Identifying a molecular phenotype for bone marrow stromal cells with in vivo bone-forming capacity

The ability of bone marrow stromal cells (BMSCs) to differentiate into osteoblasts is being exploited in cell-based therapy for repair of bone defects. However, the phenotype of ex vivo cultured BMSCs predicting their bone-forming capacity is not known. Thus we employed DNA microarrays comparing two human bone marrow stromal cell (hBMSC) populations: One is capable of in vivo heterotopic bone formation (hBMSC-TERT(+Bone)), and the other is not (hBMSC-TERT(-Bone)). Compared with hBMSC-TERT(-Bone), the hBMSC-TERT(+Bone) cells had an increased overrepresentation of extracellular matrix genes (17% versus 5%) and a larger percentage of genes with predicted SP3 transcription factor-binding sites in their promoter region (21% versus 8%). On the other hand, hBMSC-TERT(-Bone) cells expressed a larger number of immune-response-related genes (26% versus 8%). In order to test for the predictive value of these markers, we studied the correlation between their expression levels in six different hBMSC-derived clones and the ability to form bone in vivo. We found a significant correlation for decorin, lysyl oxidase-like 4, natriuretic peptide receptor C, and tetranectin. No significant positive correlation was found for canonical osteoblastic markers Runx2, alkaline phosphatase, collagen type I, osteopontin, and bone sialoprotein. Prospective isolation of four additional hBMSC clones based on their expression levels of the molecular markers correlated with their in vivo bone-formation ability. In conclusion, our data suggest an in vitro molecular signature predictive for hBMSCs' in vivo bone-formation ability. Identifying more of these predictive markers would be very useful in the quality control of osteoblastic cells before use in therapy

An overview of the features of chatbots in mental health: A scoping review

Background: Chatbots are systems that are able to converse and interact with human users using spoken, written, and visual languages. Chatbots have the potential to be useful tools for individuals with mental disorders, especially those who are reluctant to seek mental health advice due to stigmatization. While numerous studies have been conducted about using chatbots for mental health, there is a need to systematically bring this evidence together in order to inform mental health providers and potential users about the main features of chatbots and their potential uses, and to inform future research about the main gaps of the previous literature. Objective: We aimed to provide an overview of the features of chatbots used by individuals for their mental health as reported in the empirical literature. Methods: Seven bibliographic databases (Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, IEEE Xplore, ACM Digital Library, and Google Scholar) were used in our search. In addition, backward and forward reference list checking of the included studies and relevant reviews was conducted. Study selection and data extraction were carried out by two reviewers independently. Extracted data were synthesised using a narrative approach. Chatbots were classified according to their purposes, platforms, response generation, dialogue initiative, input and output modalities, embodiment, and targeted disorders. Results: Of 1039 citations retrieved, 53 unique studies were included in this review. Those studies assessed 41 different chatbots. Common uses of chatbots were: therapy (n = 17), training (n = 12), and screening (n = 10). Chatbots in most studies were rule-based (n = 49) and implemented in stand-alone software (n = 37). In 46 studies, chatbots controlled and led the conversations. While the most frequently used input modality was writing language only (n = 26), the most frequently used output modality was a combination of written, spoken and visual languages (n = 28). In the majority of studies, chatbots included virtual representations (n = 44). The most common focus of chatbots was depression (n = 16) or autism (n = 10). Conclusion: Research regarding chatbots in mental health is nascent. There are numerous chatbots that are used for various mental disorders and purposes. Healthcare providers should compare chatbots found in this review to help guide potential users to the most appropriate chatbot to support their mental health needs. More reviews are needed to summarise the evidence regarding the effectiveness and acceptability of chatbots in mental health

Higher Order Power Corrections in Inclusive B Decays

We discuss order 1/m_b^4 and 1/m_b^5 corrections in inclusive semileptonic decay of a $B$ meson. We identify relevant hadronic matrix elements of dimension seven and eight and estimate them using the ground-state saturation approximation. Within this approach the effects on the integrated rate and on kinematic moments are estimated. The overall relative shift in V_{cb} turns out about +0.4% as applied to the existing fits. Similar estimates are presented for B -> X_s+\gamma decays.Comment: 30 pages, 16 figure

Expression of DLK1 and MEG3 genes in porcine tissues during postnatal development

The Drosophila-like homolog 1 (DLK1), a transmembrane signal protein similar to other members of the Notch/Delta/Serrate family, regulates the differentiation process in many types of mammalian cells. Callipyge sheep and DLK1 knockout mice are excellent examples of a fundamental role of the gene encoding DLK1 in muscle growth and fat deposition. DLK1 is located within co-regulated imprinted clusters (the DLK1/DIO3 domain), along with other imprinted genes. Some of these, e.g. the RNA coding MEG3 gene, presumedly interfere with DLK1 transcription. The aim of our study was to analyze DLK1 and MEG3 gene expression in porcine tissues (muscle, liver, kidney, heart, brain stem) during postnatal development. The highest expression of both DLK1 and MEG3 variant 1 (MEG3 var.1) was observed in the brain-stem and muscles, whereas that of MEG3 variant 2 (MEG3var.2) was the most abundant in muscles and the heart. During development (between 60 and 210 days of age) expression of analyzed genes was down-regulated in all the tissues. An exception was the brain- stem, where there was no significant change in MEG3 (both variants) mRNA level, and relatively little decline (2-fold) in that of DLK1 transcription. This may indicate a distinct function of the DLK1 gene in the brain-stem, when compared with other tissues

