bluuebunny/crossref_metadata_2025_split huggingface dataset:
Negative selection on aSOD1mutation limits canine degenerative myelopathy while avoiding inbreeding
Authors: Ukawa Hisashi , Akiyama Noriyoshi , Yamamoto Fumiko , Ohashi Ken , Ishihara Genki , Matsumoto Yuki 
Published: July 2023

AbstractSeveral hundred disease-causing mutations are currently known in domestic dogs. Breeding management is therefore required to minimize their spread. Recently, genetic methods such as direct-to-consumer testing have gained popularity; however, their effects on dog populations are unclear. Here, we aimed to evaluate the influence of genetic testing on the frequency of mutations responsible for canine degenerative myelopathy (DM) and assess the changes in the genetic structure of a Pembroke Welsh corgi population from Japan. Genetic testing of 5,512 dogs for the causative mutation in superoxide dismutase 1 (SOD1) (c.118G>A (p.E40K)) uncovered a recent decrease in frequency, plummeting from 14.5% (95/657) in 2019 to 2.9% (24/820) in 2022. Weir and Cockerham population differentiation (FST) and simulation-based genome-wide single-nucleotide polymorphism (SNP) analysis of 117 selected dogs revealed 143 candidate SNPs for selection. The SNP with the highestFSTvalue was located in the intron ofSOD1adjacent to the c.118G>A mutation, supporting a strong selection signature onSOD1. Further genome-wide SNP analyses revealed no obvious changes in inbreeding levels and genetic diversity between the 2019 and 2022 populations. Our study highlights that genetic testing can help inform improved mating choices in breeding programs to reduce the frequency of risk variants and avoid inbreeding. This combined strategy could decrease the genetic risk of canine DM, a fatal disease, within only a few years.Significance statementGenetic breeding methods using direct-to-consumer testing have gained popularity, but their effects on dog populations remain unclear. In this study, the effect of direct-to-consumer genetic testing onSOD1mutation, the causative element of canine degenerative myelopathy, in a domestic dog population (Pembroke Welsh corgi) from Japan was investigated. Our analyses revealed that since the expansion of genetic testing in 2019, breeders used these tests to artificially select against theSOD1mutation, considerably decreasing its occurrence in the corgi population within only a few years (2019 versus 2022). Our study makes a substantial contribution to existing literature by providing empirical evidence that direct-to-consumer genetic testing can have rapid influence on pet genetics, noticeable in a span of 2–3 years.
Cell type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells
Authors: Grimes Karen , Jeong Hyobin , Amoah Amanda , Xu Nuo , Niemann Julian , Raeder Benjamin , Hasenfeld Patrick , Stober Catherine , Rausch Tobias , Benito Eva , Jann Johann-Christoph , Nowak Daniel , Emini Ramiz , Hoenicka Markus , Liebold Andreas , Ho Anthony , Shuai Shimin , Geiger Hartmut , Sanders Ashley D. , Korbel Jan O. 
Published: July 2023

AbstractThe functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single cell genomes from 19 human donors of increasing age, revealing a heterogeneous mSV landscape in hematopoietic stem and progenitor cells (HSPCs). While mSV clonal expansions are confined to individuals over 60,de novomSV formation occurs consistently across age, frequently leading to megabase-scale segmental aneuploidies. Cells harboring subclonal mosaicism show evidence for increased mSV formation. To enable high-resolution cell-typing of each Strand-seq library, we generated single-cell MNase-seq reference datasets for eight distinct HSPCs. Subclonal mSVs frequently exhibit enrichment in myeloid progenitors, and single-cell multiomic analysis suggests that these mSVs result in recurrent dysregulation of pathways related to proliferation and metabolism, including Ras signaling and lipid metabolism. The comprehensive mSV landscape identified in this study implicates mSVs in cell type-specific molecular phenotypes, establishing a foundation for deciphering links between mSVs, aging, and disease risk.
Lesions in a songbird vocal circuit increase variability in song syntax
Authors: Koparkar Avani , Warren Timothy L. , Charlesworth Jonathan D. , Shin Sooyoon , Brainard Michael S. , Veit Lena 
Published: July 2023

AbstractComplex motor skills like speech and dance are composed of ordered sequences of simpler elements, but the neuronal basis for syntactic ordering of individual actions into sequences is poorly understood. Birdsong is a learned vocal behavior composed of syntactically ordered sequences of individual syllables. Activity in song premotor nucleus HVC (proper name) has been linked to the control of syllable sequencing, but sequencing may also be affected by its recurrent inputs. We here test the contribution of one of HVC’s inputs, mMAN (medial magnocellular nucleus of the anterior nidopallium), to the variable songs of adult male Bengalese finches (Lonchura striata domestica). The syntax of Bengalese song includes several patterns: 1)chunks, where syllables follow stereotypical order 2)branch points, where a given syllable can be followed by two or more different syllables in a probabilistic manner and 3)repeat phrases, where an individual syllable is repeated a variable number of times. We found that after bilateral lesions of mMAN, the acoustic structure of syllables remained largely intact, but sequencing became more variable for each of these patterns, seen by ‘breaks’ in previously stereotyped chunks, increased uncertainty at branch points and increased variability of repeat numbers. This increase in sequencing variability highlights the potential importance of regions projecting to HVC in the ordering of vocal elements. Previous studies on zebra finches found little effect of mMAN lesions on their relatively stereotyped adult song. In contrast, our results suggest that mMAN contributes to sequencing the variable songs of Bengalese finches and highlight the utility of species with more complex song syntax in investigating neuronal control of ordered motor sequences.
The Role of Vision and Lateral Line Sensing for Schooling in Giant Danios (Devario Aequipinnatus)
Authors: Tidswell Ben , Veliko-Shapko Annushka , Tytell Eric 
Published: July 2023

AbstractTo protect themselves from predators, fishes often form schools with other fish. Previous work has identified abstract “rules” of schooling – attraction to neighbours that are far away, repulsion from neighbours that are too close, and alignment with neighbours at the correct distance – but we do not understand well how these rules emerge from the sensory physiology and behaviour of individual fish. In particular, fish use both vision and their lateral lines to sense other fish, but it is unclear how they integrate information from these sensory modalities to coordinate schooling behaviour. To address this question, we studied how the schooling of giant danios (Devario aequipinnatus) changes when they are either unable to see or unable to use their lateral lines. We found that giant danios were able to school normally without their lateral lines, but did not school in darkness. Surprisingly, giant danios in darkness had the same attraction and alignment properties as fish in light, potentially indicating that they do not feel as much risk in darkness. Overall, we suggest that differences among schooling species in sensory integration between vision and lateral line may depend on their natural predators and environment.
Dopaminoceptive D1 and D2 neurons in ventral hippocampus arbitrate approach and avoidance in anxiety
Authors: Godino Arthur , Salery Marine , Minier-Toribio Angelica M. , Patel Vishwendra , Fullard John F. , Parise Eric M. , Martinez-Rivera Freddyson J. , Morel Carole , Roussos Panos , Blitzer Robert D. , Nestler Eric J. 
Published: July 2023

AbstractThe hippocampus1–7, as well as dopamine circuits8–11, coordinate decision-making in anxiety-eliciting situations. Yet, little is known about how dopamine modulates hippocampal representations of emotionally-salient stimuli to inform appropriate resolution of approachversusavoidance conflicts. We here study dopaminoceptive neurons in mouse ventral hippocampus (vHipp), molecularly distinguished by their expression of dopamine D1 or D2 receptors. We show that these neurons are transcriptionally distinct and topographically organized across vHipp subfields and cell types. In the ventral subiculum where they are enriched, both D1 and D2 neurons are recruited during anxiogenic exploration, yet with distinct profiles related to investigation and behavioral selection. In turn, they mediate opposite approach/avoidance responses, and are differentially modulated by dopaminergic transmission in that region. Together, these results suggest that vHipp dopamine dynamics gate exploratory behaviors under contextual uncertainty, implicating dopaminoception in the complex computation engaged in vHipp to govern emotional states.
A dual target molecular MRI probe for noninvasive profiling of pathologic alpha-synuclein and microgliosis in a mouse model of Parkinson’s disease
Authors: Sun Xianwei , Badachhape Andrew , Chin Jeannie , Annapragada Ananth , Tanifum Eric 
Published: July 2023

AbstractParkinson’s disease is characterized progressive deposition of pathologic alpha-synuclein (α-syn) aggregates, neuroinflammation, and death of dopaminergic neurons in the substantia nigra projecting to the striatum. Noninvasivein vivoprofiling of α-syn aggregate accumulation and microgliosis by molecular imaging can provide insights on the underlying mechanisms of disease progression, facilitating the development of effective treatment. However, no classical imaging methods have been successful, despite several attempts. We demonstrate a novel method to noninvasivein vivoprofiling of pathologic α-syn in combination with microgliosis using molecular magnetic resonance imaging (MRI), by targeting oligomeric α-syn in cerebrospinal fluid with nano scavengers (T) bearing a T1-relaxive Gd(III) payload. In this proof-of-concept report we demonstrate,in vitro,that microglia and neuroblastoma cell lines internalize cross-linkedT/oligomeric α-syn agglomerates. Delayedin vivoT1-weighted MRI scans following intravenous administration in the M83 α-syn transgenic mouse line show statistically significant T1 signal enhancement in test mice versus controls. Thein vivodata was validated byex-vivoimmunohistochemical analysis which showed a strong correlation betweenin vivoMRI signal enhancement, Lewy pathology distribution, and microglia activity in the treated brain tissue. Furthermore, neuronal, and microglial cells in brain tissue from treated mice displayed strong cytosolic signal originating fromT, confirmingin vivocell uptake of the nano scavengers.
3D electronic implants in subretinal space: long-term follow-up in rodents
Authors: Bhuckory Mohajeet , Wang Bing-Yi , Chen Zhijie Charles , Shin Andrew , Pham-Howard Davis , Shah Sarthak , Monkongpitukkul Nicharee , Galambos Ludwig , Kamins Theodore , Mathieson Keith , Palanker Daniel 
Published: July 2023

AbstractPhotovoltaic subretinal prosthesis (PRIMA) enables restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution limited by the 100 μm pixel size. Since decreasing the pixel size below 75 μm in the current bipolar geometry is impossible, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime – up to 9 months post-implantation in aged rats. With both flat and 3D implants, VEP amplitude decreased after the day of implantation by more than 3-fold, and gradually recovered over about 3 months. With 25 μm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the second-order neurons. Retinal thickness and full-field stimulation threshold with 40 μm-wide honeycomb pixels were comparable to those with planar devices – 0.05 mW/mm2with 10ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 μm-wide wells, and stimulation threshold increased over 5 months, before stabilizing at about 0.08 mW/mm2. Such threshold is significantly lower than 1.8 mW/mm2with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.
Modular Splicing is Linked to Evolution in the Synapse-Specificity Molecule Kirrel3
Authors: Traenkner Dimitri , Shennib Omar , Johnson Alyssa , Weinbrom Adam , Taylor Matthew R. , Williams Megan E. 
Published: July 2023

