The Proliferation and Differentiation of Adipose-Derived Stem Cells in Neovascularization and Angiogenesis.

Neovascularization and angiogenesis are vital processes in the repair of damaged tissue, creating new blood vessel networks and increasing oxygen and nutrient supply for regeneration. The importance of Adipose-derived Mesenchymal Stem Cells (ASCs) contained in the adipose tissue surrounding blood vessel networks to these processes remains unknown and the exact mechanisms responsible for directing adipogenic cell fate remain to be discovered. As adipose tissue contains a heterogenous population of partially differentiated cells of adipocyte lineage; tissue repair, angiogenesis and neovascularization may be closely linked to the function of ASCs in a complex relationship. This review aims to investigate the link between ASCs and angiogenesis/neovascularization, with references to current studies. The molecular mechanisms of these processes, as well as ASC differentiation and proliferation are described in detail. ASCs may differentiate into endothelial cells during neovascularization; however, recent clinical trials have suggested that ASCs may also stimulate angiogenesis and neovascularization indirectly through the release of paracrine factors.

HyperQuaternionE: A hyperbolic embedding model for qualitative spatial and temporal reasoning.

Qualitative spatial/temporal reasoning (QSR/QTR) plays a key role in research on human cognition, e.g., as it relates to navigation, as well as in work on robotics and artificial intelligence. Although previous work has mainly focused on various spatial and temporal calculi, more recently representation learning techniques such as embedding have been applied to reasoning and inference tasks such as query answering and knowledge base completion. These subsymbolic and learnable representations are well suited for handling noise and efficiency problems that plagued prior work. However, applying embedding techniques to spatial and temporal reasoning has received little attention to date. In this paper, we explore two research questions: (1) How do embedding-based methods perform empirically compared to traditional reasoning methods on QSR/QTR problems? (2) If the embedding-based methods are better, what causes this superiority? In order to answer these questions, we first propose a hyperbolic embedding model, called HyperQuaternionE, to capture varying properties of relations (such as symmetry and anti-symmetry), to learn inversion relations and relation compositions (i.e., composition tables), and to model hierarchical structures over entities induced by transitive relations. We conduct various experiments on two synthetic datasets to demonstrate the advantages of our proposed embedding-based method against existing embedding models as well as traditional reasoners with respect to entity inference and relation inference. Additionally, our qualitative analysis reveals that our method is able to learn conceptual neighborhoods implicitly. We conclude that the success of our method is attributed to its ability to model composition tables and learn conceptual neighbors, which are among the core building blocks of QSR/QTR.

The potential of gene therapies for spinal cord injury repair: a systematic review and meta-analysis of pre-clinical studies.

Currently, there is no cure for traumatic spinal cord injury but one therapeutic approach showing promise is gene therapy. In this systematic review and meta-analysis, we aim to assess the efficacy of gene therapies in pre-clinical models of spinal cord injury and the risk of bias. In this meta-analysis, registered at PROSPERO (Registration ID: CRD42020185008), we identified relevant controlled in vivo studies published in English by searching the PubMed, Web of Science, and Embase databases. No restrictions of the year of publication were applied and the last literature search was conducted on August 3, 2020. We then conducted a random-effects meta-analysis using the restricted maximum likelihood estimator. A total of 71 studies met our inclusion criteria and were included in the systematic review. Our results showed that overall, gene therapies were associated with improvements in locomotor score (standardized mean difference [SMD]: 2.07, 95% confidence interval [CI]: 1.68-2.47, Tau2 = 2.13, I2 = 83.6%) and axonal regrowth (SMD: 2.78, 95% CI: 1.92-3.65, Tau2 = 4.13, I2 = 85.5%). There was significant asymmetry in the funnel plots of both outcome measures indicating the presence of publication bias. We used a modified CAMARADES (Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies) checklist to assess the risk of bias, finding that the median score was 4 (IQR: 3-5). In particular, reports of allocation concealment and sample size calculations were lacking. In conclusion, gene therapies are showing promise as therapies for spinal cord injury repair, but there is no consensus on which gene or genes should be targeted.

Semantically-enabled sensor plug & play for the sensor web.

Environmental sensors have continuously improved by becoming smaller, cheaper, and more intelligent over the past years. As consequence of these technological advancements, sensors are increasingly deployed to monitor our environment. The large variety of available sensor types with often incompatible protocols complicates the integration of sensors into observing systems. The standardized Web service interfaces and data encodings defined within OGC's Sensor Web Enablement (SWE) framework make sensors available over the Web and hide the heterogeneous sensor protocols from applications. So far, the SWE framework does not describe how to integrate sensors on-the-fly with minimal human intervention. The driver software which enables access to sensors has to be implemented and the measured sensor data has to be manually mapped to the SWE models. In this article we introduce a Sensor Plug & Play infrastructure for the Sensor Web by combining (1) semantic matchmaking functionality, (2) a publish/subscribe mechanism underlying the SensorWeb, as well as (3) a model for the declarative description of sensor interfaces which serves as a generic driver mechanism. We implement and evaluate our approach by applying it to an oil spill scenario. The matchmaking is realized using existing ontologies and reasoning engines and provides a strong case for the semantic integration capabilities provided by Semantic Web research.

Effect of 808 nm Semiconductor Laser on the Stability of Orthodontic Micro-Implants: A Split-Mouth Study.

BACKGROUND: To evaluate the effect of photobiomodulation (PBM) on orthodontic micro-implants (n = 44; 14 women, 8 men). METHODS: PBM with 808 nm diode laser was applied immediately, 3, 6, 9, 12, 15, and 30 days post the implantation. Results were assessed within same time frames and additionally after 60 days to check for implants stability using the Periotest device. Patients pain experiences following the first day post-treatment and potential loss of micro-implants after 60 days were recorded. The procedure involved insertion of mini-implants in the maxilla for the laser group (L, n = 22) and negative control group (C, n = 22). Irradiation was carried buccally and palatally with respect to the maxillary ridge (2 points). The energy per point was 4 J (8 J/cm2), total dose was 56 J. RESULTS: Patients did not report significant differences in terms of pain experiences comparing the L and C groups (p = 0.499). At 30 days post-treatment, higher secondary stability of implants was observed in the laser group (Periotest Test Value, PTV 6.32 ± 3.62), in contrast to the controls (PTV 11.34 ± 5.76) (p = 0.004). At 60 days post-treatment, significantly higher stability was recorded in the laser group (PTV 6.55 ± 4.66) compared with the controls, PTV (10.95 ± 4.77) (p = 0.009). Conclusions: Application of the 808 nm diode laser increased secondary micro-implant stability.

Human Cumulus Cells in Long-Term In Vitro Culture Reflect Differential Expression Profile of Genes Responsible for Planned Cell Death and Aging-A Study of New Molecular Markers.

In the ovarian follicle, maturation of the oocyte increases in the presence of somatic cells called cumulus cells (CCs). These cells form a direct barrier between the oocyte and external environment. Thanks to bidirectional communication, they have a direct impact on the oocyte, its quality and development potential. Understanding the genetic profile of CCs appears to be important in elucidating the physiology of oocytes. Long-term in vitro culture of CCs collected from patients undergoing controlled ovarian stimulation during in vitro fertilization procedure was conducted. Using microarray expression analysis, transcript levels were assessed on day 1, 7, 15, and 30 of culture. Apoptosis and aging of CCs strictly influence oocyte quality and subsequently the outcome of assisted reproductive technologies (ART). Thus, particular attention was paid to the analysis of genes involved in programmed cell death, aging, and apoptosis. Due to the detailed level of expression analysis of each of the 133 analyzed genes, three groups were selected: first with significantly decreased expression during the culture; second with the statistically lowest increase in expression; and third with the highest significant increase in expression. COL3A1, SFRP4, CTGF, HTR2B, VCAM1, TNFRSF11B genes, belonging to the third group, were identified as potential carriers of information on oocyte quality.

Inclusion Biogenesis, Methods of Isolation and Clinical Application of Human Cellular Exosomes.

Exosomes are a heterogenous subpopulation of extracellular vesicles 30-150 nm in range and of endosome-derived origin. We explored the exosome formation through different systems, including the endosomal sorting complex required for transport (ESCRT) and ESCRT-independent system, looking at the mechanisms of release. Different isolation techniques and specificities of exosomes from different tissues and cells are also discussed. Despite more than 30 years of research that followed their definition and indicated their important role in cellular physiology, the exosome biology is still in its infancy with rapidly growing interest. The reasons for the rapid increase in interest with respect to exosome biology is because they provide means of intercellular communication and transmission of macromolecules between cells, with a potential role in the development of diseases. Moreover, they have been investigated as prognostic biomarkers, with a potential for further development as diagnostic tools for neurodegenerative diseases and cancer. The interest grows further with the fact that exosomes were reported as useful vectors for drugs.

Bone Regeneration, Reconstruction and Use of Osteogenic Cells; from Basic Knowledge, Animal Models to Clinical Trials.

