ALBERT

Description: Background The results of a previous study verified that umbilical cord mesenchymal stem cells (UCMSCs) have good therapeutic effects for the treatment of HBV-related acute-on-chronic liver failure (ACLF) and liver cirrhosis (LC). Nevertheless, it is still unknown whether the effects of UCMSCs are affected by recipient age. Methods Patients treated with UCMSCs who met the criteria of HBV-related ACLF and liver cirrhosis were identified in this retrospective observational study. Patients were divided into subgroups according to the World Health Organization (WHO) age criteria (

Description: Objectives To investigate the safety for clinic use and therapeutic effects of basic fibroblast growth factor (bFGF)-overexpressing human umbilical cord-derived mesenchymal stem cells (HUCMSCs) in mice with completely transected spinal cord injury (SCI). Methods Stable bFGF-overexpressing HUCMSCs clones were established by electrotransfection and then subjected to systematic safety evaluations. Then, bFGF-overexpressing and control HUCMSCs were used to treat mice with completely transected SCI by tail intravenous injection. Therapeutic outcomes were then investigated, including functional recovery of locomotion, histological structures, nerve regeneration, and recovery mechanisms. Results Stable bFGF-overexpressing HUCMSCs met the standards and safety of MSCs for clinic use. In the mouse SCI model, stable bFGF-overexpressing HUCMSCs markedly improved therapeutic outcomes such as reducing glial scar formation, improving nerve regeneration and proliferation of endogenous neural stem cells (NSCs), and increasing locomotion functional recovery of posterior limbs compared with the control HUCMSCs group. Furthermore, bFGF-overexpressing HUCMSCs promoted the proliferation and neuronal differentiation of NSCs in vitro through the PI3K-Akt-GSK-3β pathway. Conclusion bFGF-overexpressing HUCMSCs meet the requirements of clinical MSCs and improve evident therapeutic outcomes of mouse SCI treatment, which firmly supports the safety and efficacy of gene-modified MSCs for clinical application.

Description: Objective To compare an objective with a subjective numeracy assessment for association with self-reported health status, where numeracy refers to “the degree to which individuals have the capacity to access, process, interpret, communicate, and act on numerical, quantitative, graphical, biostatistical, and probabilistic health information needed to make effective health decisions” Results We completed a secondary analysis of two population-based surveys, the Empire State Poll (n = 763) and the Program for the International Assessment of Adult Competencies (PIAAC; n = 2609). The first survey assessed numeracy with a 3-item subjective instrument. The second assessed numeracy with more than 20 math problems. Both used the same measure for self-reported health status. Lower numeracy, whether subjectively or objectively assessed, was associated with worse self-reported health, even after controlling for education and other sociodemographic confounders. The odds ratios for the association were very similar (0.91 and 0.90 respectively). A lengthy objective numeracy assessment and a brief self-report assessment had similar associations with health status. A brief self-report measure of numeracy has similar properties to a lengthy objective assessment and is likely to be more feasible to use to screen patients in practice.

Description: Background Significant investments have been made towards the implementation of mHealth applications and eRecord systems globally. However, fragmentation of these technologies remains a big challenge, often unresolved in developing countries. In particular, evidence shows little consideration for linking mHealth applications and eRecord systems. Botswana is a typical developing country in sub-Saharan Africa that has explored mHealth applications, but the solutions are not interoperable with existing eRecord systems. This paper describes Botswana’s eRecord systems interoperability landscape and provides guidance for linking mHealth applications to eRecord systems, both for Botswana and for developing countries using Botswana as an exemplar. Methods A survey and interviews of health ICT workers and a review of the Botswana National eHealth Strategy were completed. Perceived interoperability benefits, opportunities and challenges were charted and analysed, and future guidance derived. Results Survey and interview responses showed the need for interoperable mHealth applications and eRecord systems within the health sector of Botswana and within the context of the National eHealth Strategy. However, the current Strategy does not address linking mHealth applications to eRecord systems. Across Botswana’s health sectors, global interoperability standards and Application Programming Interfaces are widely used, with some level of interoperability within, but not between, public and private facilities. Further, a mix of open source and commercial eRecord systems utilising relational database systems and similar data formats are supported. Challenges for linking mHealth applications and eRecord systems in Botswana were identified and categorised into themes which led to development of guidance to enhance the National eHealth Strategy. Conclusion Interoperability between mHealth applications and eRecord systems is needed and is feasible. Opportunities and challenges for linking mHealth applications to eRecord systems were identified, and future guidance stemming from this insight presented. Findings will aid Botswana, and other developing countries, in resolving the pervasive disconnect between mHealth applications and eRecord systems.

Description: Objective The use of mice as animal models in biomedical research allows the standardization of genetic background and environmental conditions, which both affect phenotypic variability. As the use of both sexes in experiments is strongly recommended, sex-specific phenotypic variability is discussed with regard to putative consequences on the group size which is necessary for achieving valid and reproducible results. In this study, the sex-specific variability of 25 clinical chemical and hematological parameters which represent a comprehensive blood screen of laboratory mice, was analyzed in data sets which have been submitted to the Mouse Phenome Database. Results The overall analysis comprising all 25 clinical chemical and hematological parameters showed no evidence for substantial and robust general sex-specific variability. A large range of the ratio of the female and male coefficient of variation (CV) was found for every parameter among the respective strain data sets. This clearly demonstrated the appearance of unpredictable major interactions between genotype and environment regarding the sex-specific variability of the blood parameters analyzed.

Description: Objective Reported rainfall data from multiple rain gauges and its corresponding estimate from Dual-Polarization (Dual-Pol) radar is presented here. The ordered set of data pairs were collected from multiple peer reviewed publications spanning across the last decade. Data description Taken from multiple sources, the data set represents several radar sites and rain gauge sites combined for 12,734 data points. The data is relevant in various applications of hydrometeorology and engineering as well as weather forecasting. Further, the importance of accuracy in radar precipitation estimates continues to increase, necessitating the incorporation of as much data as possible.

Description: Background Hypertrophy is a critical process for chondrocyte differentiation and maturation during endochondral ossification, which is responsible for the formation of long bone and postnatal longitudinal growth. Increasing evidence suggests that melatonin, an indole hormone, plays a pivotal role in chondrogenesis. However, little is known about the effects of melatonin on the terminal differentiation of chondrocytes. Methods Mesenchymal stem cell (MSC)-derived chondrocytes generated by a high-density micromass culture system were induced to undergo hypertrophic differentiation. Melatonin-mediated hypertrophic differentiation was examined by reverse transcription polymerase chain reaction analysis (RT-PCR) analysis, histological staining and immunohistochemistry. Activation of the Wnt signaling pathway was evaluated by PCR array, RT-PCR, western blotting and immunofluorescence. XAV-939, a Wnt signaling pathway antagonist, was further used to determine whether the effect of melatonin on chondrocyte hypertrophic differentiation was mediated occurred by activation of Wnt signaling pathway. Results Histological staining showed melatonin increased chondrocyte cell volume and the expression of type X collagen but decreased the expression of type II collagen compared with the control group. RT-PCR showed that melatonin significantly up-regulated the gene expressions of biomarkers of hypertrophic chondrocytes, including type X collagen, alkaline phosphatase, runt-related transcription factor 2, Indian hedgehog and parathyroid hormone-related protein receptor, and melatonin down-regulated the mRNA expression of hallmarks of chondrocytes, including parathyroid hormone-related protein. PCR array showed that the effect of melatonin on chondrocyte hypertrophic differentiation was accompanied by the up-regulation of multiple target genes of the canonical Wnt signaling pathway, and this effect was blocked by XAV-939. Conclusions The current findings demonstrate that melatonin enhances the hypertrophic differentiation of MSC-derived chondrocytes through the Wnt signaling pathway. Our findings add evidence to the role of melatonin in promoting bone development and highlight the positive effects of melatonin on terminal differentiation of chondrocytes.

Description: Novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2. The virus causes an exaggerated immune response, resulting in a cytokine storm and acute respiratory distress syndrome, the leading cause of COVID-19-related mortality and morbidity. So far, no therapies have succeeded in circumventing the exacerbated immune response or cytokine storm associated with COVID-19. Mesenchymal stem cells (MSCs), through their immunomodulatory and regenerative activities, mostly mediated by their paracrine effect and extracellular vesicle production, have therapeutic potential in many autoimmune, inflammatory, and degenerative diseases. In this paper, we review clinical studies on the use of MSCs for COVID-19 treatment, including the salutary effects of MSCs on the pathophysiology of COVID-19 and the immunomodulation of the cytokine storm. Ongoing clinical trial designs, cell sources, dose and administration, and populations are summarized, and the paracrine mode of benefit is discussed. We also offer suggestions for optimizing MSC-based therapies, including genetic engineering, strategies for cell surface modification, nanotechnology applications, and combination therapies.

Description: Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.

Description: Objectives Peer support is rapidly being introduced into mental health services internationally, yet peer support interventions are often poorly described, limiting the usefulness of research in informing policy and practice. This paper reports the development of a peer support intervention that aims to improve outcomes of discharge from inpatient to community mental health care. People with experiential knowledge of using mental health services—peer workers and service user researchers—were involved in all stages of developing the intervention: generating intervention components; producing the intervention handbook; piloting the intervention. Results Systematic review and expert panels, including our Lived Experience Advisory Panel, identified 66 candidate intervention components in five domains: Recruitment and Role Description of Peer Workers; Training for Peer Workers; Delivery of Peer Support; Supervision and Support for Peer Workers; Organisation and Team. A series of Local Advisory Groups were used to prioritise components and explore implementation issues using consensus methods, refining an intervention blueprint. A peer support handbook and peer worker training programme were produced by the study team and piloted in two study sites. Feedback workshops were held with peer workers and their supervisors to produce a final handbook and training programme. The ENRICH trial is registered with the ISRCTN clinical trial register, number ISRCTN 10043328, and was overseen by an independent steering committee and a data monitoring committee.

Description: Background To enhance teleconsultation management, demands can be classified into different patterns, and the service of each pattern demand can be improved. Methods For the effective teleconsultation classification, a novel ensemble hierarchical clustering method is proposed in this study. In the proposed method, individual clustering results are first obtained by different hierarchical clustering methods, and then ensembled by one-hot encoding, the calculation and division of cosine similarity, and network graph representation. In the built network graph about the high cosine similarity, the connected demand series can be categorized into one pattern. For verification, 43 teleconsultation demand series are used as sample data, and the efficiency and quality of teleconsultation services are respectively analyzed before and after the demand classification. Results The teleconsultation demands are classified into three categories, erratic, lumpy, and slow. Under the fixed strategies, the service analysis after demand classification reveals the deficiencies of teleconsultation services, but analysis before demand classification can’t. Conclusion The proposed ensemble hierarchical clustering method can effectively category teleconsultation demands, and the effective demand categorization can enhance teleconsultation management.

Description: Objective The major purpose of this study was to determine the specific muscle(s) for superior sprint performance in sprinters. The cross sectional areas (CSAs) of ten muscles of the trunk and lower limb were measured using magnetic resonance images in 56 male sprinters and 40 male non-sprinters. In addition to the absolute CSA, to minimize the effect of difference in body size among participants, the relative CSA normalized to body mass was used for analysis of this study. Results Absolute and relative CSAs of most trunk and lower limb muscles, including the psoas major (PM) and gluteus maximus (GM), were significantly larger in sprinters than in non-sprinters (all P 

Description: Background First identified as a regulator of neuronal axon guidance, Slit/Robo signaling has since been implicated in additional physiologic and pathologic processes, such as angiogenesis, organogenesis and cancer progression. However, its roles in the regulation of testis function have been little explored. Methods Immunohistochemistry and RT-qPCR analyses were performed to detect the expression of Slit/Robo signaling effectors in the adult mouse testis. To identify the roles and mechanisms of Slit/Robo signaling in the regulation of steroidogenesis, RT-qPCR, immunoblotting and hormone measurements were carried out using Leydig cells (primary cultures and the MA10 cell line) treated with exogenous SLIT ligands, and testes from Robo1-null mice. Results Slit1, -2 and -3 and Robo1 and -2 expression was detected in the adult mouse testis, particularly in Leydig cells. In vitro treatment of Leydig cells with exogenous SLIT ligands led to a decrease in the expression of the steroidogenic genes Star, Cyp11a1, and Cyp17a1. SLIT2 treatment decreased the phosphorylation of the key steroidogenic gene regulator CREB, possibly in part by suppressing AKT activity. Furthermore, SLIT2 treatment reduced the responsiveness of MA10 cells to luteinizing hormone by decreasing the expression of Lhcgr. Consistent with these in vitro results, an increase in testicular Star mRNA levels and intra-testicular testosterone concentrations were found in Robo1-null mice. Finally, we showed that the expression of the Slit and Robo genes in Leydig cells is enhanced by testosterone treatment in vitro, by an AR-independent mechanism. Conclusion Taken together, these results suggest that Slit/Robo signaling represents a novel mechanism that regulates Leydig cell steroidogenesis. It may act in an autocrine/paracrine manner to mediate negative feedback by testosterone on its own synthesis.

