Miracle-dz/UniFAR-FTUs huggingface dataset:
A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding

Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood. To correlate systematically genetic, transcriptional and proteomic phenotypes, our study involved an integrative analysis of fibroid, myometrium and endometrium tissues from 137 patients, utilising genome-wide SNP arrays, targeted sequencing, RNA sequencing and proteomics. Our findings reveal 39.7% of UFs possess MED12 mutations, alongside novel variants in genes such as COL4A5 and COL4A6. Multi-omics factor analysis of integrated protein and mRNA highlighted differential regulation related to extracellular matrix remodelling, proteolysis and homeostasis in fibroid versus myometrium tissues, and distinct gene sets associated with RNA splicing in the endometrium of patients with HMB, particularly in MED12-mutated fibroids. Our study proposes a model, which is supported by in vivo evidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding. This integrative approach unravels complex molecular pathways in UF pathogenesis and HMB, offering novel insights for targeted therapeutic development.
Varying the position of phospholipid acyl chain unsaturation modulates hopanoid and sterol ordering

The cell membrane must balance mechanical stability with fluidity to function as both a barrier and an organizational platform. Key to this balance is the thermodynamic ordering of lipids. Most Eukaryotes employ sterols, which are uniquely capable of modulating lipid order to decouple membrane stability from fluidity. Ancient sterol analogues known as hopanoids are found in many bacteria and are proposed as ancestral ordering lipids. The juxtaposition of sterols and hopanoids in extant organisms prompts us to ask why both pathways persist, especially in light of their convergent ability to order lipids. We reveal that both hopanoids and sterols order unsaturated phospholipids differently based on the position of double bonds in the phospholipid’s acyl chain. We find that cholesterol and diplopterol’s methyl group distributions lead to distinct effects on unsaturated lipids. In Mesoplasma florum, diplopterol’s constrained ordering capacity reduces membrane resistance to osmotic stress, unlike cholesterol. These findings suggest cholesterol’s broader lipid ordering ability may have facilitated the exploration of a more diverse lipidomic landscape in eukaryotic membranes.
Learning within a sensory-motor circuit links action to expected outcome

The cortex integrates sound- and movement-related signals to predict the acoustic consequences of behavior and detect violations from expectations. Although expectation- and prediction-related activity has been observed in the auditory cortex of humans, monkeys, and mice during vocal and non-vocal acoustic behaviors, the specific cortical circuitry required for forming memories, recalling expectations, and making predictions remains unknown. By combining closed-loop behavior, electrophysiological recordings, longitudinal pharmacology, and targeted optogenetic circuit activation, we identify a cortical locus for the emergence of expectation and error signals. Movement-related expectation signals and sound-related error signals emerge in parallel in the auditory cortex and are concentrated in largely distinct neurons, consistent with a compartmentalization of different prediction-related computations. On a trial-by-trial basis, expectation and error signals are correlated in auditory cortex, consistent with a local circuit implementation of an internal model. Silencing the auditory cortex during motor-sensory learning prevents the emergence of expectation signals and error signals, revealing the auditory cortex as a necessary node for learning to make predictions. Prediction-like signals can be experimentally induced in the auditory cortex, even in the absence of behavioral experience, by pairing optogenetic motor cortical activation with sound playback, indicating that cortical circuits are sufficient for movement-like predictive processing. Finally, motor-sensory experience realigns the manifold dimensions in which auditory cortical populations encode movement and sound, consistent with predictive processing. These findings show that prediction-related signals reshape auditory cortex dynamics during behavior and reveal a cortical locus for the emergence of expectation and error.
Systems Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis

Multiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how a therapy-driven “in vivo perturbation” modulates the diverse immune landscape by measuring transcriptomic granularity with single-cell RNA sequencing (scRNAseq). We demonstrate that B cell depletion leads to cell type-specific changes in the abundance and function of CSF macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an anti-inflammatory transcriptomic signature and peripheral CD16+ monocytes increased in frequency post-B cell depletion. This was accompanied by increases in TNFα messenger RNA and protein in monocytes post-B cell depletion, consistent with the finding that anti-TNFα treatment exacerbates autoimmune activity in MS. In parallel, B cell depletion induced changes in peripheral CD4+ T cell populations, including increases in the frequency of TIGIT+ regulatory T cells and marked decreases in the frequency of myelin peptide loaded-tetramer binding CD4+ T cells. Collectively, this study provides an exhaustive transcriptomic map of immunological changes, revealing different mechanisms of action contributing to the high efficacy in B cell depletion treatment of MS.
Differences in milk microbiota between healthy cows and cows with recurring Klebsiella mastitis