ABSTRACTKirrel3 is a cell-adhesion molecule that instructs the formation of specific synapses during brain development in mouse and Kirrel3 variants may be risk factors for autism and intellectual disabilities in humans. Kirrel3 is predicted to undergo alternative splicing but brain isoforms have not been studied. Here, we present the first in-depth characterization of Kirrel3 isoform diversity in brain using targeted, long-read mRNA sequencing of mouse hippocampus. We identified 19 isoforms with predicted transmembrane and secreted forms and show that even rare isoforms generate detectable protein in the brain. We also analyzed publicly-available long-read mRNA databases from human brain tissue and found 11 Kirrel3 isoforms that, similar to mouse, encode transmembrane and secreted forms. In mice and humans, Kirrel3 diversity arises from alternative, independent use of protein-domain coding exons and alternative early translation-stop signals. Intriguingly, the alternatively spliced exons appear at branch points in the chordate phylogenetic tree, including one exon only found in humans and their closest living relatives, the great apes. Together, these results validate a simple pipeline for analyzing isoform diversity in genes with low expression and suggest that Kirrel3 function is fine-tuned by alternative splicing and may play a role in brain evolution.Significance StatementKirrel3 is an important molecule for synapse and circuit formation with gene variants that are associated with neurodevelopmental disorders, yet Kirrel3 function remains largely unknown. Here, we report new isoforms of mouse and human Kirrel3, including secreted and transmembrane forms, that suggest a diverse repertoire of Kirrel3 actions. Importantly, we identified a new Kirrel3 exon only present in humans and the other great apes with potential to play an important role in circuit formation unique to these species.
Surprising connections between DNA binding and function for the near-complete set of yeast transcription factors
Authors: Mahendrawada Lakshmi , Warfield Linda , Donczew Rafal , Hahn Steven 
Published: July 2023

AbstractDNA sequence-specific transcription factors (TFs) modulate transcription and chromatin architecture, acting from regulatory sites in enhancers and promoters of eukaryotic genes. How TFs locate their DNA targets and how multiple TFs cooperate to regulate individual genes is still unclear. Most yeast TFs are thought to regulate transcription via binding to upstream activating sequences, situated within a few hundred base pairs upstream of the regulated gene. While this model has been validated for individual TFs and specific genes, it has not been tested in a systematic way with the large set of yeast TFs. Here, we have integrated information on the binding and expression targets for the near-complete set of yeast TFs. While we found many instances of functional TF binding sites in upstream regulatory regions, we found many more instances that do not fit this model. In many cases, rapid TF depletion affects gene expression where there is no detectable binding of that TF to the upstream region of the affected gene. In addition, for most TFs, only a small fraction of bound TFs regulates the nearby gene, showing that TF binding does not automatically correspond to regulation of the linked gene. Finally, we found that only a small percentage of TFs are exclusively strong activators or repressors with most TFs having dual function. Overall, our comprehensive mapping of TF binding and regulatory targets have both confirmed known TF relationships and revealed surprising properties of TF function.
Atypical Biological Motion Perception in Children with Attention Deficit Hyperactivity Disorder: Local Motion and Global Configuration Processing
Authors: Tian Junbin , Yang Fang , Wang Ying , Wang Li , Wang Ning , Jiang Yi , Yang Li 
Published: July 2023

AbstractPerceiving biological motion (BM) is crucial for human survival and social interaction. Many studies have reported impaired BM perception in autism spectrum disorder, which is characterised by deficits in social interaction. Children with attention deficit hyperactivity disorder (ADHD) often exhibit similar difficulties in social interaction. However, few studies have investigated BM perception in children with ADHD. Here, we compared differences in the ability to process local kinematic and global configurational cues, two fundamental abilities of BM perception, between typically developing and ADHD children. We further investigated the relationship between BM perception and social interaction skills measured using the Social Responsiveness Scale and examined the contributions of latent factors (e.g., sex, age, attention, and intelligence) to BM perception. The results revealed that children with ADHD exhibited atypical BM perception. Local and global BM processing showed distinct features. Local BM processing ability was related to social interaction skills, whereas global BM processing ability significantly improved with age. Critically, general BM perception (i.e., both local and global BM processing) may be affected by sustained attentional ability in children with ADHD. This relationship was primarily mediated by reasoning intelligence. These findings elucidate atypical BM perception in ADHD and the latent factors related to BM perception. Moreover, this study provides new evidence that BM perception is a hallmark of social cognition and advances our understanding of the potential roles of local and global processing in BM perception and social cognitive disorders.
Overcoming the nutritional immunity by engineering iron scavenging bacteria for cancer therapy
Authors: Huang Sin-Wei , Lim See-Khai , Yu Yao-An , Pan Yi-Chung , Lien Wan-Ju , Mou Chung-Yuan , Hu Che-Ming Jack , Mou Kurt Yun 
Published: July 2023

