Miracle-dz/UniFAR-FTUs huggingface dataset:
ASXL1 Directs Neutrophilic Differentiation via Modulation of MYC and RNA Polymerase II

Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. An epigenetic regulator, ASXL1 canonically directs the deposition of H3K27me3 via the polycomb repressive complex 2. However, its precise role in myeloid lineage maturation is incompletely described. We utilized single cell RNA sequencing (scRNA-seq) on a murine model of hematopoietic-specific ASXL1 deletion and identified a specific role for ASXL1 in terminal granulocyte maturation. Terminal maturation is accompanied by down regulation of Myc expression and cell cycle exit. ASXL1 deletion leads to hyperactivation of Myc in granulocyte precursors and a quantitative decrease in neutrophil production. This failure of normal developmentallyassociated Myc suppression is not accompanied by significant changes in the landscape of covalent histone modifications including H3K27me3. Examining the genome-wide localization of ASXL1 in myeloid progenitors revealed strong co-localization with RNA Polymerase II (RNAPII) at the promoters and spread across the gene bodies of transcriptionally active genes. ASXL1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription, consistent with the known role of ASXL1 as a mediator of RNAPII pause release. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator and highlighting a novel potential oncogenic mechanism for ASXL1 mutations in myeloid malignancies.
Artificial Larval Diet Mediates the Microbiome of Queensland Fruit Fly

Larval diets used for artificial rearing can have a significant effect on insect biology. The Queensland fruit fly (aka “Qfly”), Bactrocera tryoni (Froggatt) (Diptera: Tephritidae), is one of the greatest challenges for fruit growers in Australia. The sterile insect technique (SIT) is being developed to manage outbreaks in regions that remain free of Qfly and to reduce populations in regions where this species is endemic. Factory scale rearing is essential for SIT; however, artificial larval diets are known to affect the microbiome of Qfly, which may then affect fly performance. In this study, high-throughput Illumina sequencing was used to assess the Qfly microbiome in colonies reared, for five generations from nature, on two common artificial diets (carrot and gel). At generation five (G5), the microbiome was assessed in larvae, pupae, adult males and adult females and standard fly quality control parameters were assessed together with additional performance measures of mating propensity and survival under nutritional stress. At the genus level, bacterial communities were significantly different between the colonies reared on the two larval diets. However, communities converged at Phyla to family taxonomic levels. Bacterial genera of Morganella, Citrobacter, Providencia, and Burkholderia were highly abundant in all developmental stages of Qfly reared on the gel diet, when compared to the carrot diet. Despite abundance of these genera, a greater percentage of egg hatching, heavier pupal weight and a higher percentage of fliers were found in the Qfly reared on the gel diet. Mating propensity and survival under nutritional stress was similar for adult Qfly that had been reared on the two larval diets. Overall, our findings demonstrate that the artificial larval diet strongly influences the microbiome and quality control measures of Qfly, with likely downstream effects on performance of flies released in SIT programs.
Identification and Characterization of Neuropeptides and Their G Protein-Coupled Receptors (GPCRs) in the Cowpea Aphid Aphis craccivora

Neuropeptides are the most abundant and diverse signal molecules in insects. They act as neurohormones and neuromodulators to regulate the physiology and behavior of insects. The majority of neuropeptides initiate downstream signaling pathways through binding to G protein-coupled receptors (GPCRs) on the cell surface. In this study, RNA-seq technology and bioinformatics were used to search for genes encoding neuropeptides and their GPCRs in the cowpea aphid Aphis craccivora. And the expression of these genes at different developmental stages of A. craccivora was analyzed by quantitative real-time PCR (qRT-PCR). A total of 40 candidate genes encoding neuropeptide precursors were identified from the transcriptome data, which is roughly equivalent to the number of neuropeptide genes that have been reported in other insects. On this basis, software analysis combined with homologous prediction estimated that there could be more than 60 mature neuropeptides with biological activity. In addition, 46 neuropeptide GPCRs were obtained, of which 40 belong to rhodopsin-like receptors (A-family GPCRs), including 21 families of neuropeptide receptors and 7 orphan receptors, and 6 belong to secretin-like receptors (B-family GPCRs), including receptors for diuretic hormone 31, diuretic hormone 44 and pigment-dispersing factor (PDF). Compared with holometabolous insects such as Drosophila melanogaster, the coding genes for sulfakinin, corazonin, arginine vasopressin-like peptide (AVLP), and trissin and the corresponding receptors were not found in A. craccivora. It is speculated that A. craccivora likely lacks the above neuropeptide signaling pathways, which is consistent with Acyrthosiphon pisum and that the loss of these pathways may be a common feature of aphids. In addition, expression profiling revealed neuropeptide genes and their GPCR genes that are differentially expressed at different developmental stages and in different wing morphs. This study will help to deepen our understanding of the neuropeptide signaling systems in aphids, thus laying the foundation for the development of new methods for aphid control targeting these signaling systems.
Evolution and Ecology in Widespread Acoustic Signaling Behavior Across Fishes

Acoustic signaling by fishes has been recognized for millennia, but is typically regarded as comparatively rare within ray-finned fishes; as such, it has yet to be integrated into broader concepts of vertebrate evolution. We map the most comprehensive data set of volitional sound production of ray-finned fishes (Actinopterygii) yet assembled onto a family level phylogeny of the group, a clade representing more than half of extant vertebrate species. Our choice of family-level rather than species-level analysis allows broad investigation of sonifery within actinopterygians and provides a conservative estimate of the distribution and ancestry of a character that is likely far more widespread than currently known. The results show that families with members exhibiting soniferous behavior contain nearly two-thirds of actinopterygian species, with potentially more than 20,000 species using acoustic communication. Sonic fish families also contain more extant species than those without sounds. Evolutionary analysis shows that sound production is an ancient behavior because it is present in a clade that originating circa 340 Ma, much earlier than any evidence for sound production within tetrapods. Ancestral state reconstruction indicates that sound production is not ancestral for actinopterygians; instead, it independently evolved at least 27 times, compared to six within tetrapods. This likely represents an underestimate for actinopterygians that will change as sonifery is recognized in ever more species of actinopterygians. Several important ecological factors are significantly correlated with sonifery – including physical attributes of the environment, predation by members of other vertebrate clades, and reproductive tactics – further demonstrating the broader importance of sound production in the life history evolution of fishes. These findings offer a new perspective on the role of sound production and acousticcommunication during the evolution of Actinopterygii, a clade containing more than 34,000 species of extant vertebrates.
Selective activation of FZD7 promotes mesendodermal differentiation of human pluripotent stem cells

WNT proteins are secreted symmetry breaking signals that interact with cell surface receptors of the FZD family to regulate a multitude of developmental processes. Studying selectivity between WNTs and FZDs has been hampered by the paucity of purified WNT proteins and by their apparent non-selective interactions with the FZD receptors. Here we describe an engineered protein, called F7L6, comprised of antibody-derived single chain variable fragments that selectively binds to human FZD7 and the co-receptor LRP6. F7L6 potently activates WNT/β-catenin signaling in a manner similar to Wnt3a. In contrast to Wnt3a, F7L6 engages only FZD7 and none of the other FZD proteins. Treatment of human pluripotent stem (hPS) cells with F7L6 initiates transcriptional programs similar to those observed during primitive streak formation and subsequent gastrulation in the mammalian embryo. This demonstrates that selective engagement and activation of FZD7 signaling is sufficient to promote mesendodermal differentiation of hPS cells.
Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

Purpose Patients with juvenile idiopathic arthritis (JIA) are prone to developing chronic anterior uveitis (JIA-U+). Although several risk factors for JIA-U+ have been identified, the underlying etiology is poorly understood. Histopathological studies demonstrate B cell infiltrates in eye tissues of patients with JIA-U+. Methods We performed transcriptome profiling of peripheral blood CD19-positive B cells taken from 14 cases with JIA-U+, 13 JIA cases without uveitis (JIA-U−), and five healthy controls. Deconvolution-based estimation was used to determine the immune cell fractions for each sample. Results Deconvolution results revealed that naive B cells made up on average 71% of the CD19-positive cell fractions analyzed. Differential expression analysis identified 614 differentially expressed genes (DEGs) between the groups at nominal significance and six genes at a false discovery rate of 5% (FDR < 0.05). Head-to-head comparison of all JIA-U− versus JIA-U+ revealed no DEGs in the CD19+ B cell pool (FDR < 0.05). However, principal component analysis based on a panel of key genes for B cell subsets revealed that JIA-U+ cases bifurcate into distinct clusters, characterized by markedly disparate expression for genes associated with specific memory B cell populations. CIBERSORT analysis of the overall transcriptome of the new uveitis cluster identified an increased proportion of memory B cells. Conclusion These data show that JIA-U− and JIA-U+ have a globally similar transcriptome considering the global peripheral CD19-positive B cell pool. However, heterogeneity in B cell memory genes among cases with uveitis suggests a role for specific memory B cell subsets in the etiology of JIA-U+.
Heart Rate Variability and Exceptional Longevity

Centenarians are the paradigm of human extreme longevity and healthy aging, because they have postponed, if not avoided, mayor age-related diseases. The purpose of this study was to investigate potential differences in resting heart rate variability (HRV) between young adults, octogenarians, and centenarians and assess whether HRV variables are predictors of all-cause mortality in centenarians. To this end, three groups of participants: young adults (N = 20; 20.6 ± 2.3 years), octogenarians (N = 18; 84.1 ± 2.6 years), and centenarians (N = 17; 101.9 ± 1.9 years) were monitored for 15 min at rest (seated, without moving or talking) to measure RR intervals, from which HRV was evaluated. Our results showed a clear decrease with age in the main parasympathetic HRV variables, as well as in the standard deviation (SD) of the RR series [SD of normal-to-normal interval (SDNN)] and in low frequency (LF) heart rate (HR) oscillations, although differences between octogenarians and centenarians did not reach statistical significance. In 14 centenarians followed until death, only SDNN showed significant correlation (ρ = 0.536; p = 0.048) with survival prognosis. Additionally, SDNN <19 ms was associated with early mortality (≤1 year) in centenarians (Hazard Ratio = 5.72). In conclusion, HRV indices reflecting parasympathetic outflow as well as SDNN and LF all present an age-related reduction, which could be representative of a natural exhaustion of allostatic systems related to age. Moreover, low SDNN values (<19 ms) could be associated with early mortality in centenarians. HRV seems to play a role in exceptional longevity, which could be accounted for by centenarians’ exposome.
Low hatching success in the critically endangered kākāpō (Strigops habroptilus) is driven by early embryo mortality not infertility

In many endangered species, reproductive failure is a major barrier to recovery. The critically endangered kākāpō (Strigops habroptilus) exemplifies this challenge: 61% of their eggs fail to hatch, and of these 73% show no sign of development. Undeveloped eggs have previously been attributed to male infertility, but recent studies of non-threatened bird species suggest fertilisation failure is rare in the wild. The underlying causes of fertilisation failure and embryo death differ, so distinguishing between them is essential for effective conservation management. Here we show that the majority (72%, n=124) of undeveloped kākāpō eggs are fertilised, and combine this with conservation programme data on natural copulations, artificial inseminations, and paternity of developed eggs, to generate the most precise estimate to date of fertility in a wild population. We also demonstrate, for the first time in a wild bird, that artificial insemination results in greater numbers of sperm reaching the egg.
Detrusor Smooth Muscle KV7 Channels: Emerging New Regulators of Urinary Bladder Function

Relaxation and contraction of the urinary bladder smooth muscle, also known as the detrusor smooth muscle (DSM), facilitate the micturition cycle. DSM contractility depends on cell excitability, which is established by the synchronized activity of multiple diverse ion channels. K+ channels, the largest family of channels, control DSM excitability by maintaining the resting membrane potential and shaping the action potentials that cause the phasic contractions. Among the members of the voltage-gated K+ (KV) channel superfamily, KV type 7 (KV7) channels — KV7.1–KV7.5 members encoded by KCNQ1–KCNQ5 genes — have been recently identified as functional regulators in various cell types including vascular, cardiac, and neuronal cells. Their regulatory roles in DSM, however, are just now emerging and remain to be elucidated. To address this gap, our research group has initiated the systematic investigation of human DSM KV7 channels in collaboration with clinical urologists. In this comprehensive review, we summarize the current understanding of DSM Kv7 channels and highlight recent discoveries in the field. We describe KV7 channel expression profiles at the mRNA and protein levels, and further elaborate on functional effects of KV7 channel selective modulators on DSM excitability, contractility, and intracellular Ca2+ dynamics in animal species along with in vivo studies and the limited data on human DSM. Within each topic, we highlight the main observations, current gaps in knowledge, and most pressing questions and concepts in need of resolution. We emphasize the lack of systematic studies on human DSM KV7 channels that are now actively ongoing in our laboratory.
Why Voting Does Not Imply Consenting

One of the reasons that elections have come to be so widely valued across the globe lies in their perceived ability to increase citizens' consent to be governed by their representatives. Yet, inversely, one may ask what election results tell us about citizens' consent. For instance, to what extent can election winners be assumed to enjoy citizens' consent? Does voting automatically imply consent to the outcome of the election? What does abstention mean? This paper addresses the question of what election results reveal about citizens' consent, from an empirically informed normative perspective. The question is of political importance, because the connection between voting and consenting is often exploited for political gain, and because representative institutions are now being increasingly questioned by citizens themselves. I plead for caution in any endeavor to interpret election results in terms of consent, and I argue that it would be wrong to assume, by default, that voters intend their vote to express consent. Rather, voters' motives can only be ascertained by asking voters about them, and cannot be deduced from their sole act of voting. In addition, much variation is to be expected regarding what is being consented to, and to what degree.
Differential Diagnosis of Multiple System Atrophy-Parkinsonism and Parkinson's Disease Using α-Synuclein and External Anal Sphincter Electromyography

Background and aim: Discriminating multiple system atrophy-parkinsonism (MSA-P) from Parkinson's disease (PD) is challenging. We aimed to provide a new method to make an identification between MSA-P and PD by combining biofluid marker with electrophysiology marker. Methods: The XYCQ EV Enrichment KIT was applied to extract extracellular vesicles (EVs) from saliva. The levels of α-syn which included total α-syn (α- synTotal), phosphorylated-ser129 α-syn (α-synPS129) and oligomeric α-syn (α-synOlig) in EVs of saliva were tested by new developed Electrochemiluminescence (ECL) assays. We collected multi-motor unit potential (MUP) of all participants who conducted external anal sphincter electromyography (EAS-EMG). The duration, phase, amplitude and satellite potential of EAS-EMG were analyzed. The Receiver operator characteristic (ROC) curve was adopted to analyze the diagnostic utility of α-syn in EVs of saliva, EAS-EMG for MSA-P. Results: In EVs of saliva, the α-synTotal concentrations were lower in MSA-P than PD (P = 0.003). No significant difference was shown in α-synOlig and α-synPS129. α-synTotal 4.46 pg/ng distinguished MSA-P from PD with area under the curve (AUC) 0.804. Compared with PD, the duration, phase and satellite potential of EAS-EMG in MSA-P were increased (P = 0.002, 0.008, 0.001). There was no significant difference in amplitude. ROC curve showed that the duration (AUC: 0.780), phase (AUC: 0.751), and satellite potential (AUC: 0.809) had both diagnostic value for MSA-P. The combination of α-synTotal in salivary EVs and EAS-EMG (including duration, phase and satellite potential) could efficiently make a differentiation between MSA-P and PD with sensitivity of 100% and specificity of 86%. The AUC value was 0.901. Conclusion: The study suggested the combination of α-synTotal in salivary EVs and EAS-EMG could help efficiently distinguish MSA-P from PD.
Myocardial Energy Metabolism in Non-ischemic Cardiomyopathy

As the most metabolically demanding organ in the body, the heart must generate massive amounts of energy adenosine triphosphate (ATP) from the oxidation of fatty acids, carbohydrates and other fuels (e.g., amino acids, ketone bodies), in order to sustain constant contractile function. While the healthy mature heart acts omnivorously and is highly flexible in its ability to utilize the numerous fuel sources delivered to it through its coronary circulation, the heart’s ability to produce ATP from these fuel sources becomes perturbed in numerous cardiovascular disorders. This includes ischemic heart disease and myocardial infarction, as well as in various cardiomyopathies that often precede the development of overt heart failure. We herein will provide an overview of myocardial energy metabolism in the healthy heart, while describing the numerous perturbations that take place in various non-ischemic cardiomyopathies such as hypertrophic cardiomyopathy, diabetic cardiomyopathy, arrhythmogenic cardiomyopathy, and the cardiomyopathy associated with the rare genetic disease, Barth Syndrome. Based on preclinical evidence where optimizing myocardial energy metabolism has been shown to attenuate cardiac dysfunction, we will discuss the feasibility of myocardial energetics optimization as an approach to treat the cardiac pathology associated with these various non-ischemic cardiomyopathies.
Integration of Within-Cell Experimental Data With Multi-Compartmental Modeling Predicts H-Channel Densities and Distributions in Hippocampal OLM Cells

Determining biophysical details of spatially extended neurons is a challenge that needs to be overcome if we are to understand the dynamics of brain function from cellular perspectives. Moreover, we now know that we should not average across recordings from many cells of a given cell type to obtain quantitative measures such as conductance since measures can vary multiple-fold for a given cell type. In this work we examine whether a tight combination of experimental and computational work can address this challenge. The oriens-lacunosum/moleculare (OLM) interneuron operates as a “gate” that controls incoming sensory and ongoing contextual information in the CA1 of the hippocampus, making it essential to understand how its biophysical properties contribute to memory function. OLM cells fire phase-locked to the prominent hippocampal theta rhythms, and we previously used computational models to show that OLM cells exhibit high or low theta spiking resonance frequencies that depend respectively on whether their dendrites have hyperpolarization-activated cation channels (h-channels) or not. However, whether OLM cells actually possess dendritic h-channels is unknown at present. We performed a set of whole-cell recordings of OLM cells from mouse hippocampus and constructed three multi-compartment models using morphological and electrophysiological parameters extracted from the same OLM cell, including per-cell pharmacologically isolated h-channel currents. We found that the models best matched experiments when h-channels were present in the dendrites of each of the three model cells created. This strongly suggests that h-channels must be present in OLM cell dendrites and are not localized to their somata. Importantly, this work shows that a tight integration of model and experiment can help tackle the challenge of characterizing biophysical details and distributions in spatially extended neurons. Full spiking models were built for two of the OLM cells, matching their current clamp cell-specific electrophysiological recordings. Overall, our work presents a technical advancement in modeling OLM cells. Our models are available to the community to use to gain insight into cellular dynamics underlying hippocampal function.