Klebsiella spp. infections continue to have a significant economic impact on the dairy industry, being an important cause of severe clinical mastitis, recurrent infections, and demonstrating poor response to antimicrobials. It is, therefore, essential to investigate the underlying causes of Klebsiella spp. infections. Here we used high-throughput DNA sequencing to characterize the milk microbiota of healthy dairy cows (HDC) and cows with history of recurrent Klebsiella mastitis (KLB). Our goal was to identify potential pathogenic genera associated with recurrent Klebsiella infections in cows. The relative abundance of Firmicutes and Faecalibacterium was greater in the KLB group than in the HDC group. In contrast, Proteobacteria and Labrenzia were less abundant than in the HDC group. Although the species distributions differed between groups, diversity and abundance of communities were comparable. Notably, genera of increased occurrence in the KLB group were mostly intestinal-associated, which suggests that cows in the KLB group resided in a contaminated environment or had increased teat-end exposure to fecal bacteria. We did not detect major differences in microbiota among quarters, and also between fore-strip milk and milk collected after fore-stripping. Conversely, milk of heifers had increased alpha diversity in comparison to milk of multiparous cows.
Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons

Biological resilience, broadly defined as ability to recover from acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3-17.8 years spanning across different tissues, tissue regions, and cell types including: (1) fibroblasts from skin and from heart separated into left ventricle (LV), right ventricle (RV), left atrium (LA) and right atrium (RA), (2) astrocytes from the prefrontal cortex and hippocampus and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50µM-H2O2), metabolic (1mM-glucose) and proteostasis (0.1µM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor specific. For example, astrocytes were more energetic and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to age and developmental status of donors as potential predictive markers.
Unravelling the microplastic menace: different polymers work in synergy to increase bee vulnerability

Microplastics (MPs) are growing and ubiquitous environmental pollutants and represent one of the greatest contemporary challenges caused by human activities. Current research has predominantly examined the singular toxicological effects of individual polymers, neglecting the prevailing reality of organisms confronted with complex contaminant mixtures and potential synergistic effects. To fill this research gap, we investigated the lethal and sublethal effects of two common MPs, polystyrene (PS - 4.8-5.8 μm) and poly(methyl methacrylate) (PMMA - 1-40 μm), and their combination (MIX), on the pollinating insect Apis mellifera. For each treatment, we evaluated the oral toxicity of two ecologically relevant and one higher concentration (0.5, 5 and 50 mg/L) and analysed their effects on the immune system and worker survival. As immune activation can alter the cuticular hydrocarbon profile of honey bees, we used gas chromatography-mass spectrometry (GC-MS) to investigate whether MPs lead to changes in the chemical profile of foragers and behavioural assay to test whether such changes affect behavioural patterns of social recognition, undermining overall colony integrity. The results indicate a synergistic negative effect of PS and PMMA on bee survival and immune response, even at ecologically relevant concentrations. Furthermore, alterations in cuticle profiles were observed with both MPs at the highest and intermediate concentrations, with PMMA being mainly responsible. Both MPs exposure resulted in a reduction in the abundance of several cuticular compounds. Hive entry guards did not show increased inspection or aggressive behaviour towards exposed foragers, allowing them to enter the colony without being treated differently from uncontaminated foragers. These findings raise concerns not only for the health of individual bees, but also for the entire colony, which could be at risk if contaminated nestmates enter the colony undetected, allowing MPs to spread throughout the hive.
Consequences of Cancer on Zebrafish Danio rerio: Insights into Sex Determination, Sex Ratio, and Offspring Survival

Offspring sex ratio has been proposed as an indicator of the risk of developing certain cancers in humans, but offspring sex ratio may also be a consequence of the disease. In this study, we delve into this subject using the fish Danio rerio as a model system. First, we explore whether inducing skin cancer at an early stage of the host’s life (embryonic stage) has the potential to influence sex determination and/or sex-specific mortality. Second, we investigate whether the sex ratio in offspring produced by tumor-bearing adult females differs from that of healthy females. Third, we compare the survival (until sexual maturity) of offspring produced by cancerous and non-cancerous females. We found that skin cancer did not influence sex ratio in both experiments. However, consistent with previous studies on other model systems, the survival of offspring from cancerous females was higher, suggesting that diseased females allocate more resources to current reproductive efforts compared to their healthy counterparts. This study makes a significant contribution to our understanding of the ecological and evolutionary consequences of host-tumor interactions in animals.
Fourfold increase in photocurrent generation of Synechocystis sp. PCC 6803 by exopolysaccharide deprivation

Photosynthetic microorganisms, including algae and cyanobacteria, export electrons in a light-stimulated phenomenon called ‘exoelectrogenesis’. However, the route(s) by which electrons reach an external electrode from the cell remain(s) unclear. For the model cyanobacterium Synechocystis sp. PCC 6803, it has been established that electron transfer does not depend on direct extracellular electron transfer by type IV pili. However, the role of the exopolysaccharide matrix in which cells are embedded has not been investigated. We show that a Synechocystis mutant with substantially reduced exopolysaccharide production has a four-fold greater photocurrent than wild-type cells. This increase is due in part to increased adhesion of exopolysaccharide-deficient cells to electrodes. Stirred system experiments reveal that a substantial portion of the photocurrent depends on an endogenous diffusible electron mediator, supporting indirect extracellular electron transfer as the bioelectrochemical mechanism of exoelectrogenesis. These findings will be important in harnessing exoelectrogenesis for sustainable electricity generation in biophotovoltaic devices.
A single giant cell at the origin of an evolutionary innovation

Key innovations play a central role in the diversification of lineages, yet our understanding of the mechanisms underlying their emergence remains fragmented. The propelling fan is a key innovation associated with the diversification of Rhagovelia water striders into fast flowing streams. Here, we show that a single giant cell is responsible for the development of the fan throughout embryogenesis. RNA interference against the fan-specific gene family gsha/mogsha depleted the fan in the embryo but did not alter the giant cell, indicating that these genes are not required for specifying the identity of this cell. gsha/mogsha instead seem to activate the expression of cuticular genes during early development, suggesting a role of these genes in regulating the accumulation of fan structural proteins. We also show that Hox genes act to block the giant cell in the fore- and rear-legs, thus restricting its fate to the mid-legs – the pair of legs that generates movement on water. In addition, Hox expression is specifically excluded from the giant cell, thus allowing the expression of the fan’s developmental genetic program. This study reveals that a single cell can be sufficient to generate innovative traits that have been central for a lineage to acquire new ecological opportunities and burst into diversification. One-sentence summary A single giant cell orchestrates the developmental genetic program of a key innovation
Internal structure of Mycoplasma mobile gliding machinery analyzed by negative staining electron tomography

Mycoplasma mobile is a parasitic bacterium that forms gliding machinery on the cell pole and glides on a solid surface in the direction of the cell pole. The gliding machinery consists of both internal and surface structures. The internal structure is divided into a bell at the front and chain structure extending from the bell. In this study, the internal structures prepared under several conditions were analyzed using negative-staining electron microscopy and electron tomography. The chains were constructed by linked motors containing two complexes similar to ATP synthase. A cylindrical spacer with a maximum diameter of 6 nm and a height of 13 nm, and anonymous linkers with a diameter of 0.9–8.3 nm and length of 5–30 nm were found between motors. The bell is bowl-shaped and features a honeycomb surface with a periodicity of 8.4 nm. The chains of the motor are connected to the rim of the bell through a wedge-shaped structure. These structures may play roles in the assembly and cooperation of gliding machinery units. Significance Mycoplasma mobile, a parasitic bacterium, glides on solid surfaces at speeds of up to 4.0 μm per second through a specialized mechanism. The gliding machinery, located at one pole of the cell, is composed of surface legs and internal motor structures. The force generation unit within the internal structure evolved from ATP synthase. This study aimed to clarify the entire architecture of the gliding machinery using electron tomography.
A Cautionary Note on Using STRUCTURE to Detect Hybridization in a Phylogenetic Context

Population genetic clustering methods are widely used to detect hybridization events between closely related populations within species, as well as between deeply diverged lineages across phylogenetic time-scales, although their strengths and limitations in the latter cases remain poorly explored. This study presents the first systematic evaluation of the performance of the most popular population clustering method, STRUCTURE, under a variety of cross-species hybridization scenarios, including hybrid speciation, as well as introgression involving ghost (i.e., extinct or unsampled) lineages or otherwise. Our simulations demonstrate that STRUCTURE performs well in identifying hybrids and their parental donors only when admixture happens very recently between sampled extant lineages. However, STRUCTURE generally fails to detect signals of admixture when hybridization occurs in deep time or when gene flow stems from ghost lineages. We find that symmetrical parental contribution in cases of hybrid speciation will often be revealed as extremely asymmetrical in STRUCTURE, especially when the admixture event occurred more than some time ago. Our results suggest that population-genetic clustering methods may be very inefficient for detecting either ancient or ghost admixtures, partly explaining why ghost introgression has escaped the attention of evolutionary biologists until recently.
Time-varying mediation analysis for incomplete data with application to DNA methylation study for PTSD

DNA methylation (DNAm) has been shown to mediate causal effects from traumatic experiences to post-traumatic stress disorder (PTSD). However, the scientific question about whether the mediation effect changes over time remains unclear. In this paper, we develop time-varying structural equation models to identify cytosine-phosphate-guanine (CpG) sites where DNAm mediates the effect of trauma exposure on PTSD, and to capture dynamic changes in mediation effects. The proposed methodology is motivated by the Detroit Neighborhood Health Study (DNHS) with high-dimensional and longitudinal DNAm measurements. To handle the non-monotone missing DNAm in the dataset, we propose a novel Longitudinal Multiple Imputation (LMI) method utilizing dependency among repeated measurements, and employ the generalized method of moments to integrate the multiple imputations. Simulations confirm that the proposed method outperforms existing approaches in various longitudinal settings. In DNHS data analysis, our method identifies several CpG sites where DNAm exhibits dynamic mediation effects. Some of the corresponding genes have been shown to be associated with PTSD in the existing literature, and our findings on their time-varying effects could deepen the understanding of the mediation role of DNAm on the causal path from trauma exposure to PTSD risk.
Myoelectric Prosthesis Control using Recurrent Convolutional Neural Network Regression Mitigates the Limb Position Effect

Although state-of-the-art myoelectric prostheses offer persons with upper limb amputation extensive movement capabilities, users have not been afforded a reliable means to control common movements required in daily living. Many proposed prosthesis controllers use pattern recognition, a method that learns and recognizes patterns of electromyographic (EMG) signals produced by the user’s residual limb muscles to predict and execute device movements. Such control becomes unreliable in high limb positions—a problem known as the limb position effect. Pattern recognition often uses a classification algorithm; simple to implement, but limits user-initiated control to only one device movement at a time, at a single speed. To combat position-related control deficiencies and classification controller constraints, we developed and tested two recurrent convolutional neural network (RCNN) pattern recognition-based solutions: (1) an RCNN classification controller that uses EMG plus positional inertial measurement unit (IMU) signals to offer one-speed, sequential movement control; and (2) an RCNN regression controller that uses the same data capture technique to offer simultaneous control of multiple movements and device movement velocity. We assessed both RCNN controllers by comparing them to a commonly used linear discriminant analysis classification controller (LDA-Baseline). Participants without upper limb impairment were recruited to perform multipositional tasks while wearing a simulated prosthesis. Both RCNN classification and regression controllers showed improved functional task performance over LDA-Baseline, in 11 and 38 out of 115 metrics, respectively. This work contributes an RCNN regression-based controller that provides accurate, simultaneous, and proportional movements to EMG-based technologies including prostheses, exoskeletons, and even muscle-activated video games.
Transport mechanism of DgoT, a bacterial homolog of SLC17 organic anion transporters

The solute carrier 17 (SLC17) family contains anion transporters that accumulate neu-rotransmitters in secretory vesicles, remove carboxylated monosaccharides from ly-sosomes, or extrude organic anions from the kidneys and the liver. We combined experimental and computational approaches to describe the transport mechanisms of a model bacterial protein, the D-galactonate transporter DgoT, at atomic resolution. We found that protonation of D46 and E133 precedes galactonate binding and that substrate binding induces closure of the extracellular gate, with the conserved R47 coupling substrate binding to transmembrane helix movement. After isomerization to an inward-facing conformation, deprotonation of E133 and subsequent proton trans-fer from D46 to E133 opens the intracellular gate and permits galactonate dissocia-tion. After release of the second proton, apo DgoT returns to the outward-facing con-formation. Our results provide a framework to understand how various SLC17 transport functions with distinct transport stoichiometries can be attained through subtle variations in proton and substrate binding/unbinding.