Embryonic mesenchymal cells are dispersed within an extracellular matrix but can coalesce to form condensates with key developmental roles. Cells within condensates undergo fate and morphological ...changes and induce cell fate changes in nearby epithelia to produce structures including hair follicles, feathers, or intestinal villi. Here, by imaging mouse and chicken embryonic skin, we find that mesenchymal cells undergo much of their dispersal in early interphase, in a stereotyped process of displacement driven by 3 hours of rapid and persistent migration followed by a long period of low motility. The cell division plane and the elevated migration speed and persistence of newly born mesenchymal cells are mechanosensitive, aligning with tissue tension, and are reliant on active WNT secretion. This behaviour disperses mesenchymal cells and allows daughters of recent divisions to travel long distances to enter dermal condensates, demonstrating an unanticipated effect of cell cycle subphase on core mesenchymal behaviour.
Human prostatic tissue exhibits complex mechanical behaviour due to its multiphasic, heterogeneous nature, with hierarchical microstructures involving epithelial compartments, acinar lumens and ...stromal tissue all interconnected in complex networks. This study aims to establish a computational homogenization framework for quantifying the mechanical behaviour of prostate tissue, considering its multiphasic heterogeneous microstructures and the mechanical characteristics of tissue constituents. Representative tissue microstructure models were reconstructed from high‐resolution histology images. Parametric studies on the mechanical properties of the tissue constituents, particularly the fibre‐reinforced hyper‐elasticity of the stromal tissue, were carried out to investigate their effects on the apparent tissue properties. These were then benchmarked against the experimental data reported in literature. Results showed significant anisotropy, both structural and mechanical, and tension‐compression asymmetry of the apparent behaviours of the prostatic tissue. Strong correlation with the key microstructural indices such as area fractions of tissue constituents and the tissue fabric tensor was also observed. The correlation between the stromal tissue orientation and the principal directions of the apparent properties suggested an essential role of stromal tissue in determining the directions of anisotropy and the compression‐tension asymmetry characteristics in normal human prostatic tissue. This work presented a homogenization and histology‐based computational approach to characterize the apparent mechanical behaviours of human prostatic or other similar glandular tissues, with the ultimate aim of assessing how pathological conditions (e.g., prostate cancer and benign prostatic hyperplasia) could affect the tissue mechanical properties in a future study.
This study aims to establish a computational homogenization framework for quantifying the mechanical behaviour of prostate tissue, considering its multiphasic heterogeneous microstructures and the mechanical characteristics of tissue constituents. The results showed significant anisotropy, both structural and mechanical, and tension‐compression asymmetry of the apparent behaviours of the prostatic tissue. Strong correlation with the key microstructural indices such as area fractions of tissue constituents and the tissue fabric tensor was also observed. The correlation between the stromal tissue orientation and the principal directions of the apparent properties suggested an essential role of stromal tissue in determining the directions of anisotropy and the compression‐tension asymmetry characteristics in normal human prostatic tissue.
Fingerprints are complex and individually unique patterns in the skin. Established prenatally, the molecular and cellular mechanisms that guide fingerprint ridge formation and their intricate ...arrangements are unknown. Here we show that fingerprint ridges are epithelial structures that undergo a truncated hair follicle developmental program and fail to recruit a mesenchymal condensate. Their spatial pattern is established by a Turing reaction-diffusion system, based on signaling between EDAR, WNT, and antagonistic BMP pathways. These signals resolve epithelial growth into bands of focalized proliferation under a precociously differentiated suprabasal layer. Ridge formation occurs as a set of waves spreading from variable initiation sites defined by the local signaling environments and anatomical intricacies of the digit, with the propagation and meeting of these waves determining the type of pattern that forms. Relying on a dynamic patterning system triggered at spatially distinct sites generates the characteristic types and unending variation of human fingerprint patterns.
Display omitted
•Early fingerprint ridges are epithelial buds molecularly analogous to hair placodes•Fingerprint ridges do not recruit mesenchymal cells or express late hair follicle markers•Interacting WNT and BMP signaling defines the spacing interval between ridges•Ridge initiations from anatomically variable sites determine fingerprint pattern type
Signaling pathways that determine formation of human fingerprint ridges.
Context
Linear landscape elements (LLEs) such as ditches and hedgerows can increase the ecological connectivity of habitat embedded within agricultural areas by acting as corridors for animal ...movement. However, we lack knowledge on how the spatial arrangement of LLEs influence dispersal, impeding our ability to offer robust advice on how best to add new LLEs to improve connectivity.
Objectives
To examine how the width and spatial orientations of LLEs composing an intersecting network might influence connectivity across landscapes.
Methods
We used an individual-based dispersal model to simulate the stochastic movement of small organisms through stylised LLEs of different characteristics. Landscapes were composed of two habitat patches separated by a grid-like network of LLEs composed of two types: (1)
connecting-edges
(touching patches on either end) and (2)
transecting-edges
(running perpendicular to
connecting-edges
). By altering numbers and widths of each LLE type we sought to understand the effect of these variables on inter-patch dispersal rates.
Results
Increasing the number or width of
connecting-edges
improved connectivity but, conversely, increasing numbers or widths of
transecting-edges
reduced it. The greater freedom of movement offered by increasing numbers of
transecting-edges
may have inhibited connectivity, as individuals with limited perceptual-range were more likely to become trapped in complex networks and thus fail to navigate to suitable habitat patches.
Conclusions
Orientation of LLEs with respect to landscape resources greatly affects their impact on connectivity. The addition of LLEs to landscapes may decrease their connectivity for small, flightless species if they do not directly channel dispersers toward landscape resources.
Recent studies indicate that mammals, including humans, maintain some capacity to renew cardiomyocytes throughout postnatal life. Yet, there is little or no significant cardiac muscle regeneration ...after an injury such as acute myocardial infarction. By contrast, zebrafish efficiently regenerate lost cardiac muscle, providing a model for understanding how natural heart regeneration may be blocked or enhanced. In the absence of lineage-tracing technology applicable to adult zebrafish, the cellular origins of newly regenerated cardiac muscle have remained unclear. Using new genetic fate-mapping approaches, here we identify a population of cardiomyocytes that become activated after resection of the ventricular apex and contribute prominently to cardiac muscle regeneration. Through the use of a transgenic reporter strain, we found that cardiomyocytes throughout the subepicardial ventricular layer trigger expression of the embryonic cardiogenesis gene gata4 within a week of trauma, before expression localizes to proliferating cardiomyocytes surrounding and within the injury site. Cre-recombinase-based lineage-tracing of cells expressing gata4 before evident regeneration, or of cells expressing the contractile gene cmlc2 before injury, each labelled most cardiac muscle in the ensuing regenerate. By optical voltage mapping of surface myocardium in whole ventricles, we found that electrical conduction is re-established between existing and regenerated cardiomyocytes between 2 and 4 weeks post-injury. After injury and prolonged fibroblast growth factor receptor inhibition to arrest cardiac regeneration and enable scar formation, experimental release of the signalling block led to gata4 expression and morphological improvement of the injured ventricular wall without loss of scar tissue. Our results indicate that electrically coupled cardiac muscle regenerates after resection injury, primarily through activation and expansion of cardiomyocyte populations. These findings have implications for promoting regeneration of the injured human heart.
Gene function in cancer is often cell type-specific. The epithelial cell-specific transcription factor ELF3 is a documented tumor suppressor in many epithelial tumors yet displays oncogenic ...properties in others. Here, we show that ELF3 is an oncogene in the adenocarcinoma subtype of lung cancer (LUAD), providing genetic, functional, and clinical evidence of subtype specificity. We discover a region of focal amplification at chromosome 1q32.1 encompassing the ELF3 locus in LUAD which is absent in the squamous subtype. Gene dosage and promoter hypomethylation affect the locus in up to 80% of LUAD analyzed. ELF3 expression was required for tumor growth and a pan-cancer expression network analysis supports its subtype and tissue specificity. We further show that ELF3 displays strong prognostic value in LUAD but not LUSC. We conclude that, contrary to many other tumors of epithelial origin, ELF3 is an oncogene and putative therapeutic target in LUAD.
Abstract
Atom-interferometric quantum sensors could revolutionize navigation, civil engineering, and Earth observation. However, operation in real-world environments is challenging due to external ...interference, platform noise, and constraints on size, weight, and power. Here we experimentally demonstrate that tailored light pulses designed using robust control techniques mitigate significant error sources in an atom-interferometric accelerometer. To mimic the effect of unpredictable lateral platform motion, we apply laser-intensity noise that varies up to 20% from pulse-to-pulse. Our robust control solution maintains performant sensing, while the utility of conventional pulses collapses. By measuring local gravity, we show that our robust pulses preserve interferometer scale factor and improve measurement precision by 10× in the presence of this noise. We further validate these enhancements by measuring applied accelerations over a 200
μ
g
range up to 21× more precisely at the highest applied noise level. Our demonstration provides a pathway to improved atom-interferometric inertial sensing in real-world settings.
Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used ...as clocks in cells where ongoing methylation and demethylation cause repeated 'flip-flops' between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline APC mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).
Oral cancer is a major health problem worldwide. The 5-year survival rate ranges from 30-60%, and has remained unchanged in the past few decades. This is mainly due to late diagnosis and high ...recurrence of the disease. Of the patients who receive treatment, up to one third suffer from a recurrence or a second primary tumor. It is apparent that one major cause of disease recurrence is clinically unrecognized field changes which extend beyond the visible tumor boundary. We have previously developed an approach using fluorescence visualization (FV) technology to improve the recognition of the field at risk surrounding a visible oral cancer that needs to be removed and preliminary results have shown a significant reduction in recurrence rates.
This paper describes the study design of a randomized, multi-centre, double blind, controlled surgical trial, the COOLS trial. Nine institutions across Canada will recruit a total of 400 patients with oral severe dysplasia or carcinoma in situ (N = 160) and invasive squamous cell carcinoma (N = 240). Patients will be stratified by participating institution and histology grade and randomized equally into FV-guided surgery (experimental arm) or white light-guided surgery (control arm). The primary endpoint is a composite of recurrence at or 1 cm within the previous surgery site with 1) the same or higher grade histology compared to the initial diagnosis (i.e., the diagnosis used for randomization); or 2) further treatment due to the presence of severe dysplasia or higher degree of change at follow-up. This is the first randomized, multi-centre trial to validate the effectiveness of the FV-guided surgery.
In this paper we described the strategies, novelty, and challenges of this unique trial involving a surgical approach guided by the FV technology. The success of the trial requires training, coordination, and quality assurance across multiple sites within Canada. The COOLS trial, an example of translational research, may result in reduced recurrence rates following surgical treatment of early-stage oral cancer with significant impacts on survival, morbidity, patients' quality of life and the cost to the health care system.
Clinicaltrials.gov NCT01039298.
PDF