AbstractCertain bacteria demonstrate the ability to target and colonize the tumor microenvironment, a characteristic that positions them as innovative carriers for delivering various therapeutic agents in cancer therapy. Nevertheless, our understanding of how bacteria adapt their physiological condition to the tumor microenvironment remains elusive. In this work, we employed liquid chromatography-tandem mass spectrometry to examine the proteome ofE. colicolonized in murine tumors. Comparing toE. colicultivated in the rich medium, we found thatE. colicolonized in tumors notably upregulated the processes related to ferric ions, including the enterobactin biosynthesis and iron homeostasis. This finding indicated that the tumor is an iron-deficient environment toE. coli. We also found that the colonization ofE. coliin the tumor led to an increased expression of lipocalin 2 (LCN2), a host’s protein that can sequester the enterobactin. We therefore engineeredE. coliin order to evade the nutritional immunity provided by LCN2. By introducing the IroA cluster, theE. colisynthesizes the glycosylated enterobactin, which creates steric hindrance to avoid the LCN2 sequestration. The IroA-E. colishowed enhanced resistance to LCN2 and significantly improved the anti-tumor activity in mice. Moreover, the mice cured by the IroA-E. colitreatment became resistant to the tumor re-challenge, indicating the establishment of immunological memory. Overall, our study underscores the crucial role of bacteria’s ability to acquire ferric ions within the tumor microenvironment for effective cancer therapy.
Proteomic analysis of human serum Extracellular Vesicles reveals early diagnostic markers for Amyotrophic Lateral Sclerosis
Authors: Vassileff Natasha , Leblanc Pascal , Bernard Emilien , Fourier Anthony , Quadrio Isabelle , Lowe Rohan G. T. , Spiers Jereme G. , Hill Andrew F. , Cheng Lesley 
Published: July 2023

AbstractAmyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the deposition of misfolded proteins leading to the death of motor neurons. Several ALS-associated proteins, including TAR DNA-binding protein 43 (TDP-43) and Superoxide dismutase-1 (SOD-1), have been linked to small extracellular vesicles (EVs). However, the role of these EVs and their cargo in ALS patients, prior to treatment intervention, has not been investigated. This study aims to identify the earliest protein changes facilitated by EVs in ALS by examining the serum of recently diagnosed ALS patients. EVs were isolated from the serum of ALS (n = 25) and healthy control (HC, n = 9) patients before undergoing proteomics analysis. This resulted in the identification of a panel of 9 significantly up-regulated proteins and included haptoglobin and hemoglobin subunits, complement, and afamin, which are involved in pathways including heme homeostasis and autophagy. The identification of haptoglobin in ALS serum EVs suggests it has potential as an early diagnostic biomarker whilst activation of autophagy pathways suggests early recruitment of clearance pathways in ALS. This study uncovers the processes and proteins facilitated through small EVs in the initial stages of ALS. Proteomics data are available via ProteomeXchange with identifier PXD036652.Statement of significance of the studyThe role of small EVs, which are involved in cell-to-cell communication, and their cargo in the initiation of ALS has not been investigated. This study is the first to identify the earliest protein changes occurring in ALS through small EV facilitation. This study examined serum from newly diagnosed ALS patients, prior to treatment intervention. Therefore, the EVs, isolated from ALS and healthy control patients, captured novel ALS associated changes without confoundment from medication, which could mask early changes. A panel of 9 statistically up-regulated proteins was identified after mass spectrometry analysis. These included: haptoglobin and hemoglobin subunits, complement, and afamin. The identification of up-regulated levels of these proteins in the ALS serum EVs suggests they have potential as diagnostic biomarkers whilst identifying pathways including chaperone mediated autophagy (CMA) and microautophagy suggests early recruitment of clearance pathways in ALS. Therefore, this study uncovered the proteins being facilitated through small EVs in the initial stages of ALS.