Miracle-dz/UniFAR-FTUs huggingface dataset:
Over-expression of ADAR1 in mice does not initiate or accelerate cancer formation in vivo

Adenosine to inosine editing (A-to-I) in regions of double stranded RNA (dsRNA) is mediated by adenosine deaminase acting on RNA 1 (ADAR1) or ADAR2. ADAR1 and A-to-I editing levels are increased in many human cancers. It is not established if elevated ADAR1 represents a driver or passenger during cancer formation. We established a series of murine alleles to allow in vivo overexpression of ADAR1, its individual isoforms or mutant forms of ADAR1 to understand how it contributes to cancer pathogenesis. The widespread overexpression of ADAR1 or either the p110 or p150 isoforms as sole lesions was well tolerated and did not result in cancer formation. Therefore, ADAR1 overexpression alone is not sufficient to initiate cancer. We demonstrate that endogenous ADAR1 and A-to-I editing levels increased upon immortalization by loss of p53 in murine cells, consistent with the observations from human cancers. We tested if ADAR1 overexpression could co- operate with cancer initiated by loss of tumour suppressors using a model of osteosarcoma. We did not see a disease potentiating or modifying effect of overexpressing ADAR1 or its isoforms. We conclude that the increase in ADAR1 expression and A-to-I editing in cancers is a passenger, rather than a driver, of tumor formation.
Foveolar cone subtype patterning in human retinal organoids

The mechanisms that generate patterns of cell types unique to humans are poorly understood. In the central region of the human retina, the high-acuity foveola is notable, in part, for its dense packing of green (M) and red (L) cones and absence of blue (S) cones. To identify mechanisms that promote M/L and suppress S cone patterning in the foveola, we examined human fetal retinas and differentiated human retinal organoids. During development, sparse S-opsin-expressing cones are observed in the foveola initially. Later, the foveola contains a mix of cones that either co-express S- and M/L-opsins or express M/L-opsin only. In adulthood, only M/L cones are present. Two signaling pathway regulators are highly and continuously expressed in the central retina: Cytochrome P450 26 subfamily A member 1 (CYP26A1) that degrades retinoic acid (RA) and Deiodinase 2 (DIO2) that promotes thyroid hormone (TH) signaling. CYP26A1 null mutant organoids and high RA conditions increased S cones and limited M/L cones in human retinal organoids. Sustained TH signaling promoted the generation of M/L-opsin-expressing cones and induced M/L-opsin expression in S-opsin-expressing cones, showing that cone fate is plastic. Our data suggest that early CYP26A1 degrades RA to specify M/L cones and limit S cones and that continuous DIO2 expression sustains high levels of TH to convert S cones into M/L cones, yielding the M/L cone subtype patterning of the foveola. As the foveola is highly susceptible to impairment in diseases such as macular degeneration, a leading cause of vision loss, our findings inform organoid design for potential therapeutic applications.
The parasubthalamic nucleus refeeding ensemble delays feeding initiation

The parasubthalamic nucleus (PSTN) is responsive to refeeding after food deprivation and PSTN subpopulations can suppress feeding. However, no study directly addressed the role of PSTN neurons activated upon food access resumption. Here we show that the ensemble of refeeding-activated PSTN neurons drastically increases the latency to initiate refeeding with both familiar and novel food but exerts limited control over the amount of food consumed by hungry mice. This ensemble also delays sucrose consumption but accelerates water consumption in thirsty mice. We next sought to identify which subpopulations of PSTN neurons might be driving these effects. We discovered that PSTN Tac1 neurons projecting to the CeA selectively suppress feeding initiation while PSTN Crh neurons surprisingly promote the consumption of novel, palatable substances. Our results demonstrate the key role of endogenous PSTN activity in the control of feeding initiation and identify PSTN subpopulations counteracting each other’s influence on consummatory behaviors.
Geometry and magnetic-field-induced vortices and antivortices in mesoscopic two-dimensional systems

A two-dimensional mesoscopic system of arbitrary shape placed in a perpendicular homogeneous magnetic field is investigated for arbitrary boundary conditions. The energy spectrum of quantum dots and the phase boundary of mesoscopic superconductors are obtained. The wave function for quantum dots and the complex order parameter for mesoscopic superconductors exhibit the simultaneous stabilization of vortices and antivortices at specific ranges of the magnetic field for noncircular symmetric samples. When the vorticity is changed, we found that antivortices can be introduced into the system in order to preserve the symmetry of the sample in the vortex pattern.
Emergence of distributed working memory in a human brain network model

Working memory is a fundamental cognitive function which allows to transiently store and manipulate relevant information in memory. While it has been traditionally linked to activity in specific prefrontal cortical areas, recent electrophysiological and imaging evidence has shown co-occurrent activities in different brain regions during working memory. To dissect the mechanisms behind the emergence of such distributed working memory activity in the human brain, we built and analyzed a detailed, data-constrained model of the human brain combining multiple sources of large-scale brain data. The model reveals the emergence of distributed working memory patterns which rely on long-range synaptic projections, differing from classical models where working memory emerges due to local recurrent connectivity. When compared to existing evidence regarding areas linked to working memory, our model explains almost 80% of the observed variability across brain areas. Our results predict important differences between the distributed working memory in human and non-human primates, and propose a potential solution for the debate regarding the role of early visual areas in working memory encoding. This work provides a novel approach to simulate the human brain which combines the richness of large-scale brain dynamics with the insight of mechanistic models of cognitive functions.
Delivering mRNAs to mouse tissues using the SEND system

mRNAs produced in a cell are almost always translated within the same cell. Some mRNAs are transported to other cells of the organism through processes involving membrane nanotubes or extracellular vesicles. A recent report describes a surprising new phenomenon of encapsulating mRNAs inside virus-like particles (VLPs) to deliver them to other cells in a process that was named SEND (Selective Endogenous eNcapsidation for cellular Delivery). Although the seminal work demonstrates the SEND process in cultured cells, it is unknown whether this phenomenon occurs in vivo. Here, we demonstrate the SEND process in living organisms using specially designed genetically engineered mouse models. Our proof of principle study lays a foundation for the SEND-VLP system to potentially be used as a gene therapy tool to deliver therapeutically important mRNAs to tissues.
Dimerization mechanism of an inverted-topology ion channel in membranes

Many ion channels are multi-subunit complexes with a polar permeation pathway at the oligomeric interface, but their mechanisms of assembly into functional, thermodynamically stable units within the membrane are largely unknown. Here we characterize the assembly of the inverted-topology, homodimeric fluoride channel Fluc, leveraging a known mutation, N43S, that weakens Na+ binding to the dimer interface, thereby unlocking the complex. While single-channel recordings show Na+ is required for activation, single-molecule photobleaching and bulk Förster Resonance Energy Transfer experiments in lipid bilayers demonstrate that N43S Fluc monomers and dimers exist in dynamic equilibrium, even without Na+. Molecular dynamics simulations indicate this equilibrium is dominated by a differential in the lipid-solvation energetics of monomer and dimer, which stems from hydrophobic exposure of the polar ion pathway in the monomer. These results suggest a model wherein membrane-associated forces induce channel assembly while subsequent factors, in this case Na+ binding, result in channel activation. Teaser Membrane morphology energetics foster inverted-topology Fluc channels to form dimers, which then become active upon Na+ binding.
Building a Pangenome Alignment Index via Recursive Prefix-Free Parsing

