bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence, persistence, and genetics of antibody responses to protein toxins and virulence factors
Authors: Angkeow Julia W. , Monaco Daniel R. , Chen Athena , Venkataraman Thiagarajan , Jayaraman Sahana , Valencia Cristian , Sie Brandon M. , Liechti Thomas , Farhadi Payam Noroozi , Funez-dePagnier Gabriela , Sherman-Baust Cheryl A. , Wong May Q. , Sears Cynthia L. , Simner Patricia J. , Round June L. , Duggal Priya , Laserson Uri , Steiner Theodore S. , Sen Ranjan , Lloyd Thomas E. , Roederer Mario , Mammen Andrew L. , Longman Randy S. , Rider Lisa G. , Larman H. Benjamin
Published: October 2021

Microbial exposures are crucial environmental factors that impact healthspan by sculpting the immune system and microbiota. Antibody profiling via programmable Phage ImmunoPrecipitation Sequencing (PhIP-Seq) provides a high-throughput, costeffective approach for multiplexed detection of exposure and response to thousands of microbial protein products. Here we designed and constructed a library of 95,601 56 amino acid peptide tiles spanning a subset of environmental proteins more likely to be associated with immune responses: those with “toxin” or “virulence factor” keyword annotations. PhIP-Seq was used to profile the circulating antibodies of ~1,000 individuals against this “ToxScan” library of 14,430 toxins and virulence factors from 1,312 genera of organisms. In addition to a detailed analysis of six commonly encountered human commensals and pathogens, we study the age-dependent stability of the ToxScan profile and use a genome-wide association study (GWAS) to find that the MHC-II locus modulates the selection of bacterial epitopes. We detect previously described anti-flagellin antibody responses in a Crohn’s disease cohort and identify a novel association between anti-flagellin antibodies and juvenile dermatomyositis (JDM). PhIP-Seq with the ToxScan library provides a new window into exposure and immune responses to environmental protein toxins and virulence factors, which can be used to study human health and disease at cohort scale.
Induction of autotetraploidy and microbiome associations mediate differential responses to pathogens
Authors: Mehlferber Elijah C , Song Michael J , Pelaez Julianne Naomi , Jaenisch Johan , Coate Jeremy E , Koskella Britt , Rothfels Carl J
Published: October 2021

It has become increasingly clear that the microbiome plays a critical role in shaping the host organism’s response to disease. There also exists mounting evidence that an organism’s ploidy level is important in their response to pathogens and parasites. However, no study has determined if or how these two factors influence one another. We investigate the effect of whole-genome duplication in Arabidopsis thaliana on their above-ground (phyllosphere) microbiome, and determine the interacting impacts of ploidy and the microbiome on disease outcome. Using seven independently derived synthetic auto-tetraploid Arabidopsis accessions, a synthetic leaf-associated bacterial community, and the model pathogen Pseudomonas syringae pv. Tomato DC3000, we confirm that polyploids are generally more resistant to pathogens, but illustrate that this resistance may be in part due to a decrease in the reliance on beneficial bacteria. Polyploids fare better against the pathogen than diploids regardless of microbial inoculation, while we observed that diploids harboring an intact microbiome have lower pathogen densities than those without. We then use RNA sequencing to show that diploids have many more differentially expressed defense-related genes in the presence of their phyllosphere microbiota, while polyploids exhibit constitutively activated defenses regardless of exposure to the synthetic community. These results imply that whole-genome duplication can disrupt historical host-microbiome associations, and suggest that a potential cause or consequence of disruption is a heightened capacity for pathogen defense that is less impacted by the microbiome.
Loss of α-actinin-3 confers protection from eccentric contraction damage in fast-twitch EDL muscles from aged mdx dystrophic mice by reducing pathological fibre branching
Authors: Kiriaev Leonit , Houweling Peter J. , North Kathryn N. , Head Stewart I.
Published: October 2021

The common null polymorphism (R577X) in the ACTN3 gene is present in over 1.5 billion people worldwide and results in the absence of the protein α-actinin-3 from the Z-discs of fast-twitch skeletal muscle fibres. We have previously reported that this polymorphism is a modifier of dystrophin deficient Duchenne Muscular Dystrophy. To investigate the mechanism underlying this we use a double knockout (dk)Actn3KO/mdx (dKO) mouse model which lacks both dystrophin and sarcomere α-actinin-3. We used dKO mice and mdx dystrophic mice at 12 months (aged) to investigate the correlation between morphological changes to the fast-twitch dKO EDL and the reduction in force deficit produced by an in vitro eccentric contraction protocol. In the aged dKO mouse we found a marked reduction in fibre branching complexity that correlated with protection from eccentric contraction induced force deficit. Complex branches in the aged dKO EDL fibres (28%) were substantially reduced compared to aged mdx EDL fibres (68%) and this correlates with a graded force loss over three eccentric contractions for dKO muscles (∼35% after first contraction, ∼66% overall) compared to an abrupt drop in mdx upon the first eccentric contraction (∼73% after first contraction, ∼89% after three contractions). In dKO protection from eccentric contraction damage was linked with a doubling of SERCA1 pump density the EDL. We propose that the increased oxidative metabolism of fast-twitch glycolytic fibres characteristic of the null polymorphism (R577X) and increase in SR Ca2+ pump proteins reduces muscle fibre branching and decreases susceptibility to eccentric injury in the dystrophinopathies.
Autoregulation of switching behavior by cellular compartment size
Authors: Jozsa Monika , Donchev Tihol Ivanov , Sepulchre Rodolphe , O’Leary Timothy
Published: October 2021

Many kinds of cellular compartments comprise decision making mechanisms that control growth and shrinkage of the compartment in response to external signals. Key examples include synaptic plasticity mechanisms that regulate the size and strength of synapses in the nervous system. However, when synaptic compartments and postsynaptic densities are small such mechanisms operate in a regime where chemical reactions are discrete and stochastic due to low copy numbers of the species involved. In this regime, fluctuations are large relative to mean concentrations, and inherent discreteness leads to breakdown of mass action kinetics. Understanding how synapses and other small compartments achieve reliable switching in the low copy number limit thus remains a key open problem. We propose a novel self regulating signaling motif that exploits the breakdown of mass action kinetics to generate a reliable size-regulated switch. We demonstrate this in simple two and three-species chemical reaction systems and uncover a key role for inhibitory loops among species in generating switching behavior. This provides an elementary motif that could allow size dependent regulation in more complex reaction pathways and may explain discrepant experimental results on well-studied biochemical pathways.
A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients
Authors: Degener Max J. F. , van Cruchten Remco T.P. , Otero Brittney A. , Wang Eric T. , Wansink Derick G. , ‘t Hoen Peter A.C.
Published: October 2021

In patients with myotonic dystrophy type 1 (DM1), dysregulation of RNA-binding proteins like MBNL and CELF1 leads to alternative splicing of exons and is thought to induce a return to fetal splicing patterns in adult tissues, including the central nervous system (CNS). To comprehensively evaluate this, we created an atlas of developmentally regulated splicing patterns in the frontal cortex of healthy individuals and DM1 patients by combining RNA-seq data from BrainSpan, GTEx and DM1 patients. Thirty four splice events displayed an inclusion pattern in DM1 patients that is typical for the fetal situation in healthy individuals. The regulation of DM1-relevant splicing patterns could partly be explained by changes in mRNA expression of the splice regulators MBNL1, MBNL2 and CELF1. On the contrary, interindividual differences in splicing patterns between healthy adults could not be explained by differential expression of these splice regulators. Our findings lend transcriptome-wide evidence to the previously noted shift to fetal splicing patterns in the adult DM1 brain as a consequence of an imbalance in antagonistic MBNL and CELF1 activities. Our atlas serves as a solid foundation for further study and understanding of the cognitive phenotype in patients.
Coordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue
Authors: Ojima Kento , Kakegawa Wataru , Ito Masayuki , Miura Yuta , Michibata Yukiko , Kubota Ryou , Doura Tomohiro , Yamasaki Tokiwa , Miura Eriko , Nonaka Hiroshi , Mizuno Seiya , Takahashi Satoru , Yuzaki Michisuke , Hamachi Itaru , Kiyonaka Shigeki
Published: October 2021

Direct activation of cell-surface receptors is highly desirable for elucidating the physiological roles of receptors. However, subtype-selective ligands are very limited because of the high homology among receptor subtypes. A potential approach for selective activation of a receptor subtype is chemogenetics, in which both point mutagenesis of the receptors and designed ligands are used. However, ligand-binding properties are affected in most current methods. Here, we developed a chemogenetic method for direct activation of metabotropic glutamate receptor 1 (mGlu1), which plays essential roles in cerebellar functions in the brain. Our screening identified a mGlu1 mutant, mGlu1(N264H), that was directly activated by palladium complexes. Notably, a palladium complex showing low cytotoxicity successfully activated mGlu1 in mGlu1(N264H) knock-in mice, revealing that activation of endogenous mGlu1 is sufficient to evoke the critical cellular mechanism of synaptic plasticity, a basis of motor learning in the cerebellum.
The role of parasympathetic mechanisms in the infarct-limiting effect of SGLT2 inhibitor ertugliflozin
Authors: Basalay MV , Arjun S , Davidson SM , Yellon DM
Published: October 2021

Introduction

Based on data that outcome in patients with acute myocardial infarction is predicted by final infarct size (IS), reducing IS is of paramount importance. Recent experimental studies have demonstrated a strong infarct-sparing effect of SGLT2 inhibitors – a class of drugs which have proved to be safe and beneficial in patients with heart failure. Repurposing SGLT2 inhibitors for the benefit of patients presenting with acute myocardial infarction should be preceded by investigation of the underlying mechanisms of this infarct limitation. Experimental and clinical data indicate a potential role for autonomic modulation in these mechanisms, specifically sympatho-inhibition. The aim of this study was to investigate the role of the parasympathetic mechanism in the infarct-limiting effect of SGLT2 inhibition.

Methods

Fortyeight Sprague Dawley male rats were fed with a standard diet containing either the SGLT2 inhibitor ertugliflozin or vehicle, for 5-7 days. Myocardial ischaemia/reperfusion injury was initiated by a 40-min occlusion of the left anterior descending coronary artery followed by a 2hr period of reperfusion under isoflurane anaesthesia. Bilateral cervical vagotomy was performed 10min prior to myocardial ischaemia. Alternatively, muscarinic receptors were blocked systemically with the non-selective blocker atropine sulphate (2 mg/kg bolus, then 1 mg/kg/h) or the M3-selective blocker 4-DAMP (2 mg/kg bolus).

Results

Pre-treatment with ertugliflozin reduced IS in comparison with the vehicle-treated controls (p<0.001). Bilateral vagotomy, atropine sulphate and 4-DAMP all abolished this infarct-limiting effect (IS 35±10%, 44±8%, and 35±4% respectively; P<0.01vs. Ertu for vagotomy, P<0.001vs. Ertu for both atropine sulphate and 4-DAMP).

Conclusion

These results suggest that the Infarct-limiting effect of the SGLT2 inhibitor ertugliflozin, may be mediated via activation of the vagus nerve and M3-cholinoreceptors.
HERBS: Histological E-data Registration in rodent Brain Spaces
Authors: Fuglstad Jingyi Guo , Saldanha Pearl , Paglia Jacopo , Whitlock Jonathan R.
Published: October 2021

Recording technologies for rodents have seen huge advances in the last decade, allowing users to sample thousands of neurons simultaneously from multiple brain regions. This has prompted the need for digital tool kits to aid in curating anatomical data, however, existing tools either provide limited functionality or require users to be proficient in coding to use them. To address this we created HERBS, a comprehensive new tool for rodent users that offers a broad range of functionalities through a user-friendly graphical user interface. Prior to experiments, HERBS can be used to plan coordinates for implanting electrodes, targeting viral injections or tracers. After experiments, users can register recording electrode locations (e.g. Neuropixels, tetrodes), viral expression or other anatomical features, and visualize the results in 2D or 3D. Additionally, HERBS can delineate expression from multiple injections across tissue sections and obtain individual cell counts. Regional delineations in HERBS are based either on annotated 3D volumes from the Waxholm Space Atlas of the Sprague Dawley Rat Brain or the Allen Mouse Brain Atlas. HERBS allows users to scroll through the digital brain atlases and provides custom-angle slice cuts through the volumes, and supports free-transformation of tissue sections to atlas slices. Furthermore, HERBS allows users to reconstruct a 3D brain mesh with tissue from individual animals. HERBS is a multi-platform open-source Python package that is available on PyPI and GitHub.
Towards mouse genetic-specific RNA-sequencing read mapping
Authors: Gobet Nastassia , Jan Maxime , Franken Paul , Xenarios Ioannis
Published: October 2021

Genetic variations affect behavior and cause disease but understanding how these variants drive complex traits is still an open question. A common approach is to link the genetic variants to intermediate molecular phenotypes such as the transcriptome using RNA-sequencing (RNA-seq). Paradoxically, these variants between the samples are usually ignored at the beginning of RNA-seq analyses of many model organisms. This can skew the transcriptome estimates that are used later for downstream analyses, such as expression quantitative trait locus (eQTL) detection. Here, we assessed the impact of reference-based analysis on the transcriptome and eQTLs in a widely-used mouse genetic population: the BXD panel of recombinant inbred lines. We highlight existing reference bias in the transcriptome data analysis and propose practical solutions which combine available genetic variants, genotypes, and genome reference sequence. The use of custom BXD line references improved downstream analysis compared to classical genome reference. These insights would likely benefit genetic studies with a transcriptomic component and demonstrate that genome references might need to be reassessed and improved.
Stimulating music supports attention in listeners with attentional difficulties
Authors: Woods Kevin JP , Sampaio Gonçalo , James Tedra , Przysinda Emily , Hewett Adam , Spencer Andrea E , Morillon Benjamin , Loui Psyche
Published: October 2021

Background music is widely used to sustain attention, but little is known about what musical properties aid attention. This may be due to inter-individual variability in neural responses to music. We test the hypothesis that music can sustain attention by affecting oscillations via acoustic amplitude modulation, differentially for those with varying levels of attentional difficulty. We first show that heavily-modulated music improves sustained attention for participants with more ADHD symptoms. FMRI showed this music elicited greater activity in attentional networks in this group only, and EEG showed greater stimulus-brain coupling for this group in response to the heavily-modulated music. Finally, we parametrically manipulated the depth and rate of amplitude modulations inserted in otherwise-identical music, and found that beta-range modulations helped more than other frequency ranges for participants with more ADHD symptoms. Results suggest the possibility of an oscillation-based neural mechanism for targeted music to support improved cognitive performance.
A general theoretical framework for trait-based eco-evolutionary dynamics: population structure, intraspecific variation, and community assembly
Authors: Wickman Jonas , Koffel Thomas , Klausmeier Christopher A.
Published: October 2021

To understand how functional traits shape ecological communities it is necessary to understand both how traits across the community affect its functioning and how eco-evolutionary dynamics within the community change the traits over time. Of particular interest are so-called evolutionarily stable communities (ESCs), since these are the end points of eco-evolutionary dynamics and can persist over long time scales. One theoretical framework that has successfully been used for assembling ESCs is adaptive dynamics. However, this framework cannot account for intraspecific variation— neither locally nor across structured populations. On the other hand, in moment-based approaches, intraspecific variation is accommodated, but community assembly has been neglected. This is unfortunate as some questions regarding for example local adaptation vis-a-vis diversification into multiple species requires both facets. In this paper we develop a general theoretical framework that bridges the gap between these two approaches. We showcase how ESCs can be assembled using the framework, and illustrate various aspects of the framework using two simple models of resource competition. We believe this unifying framework could be of great use to address questions regarding the role of functional traits in communities where population structure, intraspecific variation, and eco-evolutionary dynamics are all important.
It is the Locus Coeruleus! Or… is it? : A proposition for analyses and reporting standards for structural and functional magnetic resonance imaging of the noradrenergic Locus Coeruleus
Authors: Yi Yeo-Jin , Lüsebrink Falk , Maaß Anne , Ziegler Gabriel , Yakupov Renat , Kreißl Michael C. , Betts Matthew , Speck Oliver , Düzel Emrah , Hämmerer Dorothea
Published: October 2021

The noradrenergic locus coeruleus (LC) in the brainstem shows early signs of protein pathologies in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. As the LC’s small size (approximately 2.5 mm in width) presents a challenge for molecular imaging, the past decade has seen a steep rise in structural and functional Magnetic Resonance (MR) studies aiming to characterise the LC’s changes in ageing and neurodegeneration. However, given its position in the brainstem and small volume, great care must be taken to yield methodologically reliable MR results as spatial deviations in transformations can greatly reduce the statistical power of the analyses at the group level. Here, we suggest a spatial transformation procedure and a set of quality assessment methods which allow LC researchers to achieve the spatial precision necessary for investigating this small but potentially impactful brain structure.

Using a combination of available toolboxes (SPM12, ANTs, FSL, FreeSurfer), individual structural and functional 3T LC scans are transformed into MNI space via a study-specific anatomical template. Following this, the precision of spatial alignment in individual MNI-transformed images is quantified using in-plane distance measures based on slice-specific centroids of structural LC segmentations and based on landmarks of salient anatomical features in mean functional images, respectively.

Median in-plane distance of all landmarks on the transformed structural as well as functional LC imaging data were below 2 mm, thereby falling below the typical LC width of 2.5 mm suggested by post-mortem data.

With the set of spatial post-processing steps outlined in this paper and available for download, we hope to give readers interested in LC imaging a starting point for a reliable analysis of structural and functional MR data of the LC and to have also taken a first step towards establishing reporting standards of LC imaging data.
Finding and Keeping the Beat: Neural Mechanisms Differ as Beat Perception Unfolds
Authors: Cameron Daniel J. , Grahn Jessica A.
Published: October 2021

Perception of a regular beat is essential to our ability to synchronize movements to music in an anticipatory fashion. Beat perception requires multiple, distinct neural functions, corresponding to the perceptual stages that occur over time, including 1) detection that regularity is present (beat finding), 2) prediction of future regular events to enable anticipation (beat continuation), and 3) dynamic adjustment of predictions as the rhythmic stimulus changes (beat adjustment). The striatum has been shown to be crucial for beat perception generally, although it is unclear how, or whether, distinct regions of the striatum contribute to these different stages of beat perception. Here, we used fMRI to investigate the activity of striatal subregions during the different stages of beat perception. Participants listened to pairs of rhythms (polyrhythms) whose temporal structure induced distinct perceptual stages—finding, continuation, and adjustment of the beat. Dorsal putamen was preferentially active during beat finding, whereas the ventral putamen was preferentially active during beat adjustment. We also observed that anterior insula activity was sensitive to metrical structure (greater when polyrhythms were metrically incongruent than when they were congruent). These data implicate the dorsal putamen in the detection of regularity, possibly by detection of coincidences between cortical oscillations, and the ventral putamen in the adjustment of regularity perception, possibly by integration of prediction errors in ongoing beat predictions. Additionally, activity in the supramarginal and superior temporal gyri correlated with beat tapping performance, and activity in the superior temporal gyrus correlated with beat perception (performance on the Beat Alignment Test).
Ruminant-specific retrotransposons shape regulatory evolution of bovine immunity
Authors: Kelly Conor J. , Chitko-McKown Carol , Chuong Edward B.
Published: October 2021

Cattle are an important livestock species, and mapping the genomic architecture of agriculturally relevant traits such as disease susceptibility is a major challenge in the bovine research community. Lineage-specific transposable elements (TEs) are increasingly recognized to contribute to gene regulatory evolution and variation, but this possibility has been largely unexplored in ruminant genomes. We conducted epigenomic profiling of the type II interferon (IFN) response in bovine cells, and found thousands of ruminant-specific TEs including MER41_BT and Bov-A2 elements predicted to act as IFN-inducible enhancer elements. CRISPR knockout experiments in bovine cells established that critical immune factors including IFNAR2 and IL2RB are transcriptionally regulated by TE-derived enhancers. Finally, population genomic analysis of 38 individuals revealed that a subset of TE-derived enhancers represent polymorphic insertion sites in modern cattle. Our study reveals that lineage-specific TEs have shaped the evolution of ruminant IFN responses, and potentially continue to contribute to immune gene regulatory differences across modern breeds and individuals. Together with previous work in human cells, our findings demonstrate that lineage-specific TEs have been independently co-opted to regulate IFN-inducible gene expression in multiple species, supporting TE co-option as a recurrent mechanism driving the evolution of IFN-inducible transcriptional networks.
High-throughput RNA isoform sequencing using programmable cDNA concatenation
Authors: Al’Khafaji Aziz M. , Smith Jonathan T. , Garimella Kiran V , Babadi Mehrtash , Sade-Feldman Moshe , Gatzen Michael , Sarkizova Siranush , Schwartz Marc A. , Popic Victoria , Blaum Emily M. , Day Allyson , Costello Maura , Bowers Tera , Gabriel Stacey , Banks Eric , Philippakis Anthony A. , Boland Genevieve M. , Blainey Paul C. , Hacohen Nir
Published: October 2021

Alternative splicing is a core biological process that enables profound and essential diversification of gene function. Short-read RNA sequencing approaches fail to resolve RNA isoforms and therefore primarily enable gene expression measurements - an isoform unaware representation of the transcriptome. Conversely, full-length RNA sequencing using long-read technologies are able to capture complete transcript isoforms, but their utility is deeply constrained due to throughput limitations. Here, we introduce MAS-ISO-seq, a technique for programmably concatenating cDNAs into single molecules optimal for long-read sequencing, boosting the throughput >15 fold to nearly 40 million cDNA reads per run on the Sequel IIe sequencer. We validated unambiguous isoform assignment with MAS-ISO-seq using a synthetic RNA isoform library and applied this approach to single-cell RNA sequencing of tumor-infiltrating T cells. Results demonstrated a >30 fold boosted discovery of differentially spliced genes and robust cell clustering, as well as canonical PTPRC splicing patterns across T cell subpopulations and the concerted expression of the associated hnRNPLL splicing factor. Methods such as MAS-ISO-seq will drive discovery of novel isoforms and the transition from gene expression to transcript isoform expression analyses.
Genome sequencing of white-blotched river stingray (Potamotrygon leopoldi) provides novel clues for niche-adaptation and skeleton formation
Authors: Zhou Jingqi , Liu Ake , He Funan , Zhang Yunbin , Shen Libing , Yu Jun , Zhang Xiang
Published: October 2021

The white-blotched river stingray (Potamotrygon leopoldi) is a cartilaginous fish native to the Xingu River, a tributary of the Amazon River system. It possesses a lot of unique biological features such as disc-like body shape, bizarre color pattern and living in freshwater habitat while most stingrays and their close relatives are sea dwellers. As a member of the Potamotrygonidae family, P. leopoldi bears evolutionary signification in fish phylogeny, niche adaptation and skeleton formation. In this study, we present its draft genome of 4.11 Gb comprised of 16,227 contigs and 13,238 scaffolds, which has contig N50 of 3,937 kilobases and scaffold N50 of 5,675 kilobases in size. Our analysis shows that P. leopoldi is a slow-evolving fish, diverged from elephant shark about 96 million years ago. We find that two gene families related to immune system, immunoglobulin heavy constant delta genes, and T-cell receptor alpha/delta variable genes, stand out expanded in P. leopoldi only, suggesting robustness in response to freshwater pathogens in adapting novel environments. We also identified the Hox gene clusters in P. leopoldi and discovered that seven Hox genes shared by five representative fishes are missing in P. leopoldi. The RNA-seq data from P. leopoldi and other three fish species demonstrate that fishes have a more diversified tissue expression spectrum as compared to the corresponding mammalian data. Our functional studies suggest that the lack of genes encoding vitamin D-binding protein in cartilaginous (both P. leopoldi and Callorhinchus milii) fishes could partly explain the absence of hard bone in their endoskeleton. Overall, this genome resource provides new insights into the niche-adaptation, body plan and skeleton formation of P. leopoldi as well as the genome evolution in cartilaginous fish.
Expression and Neurotransmitter Association of the Synaptic Calcium Sensor Synaptotagmin in the Avian Auditory Brain Stem
Authors: MacLeod Katrina M. , Pandya Sangeeta
Published: October 2021

In the avian auditory brain stem, acoustic timing and intensity cues are processed in separate, parallel pathways via the two division of the cochlear nucleus, nucleus angularis (NA) and nucleus magnocellularis (NM). Differences in excitatory and inhibitory synaptic properties, such as release probability and short-term plasticity, contribute to differential processing of the auditory nerve inputs. We investigated the distribution of synaptotagmin, a putative calcium sensor for exocytosis, via immunohistochemistry and double immunofluorescence in the embryonic and hatchling chick brain stem (Gallus gallus). We found that the two major isoforms, synaptotagmin 1 (Syt1) and synaptotagmin 2 (Syt2), showed differential expression. In the NM, anti-Syt2 label was strong and resembled the endbulb terminals of the auditory nerve inputs, while anti-Syt1 label was weaker and more punctate. In NA, both isoforms were intensely expressed throughout the neuropil. A third isoform, synaptotagmin 7 (Syt7), was largely absent from the cochlear nuclei. In nucleus laminaris (NL, the target nucleus of NM), anti-Syt2 and anti-Syt7 strongly labeled the dendritic lamina. These patterns were established by embryonic day 18 and persisted to postnatal day 7. Double labeling immunofluorescence showed Syt1 and Syt2 were associated with Vesicular Glutamate Transporter 2 (VGluT2), but not Vesicular GABA Transporter (VGAT), suggesting these Syt isoforms were localized to excitatory, but not inhibitory, terminals. These results suggest that Syt2 is the major calcium binding protein underlying excitatory neurotransmission in the timing pathway comprising NM and NL, while Syt2 and Syt1 regulate excitatory transmission in the parallel intensity pathway via cochlear nucleus NA.
Molecular insights into phosphorylation-induced allosteric conformational changes in β2-adrenergic receptor
Authors: Madhu Midhun K. , Debroy Annesha , Murarka Rajesh K.
Published: October 2021

The large conformational flexibility of G protein-coupled receptors (GPCRs) has been a puzzle in structural and pharmacological studies for the past few decades. Apart from structural rearrangements induced by ligands, enzymatic phosphorylations by GPCR kinases (GRKs) at the carboxy-terminal tail (C-tail) of a GPCR also makes conformational alterations to the transmembrane helices and facilitates the binding of one of its transducer proteins named β-arrestin. Phosphorylation-induced conformational transition of the receptor that causes specific binding to β-arrestin but prevents the association of other transducers such as G proteins lacks atomistic understanding and is elusive to experimental studies. Using microseconds of all-atom conventional and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigate the allosteric mechanism of phosphorylation induced-conformational changes in β2-adrenergic receptor, a well-characterized GPCR model system. Free energy profiles reveal that the phosphorylated receptor samples a new conformational state in addition to the canonical active state corroborating with recent nuclear magnetic resonance experimental findings. The new state has a smaller intracellular cavity that is likely to accommodate β-arrestin better than G protein. Using contact map and inter-residue interaction energy calculations, we found the phosphorylated C-tail adheres to the cytosolic surface of the transmembrane domain of the receptor. Transfer entropy calculations show that the C-tail residues drive the correlated motions of TM residues, and the allosteric signal is relayed via several residues at the cytosolic surface. Our results also illustrate how the redistribution of inter-residue nonbonding interaction couples with the allosteric communication from the phosphorylated C-tail to the transmembrane. Atomistic insight into phosphorylation-induced β-arrestin specific conformation is therapeutically important to design drugs with higher efficacy and fewer side effects. Our results therefore open novel opportunities to fine-tune β-arrestin bias in GPCR signaling.
Current and Lifetime Somatic Symptom Burden Among Transition-aged Autistic Young Adults
Authors: Williams Zachary J. , Gotham Katherine O.
Published: October 2021

Background and Objectives

Somatic symptoms are the most common cause of outpatient medical visits in the general population, yet their presence and severity in individuals on the autism spectrum has rarely been studied. We sought to assess the prevalence, impact, and clinical correlates of fourteen commonly-reported somatic symptoms in a sample of transition-aged autistic young adults.

Methods

A sample of 290 independent and cognitively able autistic young adults (aged 18–26 years; mean [SD]: 23.10 [2.38] years) was recruited from the Simons Foundation SPARK participant pool. A modified version of the Patient Health Questionnaire–15 was used to assess somatic symptom prevalence/impact, along with measures of depression, anxiety, autistic traits, and quality of life.

Results

Somatic symptom burden was much higher in autistic young adults than previously reported in the general population. The most commonly reported current symptoms were fatigue (72.8%), sleep problems (69.0%), and menstrual problems (61.4% of females). Moderate or severe symptom levels were reported by 53.9% of females and 18.75% of males in our cohort, with the odds of females of endorsing any given symptom being 2–4 times greater than males. Both individual symptoms and total symptom burden were related to higher levels of depression, anxiety, and autistic traits, along with lower quality of life.

Conclusion

Despite little research on this topic previously, somatic symptoms are highly prevalent in autistic young adults, particularly women. Future research is needed to investigate links between somatic symptoms, medical and psychiatric morbidity, and health care utilization in the autistic population.

What’s Known on This Subject

Somatic symptoms are highly prevalent in the general population and account for a large proportion of health care costs. However, few studies have investigated the prevalence, impact, or correlates of these symptoms in individuals on the autism spectrum.

What This Study Adds

To our knowledge, this is the first study to specifically assess current and lifetime somatic symptom burden, symptom onset patterns, and the clinical correlates of multisystem symptom distress in transition-aged young adults on the autism spectrum.
A Budding Yeast Model and Screen to Define the Functional Consequences of Oncogenic Histone Missense Mutations
Authors: Lemon Laramie D. , Kannan Sneha , Mo Kim Wai , Adams Miranda , Choi Haley G. , Gulka Alexander O. D. , Withers Elise S. , Nurelegne Hasset T. , Gomez Valeria , Ambrocio Reina E. , Tumminkatti Rhea , Lee Richard S. , Wan Morris , Fasken Milo B. , Spangle Jennifer M. , Corbett Anita H.
Published: October 2021

Somatic missense mutations in histone genes turn these essential proteins into oncohistones, which can drive oncogenesis. Understanding how missense mutations alter histone function is challenging in mammals as mutations occur in a single histone gene. For example, described oncohistone mutations predominantly occur in the histoneH3.3gene, despite the human genome encoding 15 H3 genes. To understand how oncogenic histone missense mutations alter histone function, we leveraged the budding yeast model, which contains only two H3 genes, to explore the functional consequences of oncohistones H3K36M, H3G34W, H3G34L, H3G34R, and H3G34V. Analysis of cells that express each of these variants as the sole copy of H3 reveals that H3K36 mutants show different drug sensitivities compared to H3G34 mutants. This finding suggests that changes to proximal amino acids in the H3 N-terminal tail alter distinct biological pathways. We exploited the caffeine sensitive growth of H3K36 mutant cells to perform a high copy suppressor screen. This screen identified genes linked to histone function and transcriptional regulation, including Esa1, a histone H4/H2A acetyltransferase; Tos4, a forkhead-associated domain-containing gene expression regulator; Pho92, an N6-methyladenosine RNA binding protein and Sgv1/Bur1, a cyclin-dependent kinase. We show that the Esa1 lysine acetyltransferase activity is critical for suppression of the caffeine sensitive growth of H3K36R mutant cells while the previously characterized binding interactions of Tos4 and Pho92 are not required for suppression. This screen identifies pathways that could be altered by oncohistone mutations and highlights the value of yeast genetics to identify pathways altered by such mutations.
Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation
Authors: Meyers Allison K. , Wang Zhan , Han Wenzheng , Zhao Qingxia , Zabalawi Manal , Duan Likun , Liu Juan , Zhang Qianyi , Manne Rajesh K , Lorenzo Felipe , Quinn Matthew A. , Song Qianqian , Fan Daping , Lin Hui-Kuan , Furdui Cristina M. , Locasale Jason W. , McCall Charles E. , Zhu Xuewei
Published: October 2021

Activating macrophage NLRP3 inflammasome can promote excessive inflammation, with severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages and septic mice by lowering caspase-1 cleavage and IL-1β secretion. Inhibiting PDHK reverses NLRP3 inflammasome-induced metabolic reprogramming, enhances autophagy, promotes mitochondrial fusion over fission, preserves cristae ultrastructure, and attenuates mitochondrial ROS production. The suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of its canonical role as a pyruvate dehydrogenase regulator. We suggest that PDHK inhibition improves mitochondrial fitness by reversing NLRP3 inflammasome activation in acutely inflamed macrophages.
Compound Screening with Deep Learning for Neglected Diseases: Leishmaniasis
Authors: Smith Jonathan , Xu Hao , Li Xinran , Yang Laurence , Gutierrez Jahir M.
Published: October 2021

Abstract

Deep learning provides a tool for improving screening of candidates for drug re-purposing to treat neglected diseases. We show how a new pipeline can be developed to address the needs of repurposing for Leishmaniasis. In combination with traditional molecular docking techniques, this allows top candidates to be selected and analyzed, including for molecular descriptor similarity.
Pain is so close to pleasure: the same dopamine neurons can mediate approach and avoidance in Drosophila
Authors: Rohrsen Christian , Kumpf Aida , Semiz Kader , Aydin Ferruh , deBivort Benjamin , Brembs Björn
Published: October 2021

In mammals, dopamine is considered a central neuromodulator involved in all kinds of rewarding experiences (‘common currency’ hypothesis). In insects, the role of do-paminergic neurons in aversive stimuli was discovered before dopaminergic neurons were found to also be involved in processing appetitive stimuli. Here, we screened about 50 transgenic Drosophila lines, representing different subpopulations of dopa-minergic neurons for their ability to sustain approach or avoidance behavior, when activated optogenetically in four different operant self-stimulation paradigms. None of the lines sustain consistent behavioral valence in all experiments. Individual lines sustain approach in one experiment and avoidance in another. One line mediated strong avoidance early in the experiment and weak approach in later stages. The evidence presented here appears to contradict a ‘common currency’ dopamine function in flies. Instead, different dopaminergic neurons convey valence in a context-dependent and flexible manner, reflecting the genetic heterogeneity of the dopaminergic neuronal population.
Unpacking dialogic accounting: a systematic literature review and research agenda
Authors: Manetti Giacomo , Bellucci Marco , Oliva Stefania
Published: October 2021

Purpose

This article aims to contribute to the critical accounting literature by reviewing how previous studies have addressed the topic of dialogic accounting (DA), examining the main themes investigated and discussing potential further developments of the DA research agenda.

Design/methodology/approach

The present study builds on a systematic literature review of 186 research products indexed on Scopus, Web of Science and Google Scholar that were published between 2004 and 2019 in 55 accounting or non-accounting scientific journals and 14 books.

Findings

First, a content analysis of each contribution informs a classification in terms of research design, methodology, geographical setting and sector of analysis. Second, a bibliometric analysis provides several visual representations of the network of research products included in our review using bibliographic coupling, cooccurrence and coauthorship analyses. Third, and most importantly, the main narrative review discusses the development of the research strand on DA from the seminal works that introduced the topic, through the core of critical contributions inspired by the struggle between democracy and agonism, to the most recent contributions, in which new topics emerge and innovative methodologies are applied to the study of DA.

Originality/value

The main contribution of this manuscript is twofold. In addition to providing a systematic, bibliometric and narrative review of the evolution of nearly two decades of literature on DA, the present study is intended to collect ideas for further research and to discuss how the advent of new technologies and the peculiarities of various institutional contexts can shape the future research agenda on this critical form of accounting.
Targeting millers to improve rice marketing in Uganda
Authors: Twine Edgar Edwin , Adur-Okello Stella Everline , Mujawamariya Gaudiose , Ndindeng Sali Atanga
Published: October 2021

Purpose

Improving milling quality is expected to improve the quality of domestic rice and hence the competitiveness of Uganda's rice industry. Therefore, this study aims to assess the determinants of four aspects of milling, namely, choice of milling technology, millers' perceptions of the importance of paddy quality attributes, milling return and milling capacity.

Design/methodology/approach

Multinomial logit, semi-nonparametric extended ordered probit, linear regression and additive nonparametric models are applied to cross-sectional data obtained from a sample of 196 rice millers.

Findings

Physical, economic, institutional, technological and sociodemographic factors are found to be important determinants of the four aspects of milling. Physical factors include the distance of the mill from major town and availability of storage space at the milling premises, while economic factors include milling charge and backward integration of miller into paddy production. Contracting and use of a single-pass mill are important institutional and technological factors, respectively, and miller's household size, age, gender and education are the key sociodemographic variables.

Originality/value

The study's originality lies in its scope, especially in terms of its breadth. Without compromising the needed analytical rigor, it focuses on four aspects of milling that are critical to improving the marketing of Uganda's rice. In doing so, it provides a holistic understanding of this segment of the value chain and offers specific recommendations for improving the marketing of Uganda's rice.
An evaluation of the quality characteristics of kefir fortified with olive (Olea europaea) leaf extract
Authors: Okur Özge Duygu
Published: October 2021

Purpose

This study aims to produce a new type of healthy functional kefir by adding olive (Olea europaea) leaf extract and to determine its potential effect on the quality (physicochemical, sensory, phenolic contents and antioxidant properties) of kefir samples during storage at 4°C for 21 days.

Design/methodology/approach

For this purpose, four kefir samples were produced by using olive leaf extract in different amounts (A: 0% (control), B: 0.1%, C: 0.15% and D: 0.35%). The physicochemical, sensory, phenolic contents and antioxidant properties of kefir samples were investigated during Days 1, 7, 14 and 21 of storage. The study was conducted to optimize the olive leaf extract addition level to obtain better-quality kefir functional food.

Findings

From the results, it was determined that the addition of olive leaf extract affected the entire chemical components of the kefir samples (p < 0.05). It was found that the pH value decreased during storage. By contrast, it was observed that titration acidity values increased. The kefir sample with 0.35% olive leaf extract (D) had the highest total phenolic and antioxidant activity content (1,292.75 mg GAE/L and 10.20 mM TE, respectively) among the samples (p < 0.05). In the sensory analyses, the kefir sample with the highest score – in terms of sensory attributes – was the kefir sample containing 0.15% olive leaf extract (C).

Originality/value

Thus, it was concluded that kefir with added olive leaf extract could serve as a functional kefir of benefit to human health. When we looked at the enrichment studies on kefir as a functional product, no study has been found on the use of olive (Olea europaea) leaf extract, especially with kefir. In this sense, it is thought that the study will contribute to published literature.
Modelling, validation and parameter sensitivity of regenerative hydraulic-electric shock absorber
Authors: Zhang Min , Hu Cheng , Gao Jingwei , Zheng Peng
Published: October 2021

Purpose

Suspension is a significantly important component for automotive and railway vehicles. Regenerative hydraulic-electric shock absorbers (RHSA) have been proposed for the purpose of attenuating vibration of vehicle suspension, and also recover kinetic energy originated from vehicle vibration that is conventionally dissipated by hydraulic dampers. To advance the technology, the paper aims to present an RHSA system for heavy-duty and railway vehicles and create a dynamic modelling to discuss on the development process of RHSA model.

Design/methodology/approach

First, the development of RHSA dynamic model can be resolved into three stage models (an ideal one, a second one with an added accumulator and a third one that considers both accumulator and system losses) to comprehensively evaluate the RHSA's characterisation. Second, a prototype is fabricated for testing and the results meet desired agreements between simulation and measurement. Finally, the study of key parameters is carried out to investigate the influences of hydraulic-cylinder size, hydraulic-motor displacement and accumulator pre-charged pressure on the RHSA system.

Findings

The findings of sensitivity analysis indicate that the component design can satisfy the damping characteristics and power performance required for heavy-duty vehicle, freight wagon and typical passenger train. The results also show that reducing the losses is highly beneficial for saving suspension energy, improving system reliability and increasing power-conversion efficiency.

Originality/value

The paper presents a more detailed method for the development and analysis of a RHSA. Compared with the typical shock absorbers, RHSA can also recover the vibration energy dissipated by suspension.