The stele concept is one of the oldest enduring concepts in plant biology. This paper reviews the concept and its foundations, and builds an argument for an updated view of steles and their evolution. The history of studies of stelar organization has generated a widely ranging array of definitions of the stele that determine the way we classify steles and construct scenarios about the evolution of stelar architecture. Because at the level of the organism biological evolution proceeds by, and is reflected in, changes in development, concepts of structure need to be grounded in development in order to be relevant in an evolutionary perspective. For the stele, most of the traditional definitions that incorporate development have viewed it as the totality of tissues that either originate from procambium – currently the prevailing view – or are bordered by a boundary layer (e.g., endodermis). A definition of the stele that would bring consensus between these perspectives recasts the stele as a structural entity of dual nature. Here, I review briefly the history of the stele concept, basic terminology related to stelar organization, and traditional classifications of the steles. I then revisit boundary layers from the perspective of histogenesis as a dynamic mosaic of developmental domains. I use classic and recent anatomical and molecular data to reaffirm and explore the importance of boundary layers for stelar organization. Drawing on data from comparative anatomy, developmental regulation, and the fossil record, I offer a model for a stele concept that integrates both the boundary layer and the procambial perspective, consistent with a dual nature of the stele. The dual stele model posits that stelar architecture is determined in the apical meristem by two major cell fate specification events: a first one that specifies a provascular domain and its boundaries, and a second event that specifies a procambial domain (which will mature into conducting tissues) from cell subpopulations of the provascular domain. If the position and extent of the developmental domains defined by the two events are determined by different concentrations of the same morphogen (most likely auxin), then the distribution of this organizer factor in the shoot apical meristem, as modulated by changes in axis size and the effect of lateral organs, can explain the different stelar configurations documented among tracheophytes. This model provides a set of working hypotheses that incorporate assumptions and generate implications that can be tested empirically. The model also offers criteria for an updated classification of steles that is in line with current understanding of plant development. In this classification, steles fall into two major categories determined by the configuration of boundary layers – boundary protosteles and boundary siphonosteles, each with subtypes defined by the architecture of the vascular tissues. Validation the dual stele model and, more generally, in-depth understanding of the regulation of stelar architecture, will necessitate targeted efforts in two areas: (i) the regulation of procambium, vascular tissue, and boundary layer specification in all extant vascular plants, considering that most of the diversity in stelar architecture is hosted by seed-free plants, which are the least explored in terms of developmental regulation; (ii) the configuration of vascular tissues and, especially, boundary layers, in as many extinct species and lineages as possible.

Placenta-derived mesenchymal stem cells (PD-MSCs) have been highlighted as therapeutic sources in several degenerative diseases. Recently, microRNAs (miRNAs) were mediated one of the therapeutic mechanisms of PD-MSCs in regenerative medicine. To enhance the therapeutic effects of PD-MSCs, we established functionally enhanced PD-MSCs with phosphatase of regenerating liver-1 overexpression (PRL-1(+)). However, the profile and functions of miRNAs induced by PRL-1(+) PD-MSCs in a rat model with hepatic failure prepared by bile duct ligation (BDL) remained unclear. Hence, the objectives of the present study were to analyze the expression of miRNAs and investigate their therapeutic mechanisms for hepatic regeneration via PRL-1(+) in a rat model with BDL. We selected candidate miRNAs based on microarray analysis. Under hypoxic conditions, compared with invaded naïve PD-MSCs, invaded PRL-1(+) PD-MSCs showed improved integrin-dependent migration ability through RHO family-targeted miRNA expression (e.g., hsa-miR-30a-5p, 340-5p, and 146a-3p). Moreover, rno-miR-30a-5p and 340-5p regulated engraftment into injured rat liver by transplanted PRL-1(+) PD-MSCs through the integrin family. Additionally, an increase in PDGFRA by suppressing rno-miR-27a-3p improved vascular structure in rat liver tissues after PRL-1(+) PD-MSCs transplantation. Furthermore, decreased rno-miR-122-5p was significantly correlated with increased proliferation of hepatocytes in liver tissues by PRL-1(+) PD-MSCs by activating IL-6 signaling pathway through the repression of rno-miR-21-5p. Taken together, these findings improve the understanding of therapeutic mechanisms based on miRNA-mediated stem cell therapy in liver diseases.

Background: Vascular inflammation plays a crucial role in peripheral arterial disease (PAD), although the role of the mediators involved has not yet been properly defined. The aim of this work is to investigate gene expression and plasma biomarkers in chronic limb-threating ischemia (CLTI). Methods: Using patients from the GHAS trial, both blood and ischemic muscle samples were obtained to analyze plasma markers and mRNA expression, respectively. Statistical analy-sis was performed by using univariate (Spearman, t-Student, X2) and multivariate (multiple lo-gistic regression) tests. Results: 35 patients were available at baseline (29 for mRNA expression). Baseline characteristics (mean): Age:71.4±12.4 (79.4% male); TNF-α:10.7±4.9; hs-CRP:1.6±2.2; Neutrophil-to-lymphocyte ratio (NLR):3.5±2.8. Plasma TNF-α was found elevated (≥8.1) in 68.6% of patients, while high hs-CRP (≥0.5) in 60.5%. Diabetic patients with high level of inflammation showed significantly higher levels of NOX4 expression at baseline (p=0.0346). Plasma TNF-α had a negative correlation with eNOS expression (-0.5, p=0.015) and hs-CRP with VEGF-A (-0.63, p=0.005). The expression of NOX4 was parallel to that of plasma TNF-α (0.305, p=0.037), especial-ly in DM. Cumulative mortality at 12-month was related to NLR ≥3 (p=0.019) and TNF-α ≥8.1 (p=0.048). The best cut-off point for NLR to predict mortality was 3.4. Conclusions: NOX4 and TNF-α are crucial for the development and complications of lower limb ischemia, especially in DM. hs-CRP could have a negative influence on angiogenesis too. NLR and TNF-α represent suita-ble markers of mortality in CLTI. These results are novel because they connect muscle gene expres-sion and plasma information in patients with advanced PAD, deepening the search of new and ac-curate targets for this condition.

A recent study published in Nature Medicine (Mautner et al., Nat Med 2023 Nov 2. doi: 10.1038/s41591-023-02632-w. Epub ahead of print) reported findings regarding a four-arm parallel, multicenter, single-blind, randomized, controlled clinical trial with 480 patients, aimed at comparing the therapeutic effectiveness of orthobiologic interventions against corticosteroid injections for the treatment of knee osteoarthritis (OA). The study concluded that, one-year post-treatment, all orthobiologic therapies examined were equivalent in effectiveness to each other and to corticosteroid injections. While we commend the scope and methodological rigor of the trial, the publication could be enhanced by a more comprehensive presentation of data to support the conclusions drawn. Particularly, the omission of baseline data for primary outcomes, the missing context to evaluate absolute values, the lack of discussion regarding interindividual variability, and the unexpectedly favorable results for corticosteroids that contrast the established literature, are areas that merit additional examination and insight. Here we aim to highlight these points for consideration, and advocate for the release of supplementary data to facilitate a comprehensive understanding and utilization of this rich dataset.

Cornea severe inflammation produces opacity or even perforation, scarring, and angiogenesis, resulting in blindness. The cornea can be used to study the effect of new anti-angiogenic chemopreventive agents. We researched the anti-angiogenic effect of two extracts, Methanol (Met) and Hexane (Hex), from the seed of Cucurbita argyrosperma, in the inflamed corneas. The corneas of Wistar rats were alkali-injured and treated intragastrically for seven successive days. Clinical manifestation as opacity score, corneal neovascularization (CNV) area, re-epithelialization percentage, and histological evaluation were performed. Inflammatory (COX-2, NF-κB, and IL-1β), and angiogenic (VEGF-A, VEGFR1, VEGFR2) markers were assessed by immunohistochemistry. Cox-2, Il-1β, and Vegf-a mRNA levels were also determined. After treatments, we observed slim corneal thickness with lower opacity scores and low cell infiltration compared to untreated rats. Treatment also accelerated wound healing and decreased CNV area. The staining of inflammatory and angiogenic factors was significantly decreased. These effects are related to a down-expression of Cox-2, Il-1β, and Vegf. These results suggest that intake of C. argyrosperma seed can be used to attenuate the angiogenesis secondary to inflammation in corneal chemical damage.

Alzheimer’s disease (AD) and the therapies of AD with anti-amyloid1-42 (Aβ) monoclonal antibodies are associated with the vascular complications of brain edema, hemorrhage, and cerebral amyloid angiopathy (CAA) termed amyloid-related imaging abnormalities (ARIAs). The neuropathology of normal and AD brains demonstrates that monocyte/macrophages (MMs) are critical in successful brain clearance in healthy brain by up-loading, transporting, and degrading Aβ but fail degradation and clearance in AD patients by releasing Aβ into vessels at the blood-brain barrier, causing vasculitis and ARIAs. The naturally-formed epoxides (EpFAs) of polyunsaturated fatty acids (PUFA’s), including arachidonic, docosahexaenoic, and eicosapentaenoic fatty acids, may repair degradation of Aβ by regulating Aβ-degrading enzymes, inflammatory cytokines, and unfolded protein response (UPR) to endoplasmic reticulum stress in a homeostatic fashion. EpFAs are, however, degraded by the soluble epoxide hydrolase enzyme (sEH) but are protected by the sEH inhibitor (sEHI) TPPU. In the cultures of AD patients’ macrophages, TPPU with the epoxide EEQ, and the cGAS/STING inhibitor H-151 increased uptake of Aβ at 2 hours and degradation of Aβ at 24 hours. In conclusion, the soluble epoxide hydrolase inhibitor TPPU with omega-3 fatty acids and the cGAS/STING inhibitor H-151 increase Aβ uptake and degradation in macrophages of AD patients, and potentially enhancing Aβ clearance in the AD brain.

In plants, water flows are the major driving force behind the growth and play a crucial role in the life cycle. To study hydrodynamics, methods based on tracking small particles inside water flows occupy a special place. Due to these tools, it is possible to get information about the dynamics of the spatial distribution of the fluxes characteristics. In this paper, using contrast-enhanced MRI, we have shown that gadolinium chelate, used as an MRI contrast agent, marks the structural characteristics of xylem bundles of maize stem nodes and internodes. Supplementing MRI data, a high-precision visualization of xylem vessels by laser scanning microscopy was used to reveal structural and dimensional characteristics of the stem vascular system. In addition, we proposed the concept of using the prototype "Y-type xylem vascular bundles" as a model of the elementary connection of vessels within the vascular system. A Reynolds number can match the microchannel model with the real xylem vessels.

Alzheimer's disease (AD) is the most prevalent form of dementia. With the global aging population, the incidence of AD and related dementias is projected to rise dramatically, posing significant public health challenges. Traditionally, the diagnosis of AD has relied on the detection of amyloid-beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau in the brain, assessed through invasive cerebrospinal fluid (CSF) analysis and costly positron emission tomography scans. However, these methods are not feasible for widespread screening or use in low-resource settings. Recent advances in blood-based biomarkers offer a promising alternative for the early detection and monitoring of AD. These biomarkers provide a minimally invasive, cost-effective means of tracking the pathological progression of AD before the onset of clinical symptoms, potentially enabling earlier and more accurate diagnosis. Blood-based biomarkers, including those related to Aβ, phosphorylated tau, and neurofilament light polypeptide, have demonstrated significant potential in reflecting the underlying neuropathology of AD and correlating with traditional CSF and imaging biomarkers. This review synthesizes the latest research on blood-based biomarkers in AD, highlighting their role in the disease's etiopathogenesis, diagnostic accuracy, and prognostic value. We discuss the emerging evidence on proteinopathies, neuroinflammation, vascular pathology, and bioenergetic profiles, emphasizing the clinical applicability of these biomarkers. Furthermore, we explore the integration of blood-based biomarkers with advanced neuroimaging techniques and their potential to revolutionize the diagnostic landscape of AD, particularly in resource-limited settings. We have integrated protein-protein interaction (PPI) and miRNA network analyses to enhance the analysis. By incorporating these, we can explore the interactions and relationships between different proteomic, genomic, and epigenomic biomarkers, potentially unveiling new insights into the underlying biological mechanisms of AD. The continued development and validation of these biomarkers could lead to more accessible and equitable AD diagnostics, ultimately improving patient outcomes.

Endometriosis is an oestrogen-dependant reproductive disease, with genetic, vascular, neural, inflammatory and auto-immune characteristics. There are many theories about the etiology of endometriosis, however, all of these theories have limitations and do not explain all the locations that endometriosis is found or types of patients with endometriosis. The objective of this paper is to postulate the hypothesis that endometriosis is caused by Maternal Microchimerism, the presence of maternal cells in the fetus. A literature review was conducted, analysing the characteristics, current etiological theories of endometriosis, theory limitations and relationship of maternal microchimerism and endometriosis. At time of writing, there was no literature on maternal microchimerism and endometriosis. These results suggest that Maternal Microchimerism could be a cause of endometriosis. This could account for the genetic and auto-immune characteristics seen in people with endometriosis, inducing a micro-environment for vascular, neural and epigenetic changes. This could also account for account for endometriosis seen in non-menstruating patients, such as men, fetuses and post-menopausal women and endometriosis found in non-peritoneal locations. If the hypothesis of Maternal Microchimerism is correct, endometriosis could be considered a pregnancy-related disease that could affect all humans, changing the accepted demographics of patients and potentially new diagnostic techniques and treatment options for patients with endometriosis. Further studies are needed to test this hypothesis.

To investigate factors associated with the success of switching to faricimab for type 1 macular neovascularization (MNV) refractory to intravitreal aflibercept (IVA). This retrospective cohort study included patients with type 1 MNV who were switched to faricimab because they were refractory to IVA at two centers. The main outcome was an extension of the treatment interval after 6 months, and factors related to the success or failure of the extension and visual and anatomical outcomes were assessed. The analysis included 43 eyes of 43 patients. Extended dosing intervals of more than 2 weeks were identified in 14 eyes (32.6%). A short dosing interval before the switch, the absence of polypoidal lesions, and a thin central choroidal thickness before the switch were identified as factors involved in successful extension. For patients with refractory type 1 MNV, switching to faricimab is a safe and potential option to extend from existing dosing intervals.

Fossils constitute the principal repository of data that allow for independent tests of hypotheses of biological evolution derived from observations of the extant biota. Traditionally, transformational series of structure, consisting of sequences of fossils of the same lineage through time, have been employed to reconstruct and interpret morphological evolution. More recently, a move toward an updated paradigm was fueled by the deliberate integration of developmental thinking in the inclusion of fossils in reconstruction of morphological evolution. The vehicle for this is provided by structural fingerprints – recognizable morphological and anatomical structures generated by (and reflective of) the deployment of specific genes and regulatory pathways during development. Furthermore, because the regulation of plant development is both modular and hierarchical in nature, combining structural fingerprints recognized in the fossil record with our understanding of the developmental regulation of those structures produces a powerful tool for understanding plant evolution. This is particularly true when the systematic distribution of specific developmental regulatory mechanisms and modules is viewed within an evolutionary (paleo-evo-devo) framework. Here, we discuss several advances in understanding the processes and patterns of evolution, achieved by tracking structural fingerprints with their underlying regulatory modules across lineages, living and fossil: the role of polar auxin regulation in the cellular patterning of secondary xylem and the parallel evolution of arborescence in lycophytes and seed plants; the morphology and life history of early polysporangiophytes and tracheophytes; the role of modularity in the parallel evolution of leaves in euphyllophytes; leaf meristematic activity and the parallel evolution of venation patterns among euphyllophytes; mosaic deployment of regulatory modules and the diverse modes of secondary growth of euphyllophytes; modularity and hierarchy in developmental regulation and the evolution of equisetophyte reproductive morphology. More generally, inclusion of plant fossils in the evo-devo paradigm has informed discussions on the evolution of growth patterns and growth responses, sporophyte body plans and their homology, sequences of character evolution, and the evolution of reproductive systems.

This case report demonstrates the rare but potentially serious complication of pulmonary vein stenosis (PVS) diagnosed several years after radiofrequency ablation for atrial fibrillation. Pulmonary vein stenosis can remain asymptomatic until significant occlusion occurs, after which it can present with a variety of symptoms, mimicking numerous cardiovascular and pulmonary pathologies. Early diagnosis and treatment rely on consistent follow-up using appropriate diagnostic imaging modalities, which are paramount in preventing severe complications.