The deterioration of the human skeleton's capacity for self-renewal occurs naturally with age. Osteoporosis affects millions worldwide, with current treatments including pharmaceutical agents that target bone formation and/or resorption. Nevertheless, these clinical approaches often result in long-term side effects, with better alternatives being constantly researched. Mesenchymal stem cells (MSCs) derived from bone marrow and adipose tissue are known to hold therapeutic value for the treatment of a variety of bone diseases. The following review summarizes the latest studies and clinical trials related to the use of MSCs, both individually and combined with other methods, in the treatment of a variety of conditions related to skeletal health. For example, some of the most recent works noted the advantage of bone grafts based on biomimetic scaffolds combined with MSC and growth factor delivery, with a greatly increased regeneration rate and minimized side effects for patients. This review also highlights the continuing research into the mechanisms underlying bone homeostasis, including the key transcription factors and signalling pathways responsible for regulating the differentiation of osteoblast lineage. Paracrine factors and specific miRNAs are also believed to play a part in MSC differentiation. Furthering the understanding of the specific mechanisms of cellular signalling in skeletal remodelling is key to incorporating new and effective treatment methods for bone disease.

CRISPR/Cas9 in Cancer Immunotherapy: Animal Models and Human Clinical Trials.

Even though chemotherapy and immunotherapy emerged to limit continual and unregulated proliferation of cancer cells, currently available therapeutic agents are associated with high toxicity levels and low success rates. Additionally, ongoing multi-targeted therapies are limited only for few carcinogenesis pathways, due to continually emerging and evolving mutations of proto-oncogenes and tumor-suppressive genes. CRISPR/Cas9, as a specific gene-editing tool, is used to correct causative mutations with minimal toxicity, but is also employed as an adjuvant to immunotherapy to achieve a more robust immunological response. Some of the most critical limitations of the CRISPR/Cas9 technology include off-target mutations, resulting in nonspecific restrictions of DNA upstream of the Protospacer Adjacent Motifs (PAM), ethical agreements, and the lack of a scientific consensus aiming at risk evaluation. Currently, CRISPR/Cas9 is tested on animal models to enhance genome editing specificity and induce a stronger anti-tumor response. Moreover, ongoing clinical trials use the CRISPR/Cas9 system in immune cells to modify genomes in a target-specific manner. Recently, error-free in vitro systems have been engineered to overcome limitations of this gene-editing system. The aim of the article is to present the knowledge concerning the use of CRISPR Cas9 technique in targeting treatment-resistant cancers. Additionally, the use of CRISPR/Cas9 is aided as an emerging supplementation of immunotherapy, currently used in experimental oncology. Demonstrating further, applications and advances of the CRISPR/Cas9 technique are presented in animal models and human clinical trials. Concluding, an overview of the limitations of the gene-editing tool is proffered.

Epigenetic Research in Stem Cell Bioengineering-Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials.

The epigenome denotes all the information related to gene expression that is not contained in the DNA sequence but rather results from chemical changes to histones and DNA. Epigenetic modifications act in a cooperative way towards the regulation of gene expression, working at the transcriptional or post-transcriptional level, and play a key role in the determination of phenotypic variations in cells containing the same genotype. Epigenetic modifications are important considerations in relation to anti-cancer therapy and regenerative/reconstructive medicine. Moreover, a range of clinical trials have been performed, exploiting the potential of epigenetics in stem cell engineering towards application in disease treatments and diagnostics. Epigenetic studies will most likely be the basis of future cancer therapies, as epigenetic modifications play major roles in tumour formation, malignancy and metastasis. In fact, a large number of currently designed or tested clinical approaches, based on compounds regulating epigenetic pathways in various types of tumours, employ these mechanisms in stem cell bioengineering.

Human Wharton's Jelly-Cellular Specificity, Stemness Potency, Animal Models, and Current Application in Human Clinical Trials.

Stem cell therapies offer a great promise for regenerative and reconstructive medicine, due to their self-renewal and differentiation capacity. Although embryonic stem cells are pluripotent, their utilization involves embryo destruction and is ethically controversial. Therefore, adult tissues that have emerged as an alternative source of stem cells and perinatal tissues, such as the umbilical cord, appear to be particularly attractive. Wharton's jelly, a gelatinous connective tissue contained in the umbilical cord, is abundant in mesenchymal stem cells (MSCs) that express CD105, CD73, CD90, Oct-4, Sox-2, and Nanog among others, and have the ability to differentiate into osteogenic, adipogenic, chondrogenic, and other lineages. Moreover, Wharton's jelly-derived MSCs (WJ-MSCs) do not express MHC-II and exhibit immunomodulatory properties, which makes them a good alternative for allogeneic and xenogeneic transplantations in cellular therapies. Therefore, umbilical cord, especially Wharton's jelly, is a promising source of mesenchymal stem cells.

Muscle Cell Morphogenesis, Structure, Development and Differentiation Processes Are Significantly Regulated during Human Ovarian Granulosa Cells In Vitro Cultivation.

Granulosa cells (GCs) have many functions and are fundamental for both folliculogenesis and oogenesis, releasing hormones and communicating directly with the oocyte. Long-term in vitro cultures of GCs show significant stem-like characteristics. In the current study, RNA of human ovarian granulosa cells was collected at 1, 7, 15 and 30 days of long-term in vitro culture. Understanding the process of differentiation of GCs towards different cell lineages, as well as the molecular pathways underlying these mechanisms, is fundamental to revealing other possible stemness markers of this type of cell. Identifying new markers of GC plasticity may help to understand the aetiology and recurrence of a wide variety of diseases and health conditions and reveal possible clinical applications of the ovarian tissue cells, affecting not only the reproductive ability but also sex hormone production. Granulosa cells were the subject of this study, as they are readily available as remnant material leftover after in vitro fertilisation procedures and exhibit significant stem-like characteristics in culture. The change in gene expression was investigated through a range of molecular and bioinformatic analyses. Expression microarrays were used, allowing the identification of groups of genes typical of specific cellular pathways. This candidate gene study focused on ontological groups associated with muscle cell morphogenesis, structure, development and differentiation, namely, "muscle cell development", "muscle cell differentiation", "muscle contraction", "muscle organ development", "muscle organ morphogenesis", "muscle structure development", "muscle system process" and "muscle tissue development". The results showed that the 10 most upregulated genes were keratin 19, oxytocin receptor, connective tissue growth factor, nexilin, myosin light chain kinase, cysteine and glycine-rich protein 3, caveolin 1, actin, activating transcription factor 3 and tropomyosin, while the 10 most downregulated consisted of epiregulin, prostaglandin-endoperoxide synthase 2, transforming growth factor, interleukin, collagen, 5-hydroxytryptmine, interleukin 4, phosphodiesterase, wingless-type MMTV integration site family and SRY-box 9. Moreover, ultrastructural observations showing heterogeneity of granulosa cell population are presented in the study. At least two morphologically different subpopulations were identified: large, light coloured and small, darker cells. The expression of genes belonging to the mentioned ontological groups suggest the potential ability of GCs to differentiate and proliferate toward muscle lineage, showing possible application in muscle regeneration and the treatment of different diseases.

Correction: ISED: Constructing a high-resolution elevation road dataset from massive, low-quality in-situ observations derived from geosocial fitness tracking data.

[This corrects the article DOI: 10.1371/journal.pone.0186474.].

ISED: Constructing a high-resolution elevation road dataset from massive, low-quality in-situ observations derived from geosocial fitness tracking data.

Gaining access to inexpensive, high-resolution, up-to-date, three-dimensional road network data is a top priority beyond research, as such data would fuel applications in industry, governments, and the broader public alike. Road network data are openly available via user-generated content such as OpenStreetMap (OSM) but lack the resolution required for many tasks, e.g., emergency management. More importantly, however, few publicly available data offer information on elevation and slope. For most parts of the world, up-to-date digital elevation products with a resolution of less than 10 meters are a distant dream and, if available, those datasets have to be matched to the road network through an error-prone process. In this paper we present a radically different approach by deriving road network elevation data from massive amounts of in-situ observations extracted from user-contributed data from an online social fitness tracking application. While each individual observation may be of low-quality in terms of resolution and accuracy, taken together they form an accurate, high-resolution, up-to-date, three-dimensional road network that excels where other technologies such as LiDAR fail, e.g., in case of overpasses, overhangs, and so forth. In fact, the 1m spatial resolution dataset created in this research based on 350 million individual 3D location fixes has an RMSE of approximately 3.11m compared to a LiDAR-based ground-truth and can be used to enhance existing road network datasets where individual elevation fixes differ by up to 60m. In contrast, using interpolated data from the National Elevation Dataset (NED) results in 4.75m RMSE compared to the base line. We utilize Linked Data technologies to integrate the proposed high-resolution dataset with OpenStreetMap road geometries without requiring any changes to the OSM data model.