Description: Background Mesenchymal stem cells (MSCs) exert positive effects in chronic wounds. However, critical parameters, such as the most effective administration routes, remain unclear. Accordingly, the purpose of this study was to compare the effects of topical and systemic transplantation MSCs on diabetic ischemic wound healing and explored the underlying mechanisms. Method A diabetic ischemic wound model was created on the dorsal foot of type 2 diabetes mellitus (T2DM) rat. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were administered via two routes: topical injection and intravenous (IV) infusion. Wound healing outcomes and blood glucose level were assessed dynamically. Meanwhile, blood flow recovery was evaluated in ischemic gastrocnemius muscles. The homing and transdifferentiation of mKate2-labeled BM-MSCs were assessed by fluorescence imaging and immunohistochemistry (IHC) analysis. Result Both topical and systemic treatments had a positive effect on the diabetic ischemic wound showing a significant reduction in wound area at day 14. Histological results showed an increase in the length of epithelial edges, collagen content, microvessel density in the wound bed, and a higher expression of vascular endothelial growth factor (VEGF). Meanwhile, systemic administration can ameliorate hyperglycemia and improve the blood perfusion of the ischemic hindlimb. BM-MSCs administered systemically were found distributed in wounded tissue and transdifferentiated into endothelial cells. Furthermore, BM-MSCs stimulated angiogenesis at wound sites by downregulating phosphatase and tensin homolog (PTEN) and activation of AKT signaling pathway. Conclusions The results demonstrated that both transplantation delivery method (topical and systemic) of BM-MSCs accelerated wound healing remarkably under pathological conditions. Nevertheless, systemic administration has the potential to ameliorate hyperglycemia and repair the damaged tissue.

Description: Objective To explore the adipogenic effects of the small extracellular vesicles derived from the lipoma tissues (sEV-LT), and to find a new cell-free therapeutic approach for adipose tissue regeneration. Methods Adipose tissue-derived stem cells (ADSCs) and small extracellular vesicles derived from the adipose tissues (sEV-AT) were isolated from human adipose tissue, while sEV-LT were isolated from human lipomatous tissue. ADSCs were characterized by using flow cytometric analysis and adipogenic and osteogenic differentiation assays. sEV was identified by electron microscopy, nanoparticle tracking, and western blotting. ADSCs were treated with sEV-LT and sEV-AT, respectively. Fluorescence confocal microscopy was used to investigate whether sEV-LT and sEV-AT could be taken by ADSCs. The proliferation and migration abilities and adipogenic differentiation assay of ADSCs were evaluated by CCK-8 assays, scratch test, and oil red O staining test, and the expression levels of adipogenic-related genes C/EBP-δ, PPARγ2, and Adiponectin in ADSCs were assessed by real-time quantitative PCR (RT-PCR). The sEV-LT and sEV-AT transplantation tubes were implanted subcutaneously in SD rats, and the neotissues were qualitatively and histologically evaluated at 2, 4, 8, and 12 weeks after transplantation. Hematoxylin and eosin (H&E) staining was subsequently used to observe and compare the adipogenesis and angiogenesis in neotissues, while immunohistochemistry was used to examine the expression and the distribution of C/EBP-α, PPARγ, Adiponectin, and CD31 at the 4th week. Results The in vitro experiments showed that both sEV-LT and sEV-AT could be taken up by ADSCs via endocytosis. The scratch experiment and CCK-8 experiment showed that the migration area and proliferation number of ADSCs in sEV-LT group and sEV-AT group were significantly higher than those in the non-sEV group (p 

Description: Background Hypertrophic scar (HS) is a fibro-proliferative disorder of dermis after burn or trauma and usually leads to esthetic disfiguration and functionary impairment for patients. Emerging evidences demonstrated ADSC-Exo could alleviate the visceral fibrosis, but little attention had been paid to its role in skin fibrosis. In the study, we would explore the effect of ADSC-Exo on HS and investigated the exact mechanism underlying the properties. Methods ADSC-Exo were isolated, identified, and internalized by HS-derived fibroblasts (HSFs). The effect of ADSC-Exo on the proliferation and migration of HSFs were detected by flow cytometry and Ki67 immunofluorescence staining, or scratch and trans-wells assays, respectively. RT-PCR, immunoblotting, immunofluorescence, and immunohistochemistry staining were used to evaluate the expression of IL-17RA, Col1, Col3, α-SMA, SIP1, and p-Smad2/p-Smad3 in HSFs stimulated with ADSC-Exo, miR-192-5p mimics, or inhibitors, IL-17RA siRNA and their negative controls. Digital morphology, H&E, Masson’s trichrome staining, and immunohistochemistry staining were performed to measure the effect of ADSC-Exo and Lv-IL-17RA shRNA on excisional wound of BALB/c mice. Results The verified ADSC-Exo effectively inhibited the proliferation and migration of HSFs, decreased the expression of Col1, Col3, α-SMA, IL-17RA, and p-Smad2/p-Smad3 and increased the levels of SIP1 in HSFs. Besides, the mice in ADSC-Exo-treated group demonstrated faster wound healing and less collagen deposition. Furthermore, miR-192-5p was highly expressed in ADSC-Exo and ADSC-Exosomal miR-192-5p ameliorated hypertrophic scar fibrosis. Meanwhile, miR-192-5p targeted the expression of IL-17RA to decrease the pro-fibrotic proteins levels. Moreover, IL-17RA was overexpressed in HS and HSFs, and knockdown IL-17RA alleviated the expression of Col1, Col3, α-SMA, and p-Smad2/p-Smad3 and increased the expression of SIP1 in HSFs. Most importantly, IL-17RA silence also facilitated wound healing, attenuated collagen production, and modulated Smad pathway in HSFs. Conclusions This study illustrated ADSC-Exo attenuated the deposition of collagen, the trans-differentiation of fibroblasts-to-myofibroblasts, and the formation of hypertrophic scar by in vitro and in vivo experiments. ADSC-Exosomal miR-192-5p targeted IL-17RA to regulate Smad pathway in hypertrophic scar fibrosis. ADSC-Exo could be a promising therapeutic strategy for clinical treatment of hypertrophic scar and the anti-fibrotic properties could be achieved by miR-192-5p/IL-17RA/Smad axis.

Description: Kidney diseases pose a threat to human health due to their rising incidence and fatality rate. In preclinical and clinical studies, it has been acknowledged that mesenchymal stem cells (MSCs) are effective and safe when used to treat kidney diseases. MSCs play their role mainly by secreting trophic factors and delivering extracellular vesicles (EVs). The genetic materials and proteins contained in the MSC-derived EVs (MSC-EVs), as an important means of cellular communication, have become a research focus for targeted therapy of kidney diseases. At present, MSC-EVs have shown evident therapeutic effects on acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), and atherosclerotic renovascular disease (ARVD); however, their roles in the transplanted kidney remain controversial. This review summarises the mechanisms by which MSC-EVs treat these diseases in animal models and proposes certain problems, expecting to facilitate corresponding future clinical practice.

Description: Background The corneal endothelium maintains corneal hydration through the barrier and pump function, while its dysfunction may cause corneal edema and vision reduction. Considering its development from neural crest cells (NCCs), here we investigated the efficacy of the human induced pluripotent stem cell (hiPSC)-derived NCCs for corneal endothelial regeneration in rabbits. Methods Directed differentiation of hiPSC-derived NCCs was achieved using the chemically defined medium containing GSK-3 inhibitor and TGF-β inhibitor. The differentiated cells were characterized by immunofluorescence staining, FACS analysis, and in vitro multi-lineage differentiation capacity. For in vivo functional evaluation, 1.0 × 106 hiPSC-derived NCCs or NIH-3 T3 fibroblasts (as control) combined with 100 μM Y-27632 were intracamerally injected into the anterior chamber of rabbits following removal of corneal endothelium. Rabbit corneal thickness and phenotype changes of the transplanted cells were examined at 7 and 14 days with handy pachymeter, dual-immunofluorescence staining, and quantitative RT-PCR. Results The hiPSC-derived NCCs were differentiated homogenously through 7 days of induction and exhibited multi-lineage differentiation capacity into peripheral neurons, mesenchymal stem cells, and corneal keratocytes. After 7 days of intracameral injection in rabbit, the hiPSC-derived NCCs led to a gradual recovery of normal corneal thickness and clarity, when comparing to control rabbit with fibroblasts injection. However, the recovery efficacy after 14 days deteriorated and caused the reappearance of corneal edema. Mechanistically, the transplanted cells exhibited the impaired maturation, cellular senescence, and endothelial-mesenchymal transition (EnMT) after the early stage of the in vivo directional differentiation. Conclusions Transplantation of the hiPSC-derived NCCs rapidly restored rabbit corneal thickness and clarity. However, the long-term recovery efficacy was impaired by the improper maturation, senescence, and EnMT of the transplanted cells.

Description: Background and objectives Internet-based technologies play an increasingly important role in the management and outcome of patients with chronic kidney disease (CKD). The healthcare system is currently flooded with digital innovations and internet-based technologies as a consequence of the coronavirus disease 2019 (COVID-19) pandemic. However, information about the attitude of German CKD-patients with access to online tools towards the use of remote, internet-based interactions such as video conferencing, email, electronic medical records and apps in general and for health issues in particular, are missing. Design, setting, participants, and measurements To address the use, habits and willingness of CKD patients in handling internet-based technologies we conducted a nationwide cross-sectional questionnaire survey in adults with CKD. Results We used 380 questionnaires from adult CKD patients (47.6% on dialysis, 43.7% transplanted and 8.7% CKD before renal replacement therapy) for analysis. Of these 18.9% denied using the internet at all (nonusers). Nonusers were significantly older (74.4 years, SD 11.4) than users (54.5 years, SD 14.5, p 

Description: Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are syndromes of acute respiratory failure with extremely high mortality and few effective treatments. Mesenchymal stem cells (MSCs) may reportedly contribute to tissue repair in ALI and ARDS. However, applications of MSCs have been restricted due to safety considerations and limitations in terms of large-scale production and industrial delivery. Alternatively, the MSC secretome has been considered promising for use in therapeutic approaches and has been advanced in pre-clinical and clinical trials. Furthermore, the MSC secretome can be freeze-dried into a stable and ready-to-use supernatant lyophilized powder (SLP) form. Currently, there are no studies on the role of MSC SLP in ALI. Methods Intratracheal bleomycin was used to induce ALI in mice, and intratracheal MSC SLP was administered as a treatment. Histopathological assessment was performed by hematoxylin and eosin, immunohistochemistry, and immunofluorescence staining. Apoptosis, inflammatory infiltration, immunological cell counts, cytokine levels, and mRNA- and protein-expression levels of relevant targets were measured by performing terminal deoxynucleotidyl transferase dUTP nick-end labeling assays, determining total cell and protein levels in bronchoalveolar lavage fluids, flow cytometry, multiple cytokine-detection techniques, and reverse transcriptase-quantitative polymerase chain reaction and western blot analysis, respectively. Results We found that intratracheal MSC SLP considerably promoted cell survival, inhibited epithelial cell apoptosis, attenuated inflammatory cell recruitment, and reversed immunological imbalances induced by bleomycin. MSC SLP inhibited the interleukin 6–phosphorylated signal transducer and activator of transcription signaling pathway to activate tumor protein 63–jagged 2 signaling in basal cells, suppress T helper 17 cell differentiation, promote p63+ cell proliferation and lung damage repair, and attenuate inflammatory responses. Conclusions MSC SLP ameliorated ALI by activating p63 and promoting p63+ cell proliferation and the repair of damaged epithelial cells. The findings of this study also shed insight into ALI pathogenesis and imply that MSC SLP shows considerable therapeutic promise for treating ALI and ARDS.

Description: Background Dysfunction of mesenchymal stem cells (MSCs) is recognized as critical to the pathogenesis of glucocorticoid-induced osteoporosis (GIO), suggesting the potential of MSC-targeting interventions for this disorder. As the miR-133a has been shown to play an important role in bone metabolism, we hypothesized that miR-133a may also be involved in GIO. Methods In the in vitro study, we examined the effect of miR-133a antagomir on DEX-treated MSCs, including proliferation, apoptosis, osteoblast, and adipocyte differentiation, then, we explored the mechanism of these effects of miR-133a silencing through measuring the phosphorylation of ERK1/2 and its regulator FGFR1 via western blot and qRT-PCR. In the in vivo study, we developed a GIO rat model by injecting methylprednisolone and modulated the miR-133a expression in the femur by intramedullary injection of the miR-133a antagomir, and then micro-CT analyses and histological staining of the femurs were used to investigate the effect of miR-133a silencing on bone loss of the GIO rats. Results qRT-PCR analysis indicated that glucocorticoid induced high miR-133a expression in MSCs and animal models. The in vitro study showed that miR-133a antagomir significantly promoted cell proliferation, viability, and osteoblast differentiation and inhibited adipocyte differentiation in DEX-treated MSCs. Furthermore, the expression of p-ERK1/2 and FGFR1 in DEX-treated MSCs was also upregulated by miR-133a antagomir. Then we investigated the effect of miR-133a silencing on the bone architecture of GIO models, micro-CT analysis showed that miR-133a antagomir attenuated the loss of bone mass and improved the trabecular and cortical parameters induced by methylprednisolone. Histological study showed that miR-133a silencing simultaneously increased bone formation and decreased marrow fat accumulation in GIO rats. Conclusions Our findings suggested that miR-133a is strongly associated with GIO and similar disorders induced by glucocorticoids in MSCs. Silencing miR-133a resulted in positive effects on GC-treated MSCs and on bone loss in GIO animal models. Moreover, the FGFR1-MAPK/ERK signaling may be involved in the protective effect of miR-133a silencing.

Description: Background Inguinal hernia repair, gallbladder removal, and knee- and hip replacements are the most commonly performed surgical procedures, but all are subject to practice variation and variable patient-reported outcomes. Shared decision-making (SDM) has the potential to reduce surgery rates and increase patient satisfaction. This study aims to evaluate the effectiveness of an SDM strategy with online decision aids for surgical and orthopaedic practice in terms of impact on surgery rates, patient-reported outcomes, and cost-effectiveness. Methods The E-valuAID-study is designed as a multicentre, non-randomized stepped-wedge study in patients with an inguinal hernia, gallstones, knee or hip osteoarthritis in six surgical and six orthopaedic departments. The primary outcome is the surgery rate before and after implementation of the SDM strategy. Secondary outcomes are patient-reported outcomes and cost-effectiveness. Patients in the usual care cluster prior to implementation of the SDM strategy will be treated in accordance with the best available clinical evidence, physician’s knowledge and preference and the patient’s preference. The intervention consists of the implementation of the SDM strategy and provision of disease-specific online decision aids. Decision aids will be provided to the patients before the consultation in which treatment decision is made. During this consultation, treatment preferences are discussed, and the final treatment decision is confirmed. Surgery rates will be extracted from hospital files. Secondary outcomes will be evaluated using questionnaires, at baseline, 3 and 6 months. Discussion The E-valuAID-study will examine the cost-effectiveness of an SDM strategy with online decision aids in patients with an inguinal hernia, gallstones, knee or hip osteoarthritis. This study will show whether decision aids reduce operation rates while improving patient-reported outcomes. We hypothesize that the SDM strategy will lead to lower surgery rates, better patient-reported outcomes, and be cost-effective. Trial registration: The Netherlands Trial Register, Trial NL8318, registered 22 January 2020. URL: https://www.trialregister.nl/trial/8318.

Description: Background Hepatic ischaemia-reperfusion injury (HIRI) is inevitable in complicated liver surgery and is a major factor leading to postoperative complications and liver dysfunction. Studies have shown that the paracrine mechanisms of stem cell may be essential to tissue repair and functional improvement after transplantation. However, the role of the adipose-derived mesenchymal stem cell secretome (ASC-secretome) in liver regeneration in large animals remains to be determined. Methods Twenty-four miniature pigs were subjected to laparoscopic liver ischaemia-reperfusion combined with partial hepatectomy and divided into the following four groups: the saline group, the DMEM group, the ASC group and the ASC-secretome group. Serum and liver tissue samples were collected before the operation and at 1, 3 and 7 days after the operation, and changes in tissue pathology, serum inflammation, liver function, angiogenesis-related factors and liver tissue regeneration-related genes and proteins were evaluated. Results Detailed histological analysis showed that ASCs and the ASC-secretome changed pathological damage to liver tissue after liver ischaemia-reperfusion combined with partial hepatectomy (1 and 3 days: p 

Description: Background This study developed a diagnostic tool to automatically detect normal, unclear and tumor images from colonoscopy videos using artificial intelligence. Methods For the creation of training and validation sets, 47,555 images in the jpg format were extracted from colonoscopy videos for 24 patients in Korea University Anam Hospital. A gastroenterologist with the clinical experience of 15 years divided the 47,555 images into three classes of Normal (25,895), Unclear (2038) and Tumor (19,622). A single shot detector, a deep learning framework designed for object detection, was trained using the 47,255 images and validated with two sets of 300 images—each validation set included 150 images (50 normal, 50 unclear and 50 tumor cases). Half of the 47,255 images were used for building the model and the other half were used for testing the model. The learning rate of the model was 0.0001 during 250 epochs (training cycles). Results The average accuracy, precision, recall, and F1 score over the category were 0.9067, 0.9744, 0.9067 and 0.9393, respectively. These performance measures had no change with respect to the intersection-over-union threshold (0.45, 0.50, and 0.55). This finding suggests the stability of the model. Conclusion Automated detection of normal, unclear and tumor images from colonoscopy videos is possible by using a deep learning framework. This is expected to provide an invaluable decision supporting system for clinical experts.

Description: Background Diabetes is a medical and economic burden in the United States. In this study, a machine learning predictive model was developed to predict unplanned medical visits among patients with diabetes, and findings were used to design a clinical intervention in the sponsoring healthcare organization. This study presents a case study of how predictive analytics can inform clinical actions, and describes practical factors that must be incorporated in order to translate research into clinical practice. Methods Data were drawn from electronic medical records (EMRs) from a large healthcare organization in the Northern Plains region of the US, from adult (≥ 18 years old) patients with type 1 or type 2 diabetes who received care at least once during the 3-year period. A variety of machine-learning classification models were run using standard EMR variables as predictors (age, body mass index (BMI), systolic blood pressure (BP), diastolic BP, low-density lipoprotein, high-density lipoprotein (HDL), glycohemoglobin (A1C), smoking status, number of diagnoses and number of prescriptions). The best-performing model after cross-validation testing was analyzed to identify strongest predictors. Results The best-performing model was a linear-basis support vector machine, which achieved a balanced accuracy (average of sensitivity and specificity) of 65.7%. This model outperformed a conventional logistic regression by 0.4 percentage points. A sensitivity analysis identified BP and HDL as the strongest predictors, such that disrupting these variables with random noise decreased the model’s overall balanced accuracy by 1.3 and 1.4 percentage points, respectively. These recommendations, along with stakeholder engagement, behavioral economics strategies, and implementation science principles helped to inform the design of a clinical intervention targeting behavioral changes. Conclusion Our machine-learning predictive model more accurately predicted unplanned medical visits among patients with diabetes, relative to conventional models. Post-hoc analysis of the model was used for hypothesis generation, namely that HDL and BP are the strongest contributors to unplanned medical visits among patients with diabetes. These findings were translated into a clinical intervention now being piloted at the sponsoring healthcare organization. In this way, this predictive model can be used in moving from prediction to implementation and improved diabetes care management in clinical settings.

Description: Background Hepatic fibrosis is a common complication in transfusion-dependent thalassemia patients. Data on the co-transplantation of mesenchymal stem cells (MSCs) with hematopoietic stem cells (HSCs) in beta-thalassemia major patients are scarce. Therefore, we aimed to evaluate the effect of co-transplantation of bone marrow-derived MSC with HSCs on the liver fibrosis alleviation and transplant outcomes in class III beta-thalassemia major. Methods Between April 1998 and January 2017, a total of 224 consecutive patients with class III beta-thalassemia major underwent allogeneic HSCT in the Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran. To assess liver fibrotic changes after transplantation, 47 patients participated in the MSC plus HSC group and 30 patients in the HSC only group at the end of the follow-up period. All patients underwent laboratory tests, especially serum ferritin and liver function testing, hepatic T2* MRI, liver biopsy, and FibroScan before and 2 years after transplantation. Kaplan-Meier curves were derived to determine survival and were compared using the log-rank test. Repeated-measure, mixed-effect linear regression models were used to examine the changes in liver fibrosis over time. Results The 10-year OS rate was 71.84% in the mesenchymal group and 61.89% in the non-mesenchymal group (P value = 0.294), while the 10-year TFS rate was 63.64% in the mesenchymal group and 52.78% in the non-mesenchymal group (P value = 0.285). No significant difference was observed in the 10-year NRM, rejection rate, ANC engraftment, platelet engraftment, acute GvHD, and chronic GvHD between the two groups. In addition, the results of repeated-measure, mixed-effect linear regression models showed that none of the variables determining hepatic fibrosis had a significant difference between patients receiving MSCs and patients who did not receive MSCs. Conclusions Based on the results of this study, a single infusion of MSCs at the time of HSCT to patients with class III beta-thalassemia major could not significantly improve the liver fibrosis alleviation and transplantation outcomes, including OS, TFS, TRM, rejection rate, ANC engraftment, platelet engraftment, acute GvHD, and chronic GvHD.

Description: Background Cesarean scar defect (CSD) is characterized by the presence of fibrotic tissue and decreased muscular density which is induced by cesarean section. Serious CSD may eventually result in infertility or obstetrical complications. Human amniotic epithelial cells (hAECs) have shown great promise in tissue regeneration. This study aims to investigate whether hAEC transplantation has the therapeutic effects on the rat uterine scar following full-thickness injury. Methods A rat uterine scar model was established by excising the full-thickness uterine wall of about 1.0 cm in length and 1/2–2/3 of the total circumference in width. At day 30 post-surgery, hAECs were transplanted into the uterine scar. At day 30 and 60 post-transplantation, hematoxylin and eosin (H&E) staining, Masson staining, and IHC staining for vWF, VEGFA, α-SMA, and MMP-8 were performed to evaluate the regeneration of the scarred uterus and the underlying mechanism. Pregnancy outcomes were assessed at day 60 after hAEC transplantation. Finally, hAECs were incubated with hydrogen peroxide to verify the paracrine effect of hAECs. Results Collagen deposition, thin myometrium, and injured endometrium were observed in the rat uterine scar model. After hAEC transplantation, collagen deposition in the uterine scar decreased, and myometrial and endometrial recovery was facilitated. hAEC transplantation also increased the fetus number implanted within the scarred area. Moreover, we found hAECs promoted angiogenesis via upregulation of VEGFA and decreased collagen deposition by upregulating MMP-8 in the uterine scar. The in vitro studies further demonstrated an increase in the expression level of MMP-8 in hAECs cultured with hydrogen peroxide. Conclusions These results suggested that hAEC transplantation may be efficacious in the functional repair and collagen degradation of uterine scars, which provides a new therapeutic strategy to CSD.

Description: Background Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for regenerative medicine and in drugs screening. Despite displaying key cardiomyocyte phenotypic characteristics, they more closely resemble fetal/neonatal cardiomyocytes and are still immature; these cells mainly rely on glucose as a substrate for metabolic energy, while mature cardiomyocytes mainly employ oxidative phosphorylation of fatty acids. Studies showed that the alteration of metabolism pattern from glycolysis to oxidative phosphorylation improve the maturity of hiPSC-CMs. As a transcription factor, accumulating evidences showed the important role of NRF2 in the regulation of energy metabolism, which directly regulates the expression of mitochondrial respiratory complexes. Therefore, we hypothesized that NRF2 is involved in the maturation of hiPSC-CMs. Methods The morphological and functional changes related to mitochondria and cell maturation were analyzed by knock-down and activation of NRF2. Results The results showed that the inhibition of NRF2 led to the retardation of cell maturation. The activation of NRF2 leads to a more mature hiPSC-CMs phenotype, as indicated by the increase of cardiac maturation markers, sarcomere length, calcium transient dynamics, the number and fusion events of mitochondria, and mitochondrial respiration. Bioinformatics analysis showed that in addition to metabolism-related genes, NRF2 also activates the expression of myocardial ion channels. Conclusions These findings indicated that NRF2 plays an important role in the maturation of hiPSC-CMs. The present work provides greater insights into the molecular regulation of hiPSC-CMs metabolism and theoretical basis in drug screening, disease modeling, and alternative treatment.

Description: Objectives Agarwood is the aromatic heartwood formed upon wounding of Aquilaria trees either naturally formed due to physical wound sustained from natural phenomena followed by microbial infection, or artificially induced using different inoculation methods. Different induction methods produce agarwoods with different aromas which have impacts on their commercial values. In lieu of elucidating the molecular mechanisms of agarwood formation under different treatment conditions, the transcriptome profiles of trunk tissues from healthy A. malaccensis tree, and naturally and artificially induced trees were obtained. Data description The transcriptome of trunk tissues from healthy A. malaccensis, and naturally and artificially induced trees were sequenced using Illumina HiSeq™ 4000 platform which resulted in a total of 38.4 Gb clean reads with Q30 rate of at least 91%. The transcriptome consists of 85,986 unigenes containing 1305 bases on average which were annotated against several databases. From this, 44,654 unigenes were mapped to 290 metabolic pathways in the Kyoto Encyclopedia of Genes and Genomes database. These transcriptome data represent considerable contribution towards Aquilaria transcriptome data and enhance current knowledge in comprehending the molecular mechanisms underlying agarwood formation in Aquilaria spp.

Description: Objectives The research aimed to determine the prevalence and associated factors of uncontrolled hyperlipidemia among Thai patients with the disease and Clinical ASCVD. Results A total of 1,527 Thai diabetic patients with a history of ASCVD were included in the study. Uncontrolled hyperlipidemia was detected among 1,216 patients (79.6%; 95% CI 77.6–81.7). The independent factors associated with uncontrolled hyperlipidemia included being female (adjusted odds ratio (AORs); 1.5, 95% CI 1.2–2.0), using thiazolidinedione (AORs; 1.7, 95% CI 1.1–2.7), community hospital (AORs; 4.3, 95% CI 1.0–18.0) and BMI level at 18.5–22.9 kg/m2 (AORs; 2.2, 95% CI 1.2–4.0), 23.0–24.9 kg/m2 (AORs; 1.8 95% CI 0.9–3.3), 25.0–29.9 kg/m2 (AORs; 2.3 95% CI 1.3–4.3) and ≥ 30 kg/m2 (AORs; 2.5 95% CI 1.3–4.9).

Description: Background Mesenchymal stem cells (MSCs) provide potential treatments for peritoneal fibrosis. However, MSCs cultured in media containing serum bring risks of infection and other problems. In this study, we compared the effect of human MSCs in serum-free medium (SF-MSCs) on peritoneal fibrosis with that of MSCs cultured in medium containing 10% fetal bovine serum (10%MSCs). Methods Peritoneal fibrosis was induced by intraperitoneally injecting 0.1% chlorhexidine gluconate (CG). SF-MSCs or 10%MSCs were intraperitoneally administered 30 min after the CG injection. Ten days after the CG and MSC injections, we performed histological analyses and peritoneal equilibrium testing. In the in vitro experiments, we used transforming growth factor (TGF)-β1-stimulated human peritoneal mesothelial cells incubated in conditioned medium from MSCs to examine whether the SF-MSCs showed enhanced ability to produce antifibrotic humoral factors. Results Histological staining showed that the SF-MSCs significantly suppressed CG-induced cell accumulation and thickening compared with that of the 10%MSCs. Additionally, the SF-MSCs significantly inhibited mesenchymal cell expression, extracellular matrix protein deposition and inflammatory cell infiltration. Peritoneal equilibration testing showed that compared with administering 10%MSCs, administering SF-MSCs significantly reduced the functional impairments of the peritoneal membrane. The in vitro experiments showed that although the conditioned medium from MSCs suppressed TGF-β1 signaling, the suppression did not significantly differ between the SF-MSCs and 10%MSCs. Conclusions Serum-free culture conditions can enhance the antifibrotic abilities of MSCs by suppressing inflammation. Administering ex vivo expanded SF-MSCs may be a potential therapy for preventing peritoneal fibrotic progression.

Description: Glioblastoma (GBM) is the highest-grade form of glioma, as well as one of the most aggressive types of cancer, exhibiting rapid cellular growth and highly invasive behavior. Despite significant advances in diagnosis and therapy in recent decades, the outcomes for high-grade gliomas (WHO grades III-IV) remain unfavorable, with a median overall survival time of 15–18 months. The concept of cancer stem cells (CSCs) has emerged and provided new insight into GBM resistance and management. CSCs can self-renew and initiate tumor growth and are also responsible for tumor cell heterogeneity and the induction of systemic immunosuppression. The idea that GBM resistance could be dependent on innate differences in the sensitivity of clonogenic glial stem cells (GSCs) to chemotherapeutic drugs/radiation prompted the scientific community to rethink the understanding of GBM growth and therapies directed at eliminating these cells or modulating their stemness. This review aims to describe major intrinsic and extrinsic mechanisms that mediate chemoradioresistant GSCs and therapies based on antineoplastic agents from natural sources, derivatives, and synthetics used alone or in synergistic combination with conventional treatment. We will also address ongoing clinical trials focused on these promising targets. Although the development of effective therapy for GBM remains a major challenge in molecular oncology, GSC knowledge can offer new directions for a promising future.

Description: Background Due to the need for informatics competencies in the field of nursing, the present study was conducted to design a psychometric instrument to determine the qualification of informatics competencies of employed nurses in educational care centers. Methods The questionnaire was made by reviewing existing scientific resources and assessment tools. Two hundred nurses were selected using simple random sampling. Structural equation modeling was used using the measurement model technique and the average variance was calculated. Linear structural relations (LISREL) software was used to test the assumptions and correlations of the model. Results Findings showed relatively good estimation in the fit of first-order measurement model. The informatics knowledge subscale with a determining rate of 0.90 had the greatest explanatory effect among the subscales and informatics skill with a determining rate of 0.67 and basic computer skill with a determining rate of 0.60 were observed. The second-order measurement model of fitness indicators showed that the three factors can well explain the multidimensional construct of informatics competency. Conclusions The designed tool can be used to develop educational strategies in relation to nursing students in the field of informatics and prepare them in the rich environment of information technology, which can be helpful in training nursing instructors.

Description: Background Questionnaires are commonly used tools in telemedicine services that can help to evaluate different aspects. Selecting the ideal questionnaire for this purpose may be challenging for researchers. This study aims to review which questionnaires are used to evaluate telemedicine services in the studies, which are most common, and what aspects of telemedicine evaluation do they capture. Methods The PubMed database was searched in August 2020 to retrieve articles. Data extracted from the final list of articles included author/year of publication, journal of publication, type of evaluation, and evaluation questionnaire. Data were analyzed using descriptive statistics. Results Fifty-three articles were included in this study. The questionnaire was used for evaluating the satisfaction (49%), usability (34%), acceptance (11.5%), and implementation (2%) of telemedicine services. Among telemedicine specific questionnaires, Telehealth Usability Questionnaire (TUQ) (19%), Telemedicine Satisfaction Questionnaire (TSQ) (13%), and Service User Technology Acceptability Questionnaire (SUTAQ) (5.5%), were respectively most frequently used in the collected articles. Other most used questionnaires generally used for evaluating the users’ satisfaction, usability, and acceptance of technology were Client Satisfaction Questionnaire (CSQ) (5.5%), Questionnaire for User Interaction Satisfaction (QUIS) (5.5%), System Usability Scale (SUS) (5.5%), Patient Satisfaction Questionnaire (PSQ) (5.5%), and Technology Acceptance Model (TAM) (3.5%) respectively. Conclusion Employing specifically designed questionnaires or designing a new questionnaire with fewer questions and more comprehensiveness in terms of the issues studied provides a better evaluation. Attention to user needs, end-user acceptance, and implementation processes, along with users' satisfaction and usability evaluation, may optimize telemedicine efforts in the future.

Description: Background Severe, steroid-resistant asthma (SSRA) is a serious clinical problem in asthma management. Affected patients have severe clinical symptoms, worsened quality of life, and do not respond to steroid, a mainstay steroid treatment of asthma. Thus, effective therapies are urgently needed. Exosomes derived from mesenchymal stem cell (MSC-Exo) has become attractive candidates for the lung inflammatory diseases through its immunomodulatory effects. In this study, we explored the therapeutic effects of MSC-Exo in SSRA and identified the therapeutic mechanism of MSC-Exo. Method Exosomes from human umbilical cord mesenchymal stem cell (hUCMSC) were isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis and flow cytometry analysis. Effects of MSC-Exo on airway hyper responsiveness (AHR), inflammation, histopathology, and macrophage polarization in SSRA in mice were evaluated. Systematic depletion of macrophages determined the role of macrophages in the therapeutic effect of SSRA in mice. LPS-stimulated RAW 264.7 cell model was constructed to determine the underlying mechanism of MSC-Exo on macrophage polarization. qRT-PCR, Western blotting, immunofluorescence, and flow cytometry were performed to evaluate the expression of M1 or M2 markers. Tandem mass tags (TMT)-labeled quantitative proteomics were applied to explore the central protein during the regulation effect of MSC-Exo on macrophage polarization. Knockdown and overexpression of TRAF1 were used to further clarify the role of the central protein on macrophage polarization. Result We successfully isolated and characterized exosomes from hUCMSCs. We verified that the intratracheal administration of MSC-Exo reversed AHR, histopathology changes, and inflammation in SSRA mice. Systematic depletion of macrophages weakened the therapeutic effect of MSC-Exo. We found that MSC-Exo treatment inhibited M1 polarization and promoted M2 polarization in LPS-stimulated RAW 264.7 cells. Subsequently, tumor necrosis factor receptor-associated factor 1 (TRAF1) was determined as the central protein which may be closely related to the regulation of macrophage polarization from TMT-labeled quantitative proteomics analysis. Knockdown and overexpression of TRAF1 demonstrated that the effect of MSC-Exo treatment on macrophage polarization, NF-κB and PI3K/AKT signaling was dependent on TRAF1. Conclusion MSC-Exo can ameliorate SSRA by moderating inflammation, which is achieved by reshaping macrophage polarization via inhibition of TRAF1.

