk , Melo do Nascimento Larissa , Clayton Christine
Published: May 2022

Spliced leader trans splicing is the addition of a short, capped sequence to the 5’ end of mRNAs. It is widespread in eukaryotic evolution, but factors that influence trans splicing acceptor site choice have been little investigated. In Kinetoplastids, all protein-coding mRNAs are 5’ trans spliced. A polypyrimidine tract is usually found upstream of the AG splice acceptor, but there is no branch point consensus; moreover, splicing dictates polyadenylation of the preceding mRNA. We here describe a trans splicing reporter system that can be used for studies and screens concerning the roles of sequences and proteins in processing site choice and efficiency. Splicing was poor with poly(U) tracts less than 9 nt long, and was influenced by nearby secondary structures. A screen for signals resulted in selection of sequences that were on average 45% U and 35% C. Tethering of either the splicing factor SF1, or the cleavage and polyadenylation factor CPSF3 within the intron stimulated processing in the correct positions, while tethering of two possible homologues of Opisthokont PTB inhibited processing. In contrast, tethering of SR-domain proteins RBSR1, RBSR2, or TSR1 or its interaction partner TSR1IP, promoted use of alternative signals upstream of the tethering sites. RBSR1 interacts predominantly with proteins implicated in splicing, whereas the interactome of RBSR2 is more diverse. These results suggest that the functions of PTB and SR-domain proteins in splice site definition were already present in the last eukaryotic common ancestor.
Memory loss at sleep onset
Authors: Lacaux Célia , Andrillon Thomas , Arnulf Isabelle , Oudiette Delphine
Published: May 2022

Every night, we pass through a transitory zone at the borderland between wakefulness and sleep, named the first stage of non-rapid eye movement sleep (N1). N1 sleep is associated with an increased hippocampal activity and dreamlike experiences that incorporate recent wake materials, suggesting that it may be associated with memory processing. Here, we investigated the specific contribution of N1 sleep in the processing of memory traces. Participants were asked to learn the precise locations of 48 objects on a grid and were then tested on their memory for these items before and after a 30-minute rest during which participants either stayed fully awake, transitioned toward N1 or deeper (N2) sleep. We showed that memory recall was lower (10% forgetting) after a resting period including only N1 sleep compared to N2 sleep. Furthermore, the ratio of alpha/theta power (an EEG marker of the transition towards sleep) correlated negatively with the forgetting rate when taking into account all sleepers (N1 and N2 groups combined), suggesting a physiological index for memory loss that transcends sleep stages. Our findings suggest that interrupting sleep onset at N1 may alter sleep-dependent memory consolidation and promote forgetting.
Ancient dental calculus preserves signatures of biofilm succession and inter-individual variation independent of dental pathology
Authors: Velsko Irina M. , Semerau Lena , Inskip Sarah A. , García-Collado Maite Iris , Ziesemer Kirsten , Ruber Maria Serrano , Benítez de Lugo Enrich Luis , García Jesús Manuel Molero , Valle David Gallego , Ruiz Ana Cristina Peña , Salazar García Domingo C. , Hoogland Menno L.P. , Warinner Christina
Published: May 2022

Dental calculus preserves oral microbes, enabling comparative studies of the oral microbiome and health through time. However, small sample sizes and limited dental health metadata have hindered health-focused investigations to date. Here we investigate the relationship between tobacco pipe smoking and dental calculus microbiomes. Dental calculus from 75 individuals from the 19th century Middenbeemster skeletal collection (Netherlands) were analyzed by metagenomics. Demographic and dental health parameters were systematically recorded, including the presence/number of pipe notches. Comparative data sets from European populations before and after the introduction of tobacco were also analyzed. Calculus species profiles were compared with oral pathology to examine associations between microbiome community, smoking behavior, and oral health status. The Middenbeemster individuals exhibited relatively poor oral health, with a high prevalence of periodontal disease, caries, heavy calculus deposits, and antemortem tooth loss. No associations between pipe notches and dental pathologies, or microbial species composition, were found. Calculus samples before and after the introduction of tobacco showed highly similar species profiles. Observed inter-individual microbiome differences were consistent with previously described variation in human populations from the Upper Paleolithic to the present. Dental calculus may not preserve microbial indicators of health and disease status as distinctly as dental plaque.

Research Highlights

No associations between calculus species profiles and oral health metrics were detected in a single large population

A minority of individuals have a dental calculus species profile characterized by low levels ofStreptococcusand high levels of anaerobic taxa
Epigenetic Control of Hundreds of Chromosome-Associated lncRNA Genes Essential for Replication and Stability
Authors: Heskett Michael B. , Vouzas Athanasios E. , Smith Leslie G. , Yates Phillip A. , Boniface Christopher , Bouhassira Eric E. , Spellman Paul , Gilbert David M. , Thayer Mathew J.
Published: May 2022

ASARs are long noncoding RNA genes that control replication timing of entire human chromosomes in cis. The three known ASAR genes are located on human chromosomes 6 and 15, and are essential for chromosome integrity. To identify ASARs on all human chromosomes we utilized a set of distinctive ASAR characteristics that allowed for the identification of hundreds of autosomal loci with epigenetically controlled, allele-restricted behavior in expression and replication timing of coding and noncoding genes, and is distinct from genomic imprinting. Disruption of noncoding RNA genes at five of five tested loci resulted in chromosome-wide delayed replication and chromosomal instability, validating their ASAR activity. In addition to the three known essential cis-acting chromosomal loci, origins, centromeres, and telomeres, we propose that all mammalian chromosomes also contain “Inactivation/Stability Centers” that display allele-restricted epigenetic regulation of protein coding and noncoding ASAR genes that are essential for replication and stability of each chromosome.
Method for quantifying the metabolic boundary fluxes of cell cultures in large cohorts by high resolution hydrophilic liquid chromatography mass spectrometry
Authors: Groves Ryan A. , Mapar Maryam , Aburashed Raied , Ponce Luis F. , Bishop Stephanie L. , Rydzak Thomas , Drikic Marija , Bihan Dominique G. , Benediktsson Hallgrimur , Clement Fiona , Gregson Daniel B. , Lewis Ian A.
Published: May 2022

Metabolomics is a mainstream approach for investigating the metabolic underpinnings of complex biological phenomena and is increasingly being applied to large scale studies involving hundreds or thousands of samples. Although metabolomics methods are robust in smaller scale studies, they can be challenging to apply in larger cohorts due to the inherent variability of liquid chromatography mass spectrometry (LC-MS). Much of this difficulty results from the time-dependent changes in the LC-MS system, which affects both the qualitative and quantitative performance of the instrument. Herein, we introduce an analytical strategy for addressing this problem in large-scale microbial studies. Our approach quantifies microbial boundary fluxes using two zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) columns that are plumbed to enable offline column equilibration. Using this strategy, we show that over 360 common metabolites can be resolved in 4.5 minutes per sample and that metabolites can be quantified with a median coefficient of variation of 0.127 across 1,100 technical replicates. We illustrate the utility of this strategy via an analysis of 960 strains of Staphylococcus aureus isolated from blood stream infections. These data capture the diversity of metabolic phenotypes observed in clinical isolates and provide an example of how large-scale investigations can leverage our novel analytical strategy.
Isoform-specific O-glycosylation dictates Ebola virus infectivity
Authors: Bagdonaite Ieva , Abdurahman Samir , Mirandola Mattia , Frank Martin , Narimatsu Yoshiki , Vakhrushev Sergey Y. , Salata Cristiano , Mirazimi Ali , Wandall Hans H.
Published: May 2022

Ebola virus glycoprotein is one of the most heavily O-glycosylated viral envelope glycoproteins. Using glycoengineered cell lines we demonstrate that O-linked glycan truncation and perturbed initiation retarded the production of viral particles and decreased infectivity of progeny virus. Next, using TMT isobaric labelling, we performed quantitative differential O-glycoproteomics on proteins produced in wild type HEK293 cells and cell lines ablated for three key GalNAc-transferases, GalNAc-T1, -T2, and -T3, as well as compared it to patterns on wild type virus-like particles. We demonstrate selective initiation of a subset of O-glycosites by each enzyme, with GalNAc-T1 having the largest contribution. This work represents a comprehensive site-specific analysis of EBOV GP, with 47 O-glycosites identified, and sheds light on differential regulation of EBOV GP glycosylation initiated by host GalNAc-Ts. Together with the effect on viral propagation it opens prospective avenues for tailored intervention approaches and means for modulating immunogen O-glycan density.
Geographic Name Resolution Service: A tool for the standardization and indexing of world political division names, with applications to species distribution modeling
Authors: Boyle Brad L. , Maitner Brian S. , Barbosa George G. C. , Sajja Rohith K. , Feng Xiao , Merow Cory , Newman Erica A. , Park Daniel S. , Roehrdanz Patrick R. , Enquist Brian J.
Published: May 2022

Massive biological databases of species occurrences, or georeferenced locations where a species has been observed, are essential inputs for modeling present and future species distributions. Location accuracy is often assessed by determining whether the observation geocoordinates fall within the boundaries of the declared political divisions. This otherwise simple validation is complicated by the difficulty of matching political division names to the correct geospatial object. Spelling errors, abbreviations, alternative codes, and synonyms in multiple languages present daunting name disambiguation challenges. The inability to resolve political division names reduces usable data and analysis of erroneous observations can lead to flawed results.

Here, we present the Geographic Name Resolution Service (GNRS), an application for the correction, standardization and indexing of world political division names. The GNRS resolves political division names against a reference database that combines names and codes from GeoNames with geospatial object identifiers from the Global Administrative Areas Database (GADM). In a trial resolution of political division names extracted from >270 million species occurrences, only 1.9%, representing just 6% of occurrences, matched exactly to GADM political divisions in their original form. The GNRS was able to resolve, completely or in part, 92% of the remaining 378,568 political division names, or 86% of the full biodiversity occurrence dataset. In an assessment of geocoordinate accuracy for >239 million species occurrences, resolution of political divisions by the GNRS enabled detection of an order of magnitude more errors and an order of magnitude more error-free occurrences. By providing a novel solution to a major data quality impediment, the GNRS liberates a tremendous amount of biodiversity data for quantitative biodiversity research. The GNRS runs as a web service and can be accessed via an API, an R package, and a web-based graphical user interface. Its modular architecture is easily integrated into existing data validation workflows.
Great-tailed Grackles (Quiscalus mexicanus) as a tolerant host of avian malaria parasites
Authors: Pacheco M. Andreína , Ferreira Francisco C. , Logan Corina J. , McCune Kelsey B. , MacPherson Maggie P. , Miranda Sergio Albino , Santiago-Alarcon Diego , Escalante Ananias A.
Published: May 2022

Great-tailed Grackles (Quiscalus mexicanus) are a social, polygamous bird species whose populations have rapidly expanded their geographic range across North America over the past century. Before 1865, Great-tailed Grackles were only documented in Central America, Mexico, and southern Texas in the USA. Given the rapid northern expansion of this species, it is relevant to study its role in the dynamics of avian blood parasites. Here, 87 Great-tailed grackles in Arizona (a population in the new center of the range) were screened for haemosporidian parasites using microscopy and PCR targeting the parasite mitochondrial cytochrome b gene. Individuals were caught in the wild from January 2018 until February 2020. Haemosporidian parasite prevalence was 60.9% (53/87). A high Plasmodium prevalence was found (59.8%, 52/87), and one grackle was infected with Haemoproteus (Parahaemoproteus) sp. (lineage SIAMEX01). Twenty-one grackles were infected with P. cathemerium, sixteen with P. homopolare, four with P. relictum (strain GRW04), and eleven with three different genetic lineages of Plasmodium spp. that have not been characterized to species level (MOLATE01, PHPAT01, and ZEMAC01). Gametocytes were observed in birds infected with three different Plasmodium lineages, revealing that grackles are competent hosts for some parasite species. This study also suggests that grackles are highly susceptible and develop chronic infections consistent with parasite tolerance, making them competent to transmit some generalist haemosporidian lineages. It can be hypothesized that, as the Great-tailed Grackle expands its geographic range, it may affect local bird communities by increasing the transmission of local parasites but not introducing new species into the parasite species pool.
Spatial organization of Dectin-1 and TLR2 during synergistic crosstalk revealed by super-resolution imaging
Authors: Li Miao , Vultorius Christopher , Bethi Manisha , Yu Yan
Published: May 2022

Innate immune cells recognize and elicit responses against pathogens by integrating signals from different types of cell-surface receptors. How the receptors interact in the membrane to enable their signaling crosstalk is poorly understood. Here, we reveal the nanoscale organization of TLR2 and Dectin-1, a receptor pair known to cooperate in regulating antifungal immunity, through their synergistic signaling crosstalk at macrophage cell membranes. Using super-resolution single-molecule localization microscopy, we show that discrete non-colocalized nanoclusters of Dectin-1 and TLR2 are partially overlapped during their synergistic crosstalk. Compared to when one type of receptor is activated alone, the simultaneous activation of Dectin-1 and TLR2 leads to a higher percentage of both receptors being activated by their specific ligands, and consequently an increased level of tyrosine phosphorylation. Our results depict, in nanoscale detail, how Dectin-1 and TLR2 achieve synergistic signaling through the spatial organization of their receptor nanoclusters.
DNA-based detection of Aphanomyces cochlioides in soil and sugar beet plants
Authors: Botkin Jacob R. , Hirsch Cory D. , Martin Frank N. , Chanda Ashok K.
Published: May 2022

Aphanomyces cochlioides, the causal agent of seedling damping-off and Aphanomyces root rot (ARR) of sugar beet, causes yield losses in major sugar beet growing regions. Currently, a 4-week soil bioassay and a 2-day culture-based assay are used to diagnose presence of A. cochlioides. However, these assays can be time-consuming and lack sensitivity. In this study we developed a sensitive, specific, and rapid assay to detect and quantify DNA of A. cochlioides. We developed a TaqMan qPCR assay targeting a region of the mitochondrial genome of A. cochlioides representing a unique gene order for Aphanomyces with genus-specific primers and a species-specific probe. The qPCR assay detected A. cochlioides in 12 naturally infested field soil samples with disease severity index (DSI) values of 48-100, in sugar beet seedlings 5-7 days after planting, and with as little as 1 fg of pure A. cochlioides DNA. Adult sugar beet roots with ARR symptoms were sampled to further validate this qPCR assay. Aphanomyces cochlioides was detected in 95% of these samples using this qPCR assay, while only 23% of the same samples were positive using a culture-based assay. This shows the improved sensitivity of this qPCR assay for disease diagnosis and could provide growers with ARR risk of a field, which would help them make informed disease management decisions. However, further research is required to translate the results of this study to growers’ fields to quantify A. cochlioides with a high degree of accuracy.
CLASP2 stabilizes GDP-associated terminal tubulins to prevent microtubule catastrophe
Authors: Luo Wangxi , Demidov Vladimir , Shen Qi , Girão Hugo , Chakraborty Manas , Maiorov Aleksandr , Ataullakhanov Fazly I. , Lin Chenxiang , Maiato Helder , Grishchuk Ekaterina L.
Published: May 2022

CLASPs are ubiquitous stabilizers of microtubule dynamics but their molecular targets at the microtubule plus-end are not understood. Using DNA origami-based reconstructions we show that clusters of human CLASP2 form a load-bearing bond with terminal GDP-tubulins at the stabilized microtubule tip. This activity relies on the unconventional TOG2 domain of CLASP2, which releases its high-affinity bond with the GDP-dimers upon their conversion into polymerization-competent GTP-tubulin. By tethering dynamic microtubule ends near immobilized CLASP2, we show that the targets for CLASP2 binding at the polymerizing tip arise stochastically, leading to nanoscale disruptions in microtubule tip integrity. The ability of CLASP2 to recognize nucleotide-specific tubulin conformation and stabilize the catastrophe-promoting GDP-tubulins intertwines with the previously underappreciated exchange between GDP and GTP at terminal tubulins, providing a distinct molecular mechanism to suppress microtubule catastrophe without affecting tubulin incorporation.
Episodic memory retrieval affects the onset and dynamics of evidence accumulation during value-based decisions
Authors: Kraemer Peter M. , Gluth Sebastian
Published: May 2022

Abstract

In neuroeconomics, there is much interest in understanding simple value-based choices where agents choose between visually presented goods, comparable to a shopping scenario in a supermarket. However, many everyday decisions are made in the physical absence of the considered goods, requiring agents to recall information about the goods from memory. Here, we asked whether and how this reliance on an internal memory representation affects the temporal dynamics of decision making on a cognitive and neural level. Participants performed a remember-and-decide task, in which they made simple purchasing decisions between money offers and snack items while undergoing EEG. Snack identity was presented either visually (value trials) or had to be recalled from memory (memory trials). Behavioral data indicated comparable choice consistency across both trial types, but considerably longer response times (RT) in memory trials. Drift-diffusion modeling suggested that this RT difference was due to longer non-decision time of decision processes as well as altered evidence accumulation dynamics (lower accumulation rate and higher decision threshold). The non-decision time effect was supported by a delayed onset of the lateralized readiness potential. These results show that both, decision and non-decision processes are prolonged when participants need to resort to internal memory representations during value-based decisions.
The rediscovery of a relict unlocks the first global phylogeny of whip spiders (Amblypygi)
Authors: de Miranda Gustavo S. , Kulkarni Siddharth S. , Tagliatela Jéssica , Baker Caitlin M. , Giupponi Alessandro P.L. , Labarque Facundo M. , Gavish-Regev Efrat , Rix Michael G. , Carvalho Leonardo S. , Fusari Lívia Maria , Wood Hannah M. , Sharma Prashant P.
Published: May 2022

Asymmetrical rates of cladogenesis and extinction abound in the Tree of Life, resulting in numerous minute clades that are dwarfed by larger sister groups. Such taxa are commonly regarded as phylogenetic relicts or “living fossils” when they exhibit an ancient first appearance in the fossil record and prolonged external morphological stasis, particularly in comparison to their more diversified sister groups. Due to their special status, various phylogenetic relicts tend to be well-studied and prioritized for conservation. A notable exception to this trend is found within Amblypygi (“whip spiders”), a visually striking order of functionally hexapodous arachnids that are notable for their antenniform first walking leg pair (the eponymous “whips”). Paleoamblypygi, the putative sister group to the remaining Amblypygi, is known from Late Carboniferous and Eocene deposits, but is survived by a single living species, Paracharon caecus Hansen, 1921, that was last collected in 1899. Due to the absence of genomic sequence-grade tissue for this vital taxon, there is no global molecular phylogeny for Amblypygi to date, nor a fossil-calibrated estimation of divergences within the group. Here, we report several individuals of a previously unknown species of Paleoamblypygi from a cave site in Colombia. Capitalizing upon this discovery, we generated the first molecular phylogeny of Amblypygi, integrating ultraconserved element sequencing with legacy Sanger datasets and including described extant genera. To quantify the impact of sampling Paleoamblypygi on divergence time estimation, we performed in silico experiments with pruning of Paracharon. We demonstrate that the omission of relicts has a significant impact on the accuracy of node dating approaches that outweighs the impact of excluding ingroup fossils. Our results underscore the imperative for biodiversity discovery efforts in elucidating the phylogenetic relationships of “dark taxa”, and especially phylogenetic relicts in tropical and subtropical habitats.
Interactions between seasonal temperature variation and temporal synchrony drive increased arbovirus co-infection incidence
Authors: Poterek Marya L. , Vogels Chantal B.F. , Grubaugh Nathan D. , Ebel Gregory D. , Perkins T. Alex , Cavany Sean M.
Published: May 2022

Though instances of arthropod-borne (arbo)virus co-infection have been documented clinically, the overall incidence of arbovirus co-infection and its drivers are not well understood. Now that dengue, Zika, and chikungunya viruses are all in circulation across tropical and subtropical regions of the Americas, it is important to understand the environmental and biological conditions that make co-infections more likely to occur. To understand this, we developed a mathematical model of cocirculation of two arboviruses, with transmission parameters approximating dengue, Zika, and/or chikungunya viruses and co-infection possible in both humans and mosquitoes. We examined the influence of seasonal timing of arbovirus cocirculation on the extent of co-infection. By undertaking a sensitivity analysis of this model, we examined how biological factors interact with seasonality to determine arbovirus co-infection transmission and prevalence. We found that temporal synchrony of the co-infecting viruses and average temperature were the most influential drivers of co-infection incidence. For seasonal patterns typical of a tropical region, we observed non-negligible incidence irrespective of arrival time when two arboviruses arrived simultaneously. Under our default parameter settings, this corresponded to a maximum co-infection cumulative incidence of 83 per 1,000 individuals and a minimum cumulative incidence of 32 per 1,000 individuals in the year following arrival. For seasonal patterns typical of a more temperate region, co-infections only occurred if arrivals took place near the seasonal peak, and even then, did not reach 0.01 co-infections per 1,000 individuals. Our model highlights the synergistic effect of co-transmission from mosquitoes, which leads to more than double the number of co-infections than would be expected in a scenario without co-transmission. Our results show that arbovirus co-infections are unlikely to occur in appreciable numbers unless epidemics overlap in space and time and in a tropical region.
Quantifying dynamic facial expressions under naturalistic conditions
Authors: Jeganathan Jayson , Campbell Megan , Hyett Matthew , Parker Gordon , Breakspear Michael
Published: May 2022

Facial affect is expressed dynamically – a giggle, grimace, or an agitated frown. However, the characterization of human affect has relied almost exclusively on static images. This approach cannot capture the nuances of human communication or support the naturalistic assessment of affective disorders. Using the latest in machine vision and systems modelling, we studied dynamic facial expressions of people viewing emotionally salient film clips. We found that the apparent complexity of dynamic facial expressions can be captured by a small number of simple spatiotemporal states - composites of distinct facial actions, each expressed with a unique spectral fingerprint. Sequential expression of these states is common across individuals viewing the same film stimuli but varies in those with the melancholic subtype of major depressive disorder. This approach provides a platform for translational research, capturing dynamic facial expressions under naturalistic conditions and enabling new quantitative tools for the study of affective disorders and related mental illnesses.
Beyond the Euclidean brain: inferring non-Euclidean latent trajectories from spike trains
Authors: Jensen Kristopher T. , Liu David , Kao Ta-Chu , Lengyel Máté , Hennequin Guillaume
Published: May 2022

Neuroscience faces a growing need for scalable data analysis methods that reduce the dimensionality of population recordings yet retain key aspects of the computation or behaviour. To extract interpretable latent trajectories from neural data, it is critical to embrace the inherent topology of the features of interest: head direction evolves on a ring or torus, 3D body rotations on the special orthogonal group, and navigation is best described in the intrinsic coordinates of the environment. Accordingly, we recently proposed the manifold Gaussian process latent variable model (mGPLVM) to simultaneously infer latent representations on non-Euclidean manifolds and how neurons are tuned to these representations. This probabilistic method generalizes previous Euclidean models and allows principled selection between candidate latent topologies. While powerful, mGPLVM makes two unjustified approximations that limit its practical applicability to neural datasets. First, consecutive latent states are assumed independent a priori, whereas behaviour is continuous in time. Second, its Gaussian noise model is inappropriate for positive integer spike counts. Previous work in Euclidean LVMs such as GPFA has shown significant improvements in performance when modeling such features appropriately (Jensen et al., 2021). Here, we extend mGPLVM by incorporating temporally continuous priors over latent states and flexible count-based noise models. This improves inference on synthetic data, avoiding negative spike count predictions and discontinuous jumps in latent trajectories. On real data, we also mitigate these pathologies while improving model fit compared to the original mGPLVM formulation. In summary, our extended mGPLVM provides a widely applicable tool for inferring (non-)Euclidean neural representations from large-scale, heterogeneous population recordings. We provide an efficient implementation in python, relying on recent advances in approximate inference to e.g. fit 10,000 time bins of recording for 100 neurons in five minutes on a single GPU.
Mitotic chromosome condensation resets chromatin to maintain transcriptional homeostasis
Authors: Ramos-Alonso Lucía , Holland Petter , Le Gras Stéphanie , Zhao Xu , Jost Bernard , Bjørås Magnar , Barral Yves , Enserink Jorrit M. , Chymkowitch Pierre
Published: May 2022

Mitotic entry correlates with the condensation of the chromosomes, remodeling of histone modifications, exclusion of transcription factors from DNA and the broad downregulation of transcription. However, whether mitotic condensation influences transcription in the subsequent interphase is unknown. Here, we show that preventing one chromosome to condense during mitosis causes it to fail resetting transcription. Rather it diverted the transcription machinery and underwent unscheduled initiation of gene expression. This caused the activation of inducible transcriptional programs, such as the GAL genes, even in absence of the relevant stimuli. Strikingly, aberrant gene expression persisted into the next interphase. Thus, our study identifies the maintenance of transcriptional homeostasis as an unexpected and yet unexplored function of mitotic chromosome condensation.

One-Sentence Summary

Mitotic chromatin condensation resets the transcriptome to protect cells from transcriptional drifting after anaphase.
A lysine residue from an extracellular turret switches the ion preference in a Cav3 T-Type channel
Authors: Guan W. , Orellana K. G. , Stephens R.F. , Zhorov B. , Spafford J.D
Published: May 2022

A dominant sodium influx is mediated by a lysine residue in a novel extracellular loop of T-type Cav3 channels. Here we expressed calcium- and sodium-permeable splice variants which have exons 12b and 12a, respectively, as well as mutated channels containing exons Lys-12a-Ala and Ala-12b-Lys. We demonstrate that the mutant channels render high sodium permeability and calcium selectivity, respectively. Modelling illustrate that the pore lysine is salt-bridged to an aspartate residue immediately C-terminal to the second-domain glutamate of the selectivity-filter. We propose that a calcium ion chelated between the aspartate and the selectivity-filter glutamate is knocked-out by the incoming calcium ion in the process of calcium permeation, but sodium ions are repelled. The aspartate is neutralized by the lysine residue in the sodium-permeant variant, allowing for sodium permeation through the selectivity filter ring of four acidic residues akin to the prokaryotic sodium channels with four glutamates in the selectivity filter.
Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
Authors: Nutma Erik , Fancy Nurun , Weinert Maria , Marzin Manuel C. , Tsartsalis Stergios , Muirhead Robert C.J. , Falk Irene , de Bruin Joy , Hollaus David , Pieterman Robin , Anink Jasper , Story David , Chandran Siddharthan , Tang Jiabin , Trolese Maria C. , Saito Takashi , Saido Takaomi C. , Wiltshire Katie , Beltran-Lobo Paula , Philips Alexandra , Antel Jack , Healy Luke , Moore Craig S. , Bendotti Caterina , Aronica Eleonora , Radulescu Carola I. , Barnes Samuel J. , Hampton David W. , van der Valk Paul , Jacobson Steven , Matthews Paul M. , Amor Sandra , Owen David R.
Published: May 2022

Microglial activation plays central roles in neuro-inflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells is unique to a subset of species within the Muroidea superfamily of rodents. We show that TSPO is mechanistically linked to classical pro-inflammatory myeloid cell function in rodents but not humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO PET reflects density of inflammatory cells rather than activation state.
Membrane-associated shortened Trk receptors promote neuroprotection and robust axon regeneration without ligands
Authors: Nishijima Euido , Honda Sari , Kitamura Yuta , Namekata Kazuhiko , Kimura Atsuko , Guo Xiaoli , Azuchi Yuriko , Harada Chikako , Murakami Akira , Matsuda Akira , Nakano Tadashi , Parada Luis F. , Harada Takayuki
Published: May 2022

Activation of neurotrophic factor signaling is a promising therapy for neurodegeneration. However, limited availability of both ligands and receptors permits only transient activation. In this study, we conquered this problem by inventing a new system that forces membrane localization of the intracellular domain of neurotrophin receptor TrkB, which results in constitutive activation without ligands. Our new system overcomes the small size limitation of the genome packaging in adeno-associated virus and allows high expression of the transgene. Single gene therapy using the modified form of TrkB enhances neuroprotection in mose models of glaucoma, and stimulates robust axon regeneration after optic nerve injury. Our system may be also applicable to other trophic factor signaling and lead to a significant advance in the field of gene therapy for neurodegenerative disorders.