Motivation Pangenomics alignment has emerged as an opportunity to reduce bias in biomedical research. Traditionally, short read aligners—such as Bowtie and BWA—were used to index a single reference genome, which was then used to find approximate alignments of reads to that genome. Unfortunately, these methods can only index a small number of genomes due to the linear-memory requirement of the algorithms used to construct the index. Although there are a couple of emerging pangenome aligners that can index a larger number of genomes more algorithmic progress is needed to build an index for all available data. Results Emerging pangenomic methods include VG, Giraffe, and Moni, where the first two methods build an index a variation graph from the multiple alignment of the sequences, and Moni simply indexes all the sequences in a manner that takes the repetition of the sequences into account. Moni uses a preprocessing technique called prefix-free parsing to build a dictionary and parse from the input—these, in turn, are used to build the main run-length encoded BWT, and suffix array of the input. This is accomplished in linear space in the size of the dictionary and parse. Therein lies the open problem that we tackle in this paper. Although the dictionary scales nicely (sub-linear) with the size of the input, the parse becomes orders of magnitude larger than the dictionary. To scale the construction of Moni, we need to remove the parse from the construction of the RLBWT and suffix array. We accomplish this, in this paper by applying prefix-free parsing recursively on the parse. Although conceptually simple, this leads to an algorithmic challenge of constructing the RLBWT and suffix array without access to the parse. We solve this problem, implement it, and demonstrate that this improves the construction time by a factor of 8.9 the running time and by a factor of 2.7 the memory required. Availability Our implementation is open source and available at https://github.com/marco-oliva/r-pfbwt. Contact Marco Oliva at marco.oliva@ufl.edu
Left-Hemisphere Cortical Language Regions Respond Equally to Observed Dialogue and Monologue

Much of the language we encounter in our everyday lives comes in the form of conversation, yet the majority of research on the neural basis of language comprehension has used input from only one speaker at a time. 20 adults were scanned while passively observing audiovisual conversations using functional magnetic resonance imaging. In a block-design task, participants watched 20-second videos of puppets speaking either to another puppet (the “dialogue” condition) or directly to the viewer (“monologue”), while the audio was either comprehensible (played forward) or incomprehensible (played backward). Individually functionally-localized left-hemisphere language regions responded more to comprehensible than incomprehensible speech but did not respond differently to dialogue than monologue. In a second task, participants watched videos (1-3 minutes each) of two puppets conversing with each other, in which one puppet was comprehensible while the other’s speech was reversed. All participants saw the same visual input but were randomly assigned which character’s speech was comprehensible. In left-hemisphere cortical language regions, the timecourse of activity was correlated only among participants who heard the same character speaking comprehensibly, despite identical visual input across all participants. For comparison, some individually-localized theory of mind regions and right hemisphere homologues of language regions responded more to dialogue than monologue in the first task, and in the second task, activity in some regions was correlated across all participants regardless of which character was speaking comprehensibly. Together, these results suggest that canonical left-hemisphere cortical language regions are not sensitive to differences between observed dialogue and monologue.
Supplemental oxygen did not significantly affect two-year mortality in patients at-risk for cardiovascular complications undergoing moderate- to high-risk abdominal surgery–A follow-up analysis of a prospective randomized clinical trial

Background In relatively healthy middle-aged patients, recent studies have shown that supplemental oxygen did not significantly increase one-year mortality after noncardiac surgery. If supplemental oxygen influences long-term mortality, specifically in elderly patients with cardiovascular risk-factors, remains unknown. Thus, we evaluated the effect of supplemental oxygen on two-year mortality in patients with cardiovascular risk factors undergoing moderate- to high-risk major abdominal surgery. Methods This is a follow-up study of a prospective, randomized, double-blinded, clinical trial. Two hundred fifty-eight patients, who were at least 45 years of age and at-risk for cardiovascular complications were randomly assigned to receive 80 vs. 30% oxygen during surgery and for the first two postoperative hours. Vital status was obtained from all patients 2 years after surgery using the national registry. Preoperative and postoperative maximum concentrations of NT-proBNP, Troponin T (TnT), Copeptin, von Willebrand Factor (vWF), static oxidation-reduction potential (sORP) and oxidation-reduction potential capacity (cORP) were tested for association with two-year mortality. Results The median age of patients was 74 years (25th-75th percentile 70–78 years). 25.8% (95% CI: 17.3–32.4%) of patients in the 80% oxygen group and 22.3% (95% CI: 14.8–29.1%) in the 30% oxygen group died within 2 years after surgery. No significant difference in two-year mortality was found between patients, who received 80% oxygen concentration, versus patients, who received 30% oxygen concentration (estimated hazard ratio 1.145; 95% CI 0.693–1.893; p = 0.597). Preoperative Copeptin concentrations and postoperative maximum vWF activity were significantly associated with two-year mortality (p < 0.001). Conclusion Our results are consistent with previous studies, that showed that supplemental oxygen did not increase long-term mortality. Therefore, it is becoming more evident that supplemental oxygen may not have a significant effect on long-term outcome in patients undergoing major abdominal surgery.
A cross-sectional examination of service complexity in youths with co-occurring autism spectrum disorder and psychiatric or medical diagnoses across service sectors

Introduction Autism spectrum disorder (ASD) is a heterogeneous, life-long, and complex condition. Youth diagnosed with ASD require several supports addressing core symptoms associated with the disorder, but also those resulting from co-occurring mental and physical health conditions. As a result, their care is overseen by numerous professionals spanning various service sectors, but communication between sectors is hindered due to the absence of a standardized assessment system to identify and triage youth to services. A paucity of information surrounding this population’s service use lingers and a siloed delivery system persists. Methods Using archival data collected from 1,020 youth between 12 and 18 years of age, this study explored service complexity among autistic youth with and without psychiatric and medical co-occurring conditions in Ontario, Canada. In doing so, a negative binomial regression was utilized to investigate which predisposing, enabling, and need variables were associated with service complexity. Results Results revealed that experiencing financial difficulties was not associated with service complexity. However, age, sex, caregiver distress, comorbidity, intellectual disability, and evaluated health status were significant predictors. More specifically, female youth and youth with distressed caregivers had greater mental health service complexity scores. Additionally, youth diagnosed with two or more conditions in addition to ASD who required longer durations of programming, controlling for other predictors, had greater mental health service complexity scores. Yet, youth with an intellectual disability had lower service complexity scores. Discussion Clinical implications of this study are discussed to inform future investments into mental health efforts for autistic youth.
Hybridized bio-inspired intrusion detection system for Internet of Things

The Internet of Things (IoT) consists of several smart devices equipped with computing, sensing, and network capabilities, which enable them to collect and exchange heterogeneous data wirelessly. The increasing usage of IoT devices in daily activities increases the security needs of IoT systems. These IoT devices are an easy target for intruders to perform malicious activities and make the underlying network corrupt. Hence, this paper proposes a hybridized bio-inspired-based intrusion detection system (IDS) for the IoT framework. The hybridized sine-cosine algorithm (SCA) and salp swarm algorithm (SSA) determines the essential features of the network traffic. Selected features are passed to a machine learning (ML) classifier for the detection and classification of intrusive traffic. The IoT network intrusion dataset determines the performance of the proposed system in a python environment. The proposed hybridized system achieves maximum accuracy of 84.75% with minimum selected features i.e., 8 and takes minimum time of 96.42 s in detecting intrusion for the IoT network. The proposed system's effectiveness is shown by comparing it with other similar approaches for performing multiclass classification.
Combined analysis of multi-omics reveals the potential mechanism of flower color and aroma formation in Macadamia integrifolia

Introduction Macadamia integrifolia Maiden & Betche is a domesticated high-value nut crop. The development of nut flower affects the fruit setting rate, yield and quality of nuts. Therefore, in this experiment, two varieties with different flower color, flowering time, flowering quantity and nut yield (single fruit weight) were selected as the research objects. Methods Transcriptome (RNA-Seq) and metabolome (LC-MS/MS, GC-MS) analyses were performed to study the regulatory mechanisms of nut flower development, color and aroma. Results The results indicated that plant hormone signal transduction, starch sucrose metabolism, phenylpropanoid metabolism, flavonoid biosynthesis, and anthocyanin biosynthesis pathways were related to nut flower development and flower color formation. In the early stage of flowering, most of the differentially expressed genes (DEGs) are involved in the IAA signal transduction pathway, while in the later stage, the brassinolide signal pathway is mainly involved. In starch and sugar metabolism, DEGs are mainly involved in regulating and hydrolyzing stored starch into small molecular sugars in flower tissues. In the phenylpropanoid biosynthesis pathway, DEGs are mainly related to the color and aroma (volatile organic compounds, VOCs) formation of nut flowers. Four color formation metabolites (anthocyanins) in nut flowers were found by LC-MS/MS detection. In addition, the VOCs showed no significant difference between red nut flowers (R) and white nut flowers (W), which was mainly reflected in the aroma formation stage (flowering time). And 12 common differentially accumulation metabolites (DAMs) were detected by GC-MS and LC-MS/MS. At the same time, the DEGs, AAT, LOX and PAL genes, were also identified to regulate key metabolite synthesis during nut flower development. These genes were further verified by qRT-PCR. Conclusion Our results provide insights to clarify the molecular mechanism of color and aroma formation during M. integrifolia flower development that pave the way for nut quality and yield breeding.
Deciphering the sequential changes of monocytes/macrophages in the progression of IDD with longitudinal approach using single-cell transcriptome

Intervertebral disk degeneration (IDD) is a chronic inflammatory disease with intricate connections between immune infiltration and oxidative stress (OS). Complex cell niches exist in degenerative intervertebral disk (IVD) and interact with each other and regulate the disk homeostasis together. However, few studies have used longitudinal approach to describe the immune response of IDD progression. Here, we conducted conjoint analysis of bulk-RNA sequencing and single-cell sequencing, together with a series of techniques like weighted gene co-expression network analysis (WGCNA), immune infiltration analysis, and differential analysis, to systematically decipher the difference in OS-related functions of different cell populations within degenerative IVD tissues, and further depicted the longitudinal alterations of immune cells, especially monocytes/macrophages in the progression of IDD. The OS-related genes CYP1A1, MMP1, CCND1, and NQO1 are highly expressed and might be diagnostic biomarkers for the progression of IDD. Further landscape of IVD microenvironment showed distinct changes in cell proportions and characteristics at late degeneration compared to early degeneration of IDD. Monocytes/macrophages were classified into five distinct subpopulations with different roles. The trajectory lineage analysis revealed transcriptome alterations from effector monocytes/macrophages and regulatory macrophages to other subtypes during the evolution process and identified monocytes/macrophage subpopulations that had rapidly experienced the activation of inflammatory or anti-inflammatory responses. This study further proposed that personalized therapeutic strategies are needed to be formulated based on specific monocyte/macrophage subtypes and degenerative stages of IDD.
The legacy of intensive agricultural history on the soil health of (sub)tropical landscapes

Soil health conceptualized as a measurable ecosystem property provides a powerful tool for monitoring progress in restoration projects or implementation of best management practices to improve degraded lands and promote sustainable agroecosystems. We surveyed soils collected from a range of land uses (i.e., protected native and non-native forest, managed pasture, unmanaged previously intensive agricultural lands, organic cropland, and conventional cropland) across a range of soil orders (Oxisol, Mollisol, Andisol, Inceptisol, and Vertisol) on three Hawaiian Islands. Forty-six soil health indicators encompassing biological, chemical, and physical properties were measured. In this multivariate survey, the most distinct group was the unmanaged, previously intensive agriculture lands, which was significantly different from all other land uses even when considering differences in mineralogy. Importantly, the soil health indicators of well-managed pastures in Hawaiʻi were not different from protected forests, suggesting that well-managed grazing lands may be as healthy and resilient as protected forests. A suite of 11 readily measured indicators emerged out of a first-principle approach to determining a holistic indication of soil health across a range of soils and systems in Hawaiʻi encompassing much of the diversity in the tropics and subtropics. Every land use may improve its soil health status within a reasonable range of expectations for a soil’s land use history, current land use, and mineralogy. Key drivers of inherent differences in the soil health indicators, including intensive land use history, current land use practices, and mineralogy, must be interwoven into the soil health index, which should set minimum and maximum benchmarks and weight indicators according to equitable standards.