Description: Objective The use of genome sequences from strains authenticated to correct species level is a prerequisite for confidently exploring the evolutionary relationship among related species. Aspergillus strains erroneously curated as Aspergillus oryzae and Aspergillus fumigatus have been noticed in the National Center for Biotechnology Information (NCBI) genome database. Aspergillus parasiticus is one of several aspergilli that produce aflatoxin, the most potent carcinogenic mycotoxin known up to now. To ensure that valid conclusions are drawn by researchers from their genomics-related studies, molecular analyses were carried out to authenticate identities of A. parasiticus strains in the NCBI genome database. Results Two of the nine supposedly A. parasiticus strains, E1365 and NRRL2999, were found to be misidentified. They turned out to be Aspergillus flavus based on genome-wide single nucleotide polymorphisms (SNPs) and genetic features associated with production of aflatoxin and cyclopiazonic acid. NRRL2999 lacked the additional partial aflatoxin gene cluster known to be present in its equivalent strain, designated as SU-1, and shared a very low total SNPs count specifically with A. flavus NRRL3357 but not with other A. flavus isolates. Therefore, the mislabeled NRRL2999 strain actually is a clonal strain of A. flavus NRRL3357, whose genome was first sequenced in 2005.

Description: Objective Intellectual Disability (ID) represents a neuropsychiatric disorder, which its etiopathogenesis remains insufficiently understood. Mutations in the Aristaless Related Homeobox gene (ARX) have been identified to cause syndromic and nonsyndromic (NS-ID). The most recurrent mutation of this gene is a duplication of 24pb, c.428-451dup. Epidemiological and genetic studies about ID in the Moroccan population remain very scarce, and none study is carried out on the ARX gene. This work aimed to study c.428–451dup (24 bp) mutation in the exon 2 of the ARX gene in 118 males’ Moroccan patients with milder NS-ID to evaluate if the gene screening is a good tool for identifying NS-ID. Results Our mutational analysis did not show any dup(24pb) in our patients. This is because based on findings from previous studies that found ARX mutations in 70% of families with NS-ID, and in most cases, 1.5–6.1% of individuals with NS-ID have this duplication. Since 1/118 = 0.0084 (0.84%) is not much different from 1.5%, then it is reasonable that this could a sample size artifact. A complete screening of the entire ARX gene, including the five exons, should be fulfilled. Further investigations are required to confirm these results.

Description: Objectives Microbes can contaminate foodstuffs resulting in foodborne illnesses. Investigating microbial hazards in foods at the point of sale with rapid tools is required to avoid foodborne illness outbreaks. The current study aimed to identify the microbial hazards in food samples collected from retail shops at sale points using MALDI-TOF MS. Results Food samples were collected from stores and supermarkets in four Delta cities (Tanta, Kutour, Kafr-Elzayat and Benha). Analysis of 178 samples of fish, meat and dairy products revealed 20 different bacterial species. 44.76% of isolates were identified as E. coli, 17.44% were identified as Enterobacter spp., and E. cloacae was predominant. 12.2% were identified as Citrobacter spp., and C. braakii was predominant, and 8.7% were identified as Klebsiella spp., and K. pneumoniae was predominant. Moreover, eight Proteus mirabilis, six Morganella morganii, five Staphylococcus hominis, three Serratia marcescens, two Pseudomonas aeruginosa, one Salmonella typhimurium and one Enterococcus faecalis were detected. Foodstuffs not only be contaminated during production and processing but also during storage and transport. Identification of harmful human pathogens in foodstuffs is alarming and consider threatening to public health. Identification of microbiological hazards in foods using MALDI-TOF MS provides an efficient tool for identifying foodborne pathogens.

Description: Background While therapeutic success of the limbal tissue or cell transplantation to treat severe cases of limbal stem cell (LSC) deficiency (LSCD) strongly depends on the percentage of LSCs within the transplanted cells, prospective LSC enrichment has been hampered by the intranuclear localization of the previously reported LSC marker p63. The recent identification of the ATP-binding cassette transporter ABCB5 as a plasma membrane-spanning marker of LSCs that are capable of restoring the cornea and the development of an antibody directed against an extracellular loop of the ABCB5 molecule stimulated us to develop a novel treatment strategy based on the utilization of in vitro expanded allogeneic ABCB5+ LSCs derived from human cadaveric limbal tissue. Methods We developed and validated a Good Manufacturing Practice- and European Pharmacopeia-conform production and quality-control process, by which ABCB5+ LSCs are derived from human corneal rims, expanded ex vivo, isolated as homogenous cell population, and manufactured as an advanced-therapy medicinal product (ATMP). This product was tested in a preclinical study program investigating the cells’ engraftment potential, biodistribution behavior, and safety. Results ABCB5+ LSCs were reliably expanded and manufactured as an ATMP that contains comparably high percentages of cells expressing transcription factors critical for LSC stemness maintenance (p63) and corneal epithelial differentiation (PAX6). Preclinical studies confirmed local engraftment potential of the cells and gave no signals of toxicity and tumorgenicity. These findings were sufficient for the product to be approved by the German Paul Ehrlich Institute and the U.S. Food & Drug Administration to be tested in an international multicenter phase I/IIa clinical trial (NCT03549299) to evaluate the safety and therapeutic efficacy in patients with LSCD. Conclusion Building upon these data in conjunction with the previously shown cornea-restoring capacity of human ABCB5+ LSCs in animal models of LSCD, we provide an advanced allogeneic LSC-based treatment strategy that shows promise for replenishment of the patient’s LSC pool, recreation of a functional barrier against invading conjunctival cells and restoration of a transparent, avascular cornea.

Description: Objectives To reduce the spread of the infection, especially during aerosol generating procedures, we invented “The Cupola”, a shield that creates a mechanical barrier around the patient’s head and body. With this pilot study we aimed to assess the effectiveness of an additional layer of protection (The Cupola) developed for providers working in the oropharyngeal region. Results The mean number of 0.3 μm particles with no Cupola was 3777 (SD: ± 556), with The Cupola was 2068 (SD: ± 1468) and with the Cupola and Drape was 2031 (SD: ± 1108) (p 

Description: Objective CD4 Lymphocyte Count (CD4) is a major predictor of HIV progression to AIDS. Exploring the factors affecting CD4 levels may assist healthcare staff and patients in management and monitoring of health cares. This retrospective cohort study aimed to explore factors associated with CD4 cell counts at the time of diagnosis in HIV patients using Poisson, Generalized Poisson, and Negative Binomial regression models. Results Out of 4402 HIV patients diagnosis in Iran from 1987 to 2016, 3030 (68.8%) were males, and the mean age was 34.8 ± 10.4 years. The results indicate that the Negative Binomial model outperformed the other models in terms of AIC, log-likelihood and RMSE criteria. In this model, factors include sex, age, clinical stage and Tuberculosis (TB) co-infection were significantly associated with CD4 count (P 

Description: Objectives Universal stool banks provide stool to physicians for use in treating recurrent Clostridioides difficile infection via fecal microbiota transplantation. Stool donors providing the material are rigorