Miracle-dz/UniFAR-FTUs huggingface dataset:
Modelling cell guidance and curvature control in evolving biological tissues

Tissue geometry is an important influence on the evolution of many biological tissues. The local curvature of an evolving tissue induces tissue crowding or spreading, which leads to differential tissue growth rates, and to changes in cellular tension, which can influence cell behaviour. Here, we investigate how directed cell motion interacts with curvature control in evolving biological tissues. Directed cell motion is involved in the generation of angled tissue growth and anisotropic tissue material properties, such as tissue fibre orientation. We develop a new cell-based mathematical model of tissue growth that includes both curvature control and cell guidance mechanisms to investigate their interplay. The model is based on conservation principles applied to the density of tissue synthesising cells at or near the tissue’s moving boundary. The resulting mathematical model is a partial differential equation for cell density on a moving boundary, which is solved numerically using a hybrid front-tracking method called the cell-based particle method. The inclusion of directed cell motion allows us to model new types of biological growth, where tangential cell motion is important for the evolution of the interface, or for the generation of anisotropic tissue properties. We illustrate such situations by applying the model to simulate both the resorption and infilling components of the bone remodelling process, and provide user-friendly MATLAB code to implement the algorithms.
Ventricular, atrial, and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak

The heart develops from two sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single cell transcriptomic assay in combination with genetic lineage tracing, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are pre-patterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function and disease.
SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function

Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.
Both Default and Multiple-Demand Regions Represent Semantic Goal Information

We used a semantic feature-matching task combined with multivoxel pattern decoding to test contrasting accounts of the role of the default mode network (DMN) in cognitive flexibility. By one view, DMN and multiple-demand cortex have opposing roles in cognition, with DMN and multiple-demand regions within the dorsal attention network (DAN) supporting internal and external cognition, respectively. Consequently, while multiple-demand regions can decode current goal information, semantically relevant DMN regions might decode conceptual similarity regardless of task demands. Alternatively, DMN regions, like multiple-demand cortex, might show sensitivity to changing task demands, since both networks dynamically alter their patterns of connectivity depending on the context. Our task required human participants (any sex) to integrate conceptual knowledge with changing task goals, such that successive decisions were based on different features of the items (color, shape, and size). This allowed us to simultaneously decode semantic category and current goal information using whole-brain searchlight decoding. As expected, multiple-demand cortex, including DAN and frontoparietal control network, represented information about currently relevant conceptual features. Similar decoding results were found in DMN, including in angular gyrus and posterior cingulate cortex, indicating that DMN and multiple-demand regions can support the same function rather than being strictly competitive. Semantic category could be decoded in lateral occipital cortex independently of task demands, but not in most regions of DMN. Conceptual information related to the current goal dominates the multivariate response within DMN, which supports flexible retrieval by modulating its response to suit the task demands, alongside regions of multiple-demand cortex. SIGNIFICANCE STATEMENT We tested contrasting accounts of default mode network (DMN) function using multivoxel pattern analysis. By one view, semantically relevant parts of DMN represent conceptual similarity, regardless of task context. By an alternative view, DMN tracks changing task demands. Our semantic feature-matching task required participants to integrate conceptual knowledge with task goals, such that successive decisions were based on different features of the items. We demonstrate that DMN regions can decode the current goal, as it is applied, alongside multiple-demand regions traditionally associated with cognitive control, speaking to how DMN supports flexible cognition.
Quantifying the effects of switchgrass (Panicum virgatum) on deep organic C stocks using natural abundance 14C in three marginal soils

Perennial bioenergy crops have been shown to increase soil organic carbon (SOC) stocks, potentially offsetting anthropogenic C emissions. The effects of perennial bioenergy crops on SOC are typically assessed at shallow depths (< 30 cm), but the deep root systems of these crops may also have substantial effects on SOC stocks at greater depths. We hypothesized that deep (> 30 cm) soil organic carbon (SOC) stocks would be greater under bioenergy crops relative to stocks under shallow-rooted conventional crop cover. To test this, we sampled soils to between 1- and 3-meters depth at three sites in Oklahoma with 10-20 year old switchgrass (Panicum virgatum) stands, and collected paired samples from nearby fields cultivated with shallow rooted annual crops. We measured root biomass, total organic C, 14C, 13C, and other soil properties in three replicate soil cores in each field and used a mixing model to estimate the proportion of recently fixed C under switchgrass based on 14C. The subsoil C stock under switchgrass (defined over 500-1500 kg m-2 equivalent soil mass, approximately 30-100 cm depth) exceeded the subsoil stock in neighboring fields by 1.5 kg C m-2 at a sandy loam site, 0.6 kg C m-2 at a site with loam soils, and showed no significant difference at a third site with clay soils. Using the mixing model, we estimated that additional SOC introduced after switchgrass cultivation comprised 31% of the subsoil C stock at the sandy loam site, 22% at the loam site, and 0% at the clay site. These results suggest that switchgrass can contribute significantly to subsoil organic C—but also indicated that this effect varies across sites. Our analysis shows that agricultural strategies that emphasize deep-rooted grass cultivars can increase soil C relative to conventional crops while expanding energy biomass production on marginal lands.
Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease

The emergence of SARS-CoV-2 has created an international health crisis. Small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection due to low affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promotor. In contrast to non-transgenic mice, intranasal exposure of K18-hACE2 animals to two different doses of SARS-CoV-2 resulted in acute disease including weight loss, lung injury, brain infection and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals revealed increases in transcripts involved in lung injury and inflammatory cytokines. In the lower dose challenge groups, there was a survival advantage in the female mice with 60% surviving infection whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared to female mice. This is the first highly lethal murine infection model for SARS-CoV-2. The K18-hACE2 murine model will be valuable for the study of SARS-CoV-2 pathogenesis and the assessment of MCMs.
Single-Nucleus RNA-Seq Reveals Dysregulation of Striatal Cell Identity Due to Huntington's Disease Mutations

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, HttQ175/+, and from wild-type controls. We used 14- to 15-month-old male mice, a time point at which multiple behavioral, neuroanatomical, and neurophysiological changes are present but at which there is no known cell death. Thousands of differentially expressed genes (DEGs) were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell type-specific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes. Typically, these genes were repressed in their primary cell type, yet de-repressed in other striatal cell types. Integration with existing epigenomic and transcriptomic data suggest that partial loss-of-function of the polycomb repressive complex 2 (PRC2) may underlie many of these transcriptional changes, leading to deficits in the maintenance of cell identity across virtually all cell types in the adult striatum. SIGNIFICANCE STATEMENT Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by specific loss of medium spiny neurons (MSNs) in the striatum, accompanied by more subtle changes in many other cell types. It is thought that changes in transcriptional regulation are an important underlying mechanism, but cell type-specific gene expression changes are not well understood, particularly at time points relevant to the onset of disease-related symptoms. Single-nucleus (sn)RNA-seq in a genetically precise mouse model enabled us to identify novel patterns of transcriptional dysregulation because of HD mutations, including bidirectional dysregulation of many cell type identity genes that may be driven by partial loss-of-function of the polycomb repressive complex (PRC). Identifying these regulators of transcriptional dysregulation in HD can be leveraged to design novel disease-modifying therapeutics.
A formin-mediated cell wall- plasma membrane- cytoskeleton continuum is required for symbiotic infections in Medicago truncatula

Plant cell infections are tightly orchestrated by cell wall (CW) alterations, plasma membrane (PM) resident signalling processes and dynamic remodelling of the cytoskeleton. During root nodule symbiosis these processes result in morpho-dynamic responses including root hair swelling and curling, PM invagination and polar growth of a tubular infection structure, the infection thread (IT). However, the molecular details driving and guiding these PM remodelling events remain to be unravelled. Here, we studied a formin protein (SYFO1) in M. truncatula that is specifically induced during rhizobial infection. Phenotypical analysis of syfo1 mutants clearly indicates that the encoded protein is required for efficient rhizobial colonization of root hairs. SYFO1 itself creates a proteinaceous bridge between the CW and the polarized cytoskeleton. It binds to CW components via a proline-rich N-terminal segment, which is indispensable for its function. On the cytoplasmic side of the PM SYFO1 is associated with actin accumulations supporting the hypothesis that it contributes to cell polarization in vivo. This is further sustained by the fact that cell shape changes can be induced in a stimulus-dependent manner in root protoplasts expressing SYFO1. Taken together we provide evidence for the evolutionary re-wiring of a generic cytoskeleton modulator into a symbiosis-specific response.
Metabolism of the gravid uterus, foetus and utero-placenta at several stages of gestation in cows

Summary To quantify changes in rates of metabolism and nutrient uptake of gravid uteiine, foetal and utero-placental tissues throughout gestation, mature Hereford cows received surgery at 132 ± 0·6 (n = 12), 176 ± 0·5 (n = 8), 220 ±0·4 (n = 11) and 245 ±1·5 (n = 7) days after mating. Indwelling catheters were implanted into a uterine artery and vein of all cows. Foetal catheters also were implanted into an umbilical vein and foetal femoral artery and vein (days 176 and 220) or into a placental artery and two placental veins (days 132 and 245). Approximately 5 days after surgery, deuterium oxide was infused into a foetal femoral venous or placental venous catheter during a 3 h period to quantify uterine and umbilical blood flows by steady-state diffusion methods. Oxygen, glucose, lactate and α-amino acid nitrogen concentrations were determined for uterine and foetal blood samples collected during this procedure. Uterine blood flow increased 4·5-fold (2·92–13·181/min) and umbilical blood flow increased 21-fold (0·28–5·861–min) during the interval of gestation studied. The relative rate of increase of umbilical blood flow was about twice as great as that of uterine blood flow. Uterine arterial and umbilical venous concentrations as well as uterine arterial-venous and umbilical venous-arterial concentration differences in metabolites changed little with stage of gestation. However, because rates of blood flow increased, uptakes of O2, glucose and α-amino N by the gravid uterus and foetus increased as gestation advanced. The proportion of gravid uterine uptakes utilized by the foetus increased from day 137 to 226 for O2 (24–58%) and from day 137 to 180 for glucose (4–19%), then remained relatively constant. The proportion of gravid uterine α-amino N uptake utilized by the foetus remained relatively constant and averaged 60%. A net secretion of lactate from the utero-placenta to the uterine and foetal circulations was observed and increased as gestation advanced. These data indicate that increased rates of uptake or secretion of metabolites by tissues of the gravid uterus can be explained primarily by increased rates of uterine and umbilical blood flows.
Effect of acute low oxygen exposure on the proliferation rate, viability and gene expression of C2C12 myoblasts in vitro

INTRODUCTION Changes in the oxygen concentration of cellular microenvironments play a significant role in regulating cell function during muscle regeneration. Generally, most in-vitro cell culture experiments have been carried out in atmospheric conditions with 21% O2, which compared to the actual micro-environment of mature skeletal muscle of between 1% and 10% pO2 is extremely hyperoxic (Li et al, 2007). Culturing skeletal muscle cells in vitro within their typical physiologically hypoxic environment in situ (2-10% pO2) has been shown to increase proliferation rate, reduce apoptosis and increase multiple MRF gene expressions, compared to culturing in a normoxic environment (21% O2). However, chronic exposure (>24 hr) to a semi-severe hypoxic environment (≤5% O2) can lead to a decrease in cell proliferation and differentiation (Chakravarthy et al, 2001). The effects of acute hypoxic exposure (24 h) has limited research and could be important in understanding the effects of hypoxia on skeletal muscle during brief exposures such as those observed within intermittent hypoxic training programmes. The purpose of this work was to examine the role of acute hypoxia (24 h) on C2C12 proliferation and relevant gene expression in 2D culture. METHODS C2C12 mouse myoblast cells were seeded into six well plates. The cells were maintained in DMEM with 20% FCS. C2C12 myoblasts were either exposed to 21% or 5% O2. The effects of acute hypoxic exposure (24hours) at different time points during the proliferative phase of myogenesis, rather than chronic exposure, on cell proliferation, cellular viability and myogenic regulatory factor gene expression was examined. At 24, 48, 72 and 96 hours RNA was extracted using the Trizol® method and mRNA expression of myogenic regulatory factors, myoD, myf5 and myogenin were detected using the 2-ΔΔCT method. Cell counts and cell viability were also quantified RESULTS No significant difference was found between cells cultured in normoxic conditions (21%) and those that were exposed to low oxygen conditions for 24hours at various time points over a 96 hour culture period, with regards to proliferation rate, cell viability, and myogenic regulatory gene expression (Myf5, MyoD and Myogenin). DISCUSSION The effect of acute low oxygen exposure lasting 24hours appears to not be insufficient in having an effect on the proliferation rate, viability or transcription factor expression of C2C12 cells during the proliferative phase of myogenesis.
A transcriptional regulatory circuit for the photosynthetic acclimation of microalgae to carbon dioxide limitation

In green microalgae, prolonged exposure to inorganic carbon depletion requires long-term acclimation responses, based on a modulated expression of genes and adjusting photosynthetic activity to the prevailing supply of carbon dioxide. Here, we depict a microalgal regulatory cycle, adjusting the light-harvesting capacity at PSII to the prevailing supply of carbon dioxide in Chlamydomonas reinhardtii. It engages a newly identified low carbon dioxide response factor (LCRF), which belongs to the Squamosa promoter binding protein (SBP) family of transcription factors, and the previously characterized cytosolic translation repressor NAB1. LCRF combines a DNA-binding SBP domain with a conserved domain for protein-protein interactions and transcription of the LCRF gene is rapidly induced by carbon dioxide depletion. LCRF activates transcription of the NAB1 gene by specifically binding to tetranucleotide motifs present in its promoter. Accumulation of the NAB1 protein enhances translational repression of its prime target mRNA, encoding the PSII-associated major light-harvesting protein LHCBM6. The resulting reduction of the PSII antenna size helps maintaining a low excitation during the prevailing carbon dioxide limitation. Analyses of low carbon dioxide acclimation in nuclear insertion mutants devoid of a functional LCRF gene confirm the essentiality of this novel transcription factor for the regulatory circuit.
Somatotopic specificity of perceptual and neurophysiological changes associated with visuo-proprioceptive realignment

Spatial realignment of visual and proprioceptive estimates of hand position can occur in response to a perturbation. E.g., viewing the hand underwater while washing dishes. This form of multisensory perceptual learning presumably affects perceived hand position, which is used in movement planning. Consistent with this idea, we recently observed changes in motor cortex (M1) index finger representation associated with visuo-proprioceptive misalignment at that fingertip (Munoz-Rubke et al., 2017). In three experiments with healthy human participants, we asked whether these changes are specific to the brain’s representation of the misaligned finger (somatotopically focal), or whether they extend to other parts of the hand and arm that would be needed to move the misaligned finger (somatotopically broad). In Experiments 1 and 2, participants experienced misaligned or veridical visuo-proprioceptive information about the index fingertip. Before and after the perceptual alignment task, we used transcranial magnetic stimulation (TMS) to assess M1 representation of five hand and arm muscles. The index finger representation showed the expected association between M1 excitability and visuo-proprioceptive realignment, as did the pinkie finger representation to a lesser extent. Forearm flexors, forearm extensors, and biceps did not show any such relationship. In Experiment 3, we asked subjects to indicate their proprioceptive estimate of the fingertip, knuckle, wrist, and elbow, before and after misalignment at the fingertip. Proprioceptive realignment at the knuckle, but not the wrist or elbow, was correlated with realignment at the fingertip. These results suggest the effects of perceptual perturbation are somatotopically focal in both sensory and motor domains. Significance Statement Multisensory and motor processing have largely been examined separately, limiting our understanding of how these systems interact. Motor adaptation is thought to affect somatosensory perception and neurophysiology, but the reverse interaction, an effect of perceptual learning on the motor system, has rarely been considered. Here we examine the effect of a somatotopically localized visuo-proprioceptive perturbation on motor neurophysiology and conscious perception. We found somatotopically-focal effects in both domains. This correspondence highlights the tight relationship between sensory and motor systems, but also raises the possibility that perceptual learning may not generalize to other body parts as motor learning does. Rather, it appears to create a localized distortion in the multisensory body representation, with correspondingly local changes in the motor cortex representation.