Potential of Resveratrol Analogues as Antagonists of Osteoclasts and Promoters of Osteoblasts

The plant phytoalexin resveratrol was previously demonstrated to inhibit the differentiation and bone resorbing activity of osteoclasts, to promote the formation of osteoblasts from mesenchymal precursors in cultures, and inhibit myeloma cell proliferation, when used at high concentrations. In the current study, we screened five structurally modified resveratrol analogues for their ability to modify the differentiation of osteoclasts and osteoblasts and proliferation of myeloma cells. Compared to resveratrol, analogues showed an up to 5,000-fold increased potency to inhibit osteoclast differentiation. To a lesser extent, resveratrol analogues also promoted osteoblast maturation. However, they did not antagonize the proliferation of myeloma cells. The potency of the best-performing candidate in vitro was tested in vivo in an ovariectomy-induced model of osteoporosis, but an effect on bone loss could not be detected. Based on their powerful antiresorptive activity in vitro, resveratrol analogues might be attractive modulators of bone remodeling. However, further studies are required to establish their efficacy in vivo

Targeted Inactivation of Rin3 Increases Trabecular Bone Mass by Reducing Bone Resorption and Favouring Bone Formation

AbstractCommon genetic variants at the RIN3 locus on chromosome 14q32 predispose to Paget’s disease of bone (PDB) but the mechanisms by which they do so are unknown. Here, we analysed the skeletal phenotype of female mice with targeted inactivation of the mouse Rin3 gene (Rin3−/−) as compared with wild-type littermates. The Rin3−/− mice had higher trabecular bone volume (BV/TV%) compared with wild type. Mean ± standard deviation values at the distal femur at 8 weeks were 9.0 ± 2.5 vs. 7.0 ± 1.5 (p = 0.002) and at 52 weeks were 15.8 ± 9.5 vs. 8.5 ± 4.2 (p = 0.002). No differences were observed in femoral cortical bone parameters with the exception of marrow diameter which was significantly smaller in 52-week-old Rin3−/− mice compared to wild type: (0.43 mm ± 0.1 vs. 0.57 mm ± 0.2 (p = 0.001). Bone histomorphometry showed a lower osteoclast surface / bone surface (Oc.S/BS%) at 8 weeks in Rin3−/− mice compared to wild type (24.1 ± 4.7 vs. 29.7 ± 6.6; p = 0.025) but there were no significant differences in markers of bone formation at this time. At 52 weeks, Oc.S/BS did not differ between genotypes but single labelled perimeter (SL.Pm/B.Pm (%)) was significantly higher in Rin3−/− mice (24.4 ± 6.4 vs. 16.5 ± 3.8, p = 0.003). We conclude that Rin3 negatively regulates trabecular bone mass in mice by inhibiting osteoclastic bone resorption and favouring bone formation. Our observations also suggest that the variants that predispose to PDB in humans probably do so by causing a gain-in-function of RIN3.</jats:p

Multifunctional Properties of Chicken Embryonic Prenatal Mesenchymal Stem Cells- Pluripotency, Plasticity, and Tumor Suppression

The chick embryo represents an accessible and economical in vivo model, which has long been used in developmental biology, gene expression analysis, and loss/gain of function experiments. In the present study, we assessed and characterized bone marrow derived mesenchymal stem cells from prenatal day 13 chicken embryos (chBMMSCs) and determined some novel properties. After assessing the mesenchymal stem cell (MSC) properties of these cells by the presence of their signature markers (CD 44, CD 73, CD 90, CD 105, and vimentin), we ascertained a very broad spectrum of multipotentiality as these MSCs not only differentiated into the classic tri-lineages of MSCs but also into ectodermal, endodermal, and mesodermal lineages such as neuron, hepatocyte, islet cell, and cardiac. In addition to wide plasticity, we detected the presence of several pluripotent markers such as Oct4, Sox2, and Nanog. This is the first study characterizing prenatal chBMMSCs and their ability to not only differentiate into mesenchymal lineages but also into all the germ cell layer lineages. Furthermore, our studies indicate that prenatal chBMMSCs derived from the chick provide an excellent model for multi-lineage development studies because of their broad plasticity and faithful reproduction of MSC traits as seen in the human. Here, we also present evidence for the first time that media derived from prenatal chBMMSC cultures have an anti-tumorigenic, anti-migratory, and pro-apoptotic effect on human tumors cells acting through the Wnt-ß-catenin pathway. These data confirm that chBMMSCs are enriched with factors in their secretome that are able to destroy tumor cells. This suggests a commonality of properties of MSCs across species between human and chicken

Transit amplifying cells coordinate mouse incisor mesenchymal stem cell activation

10.1038/s41467-019-11611-0Nature Communications101359

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT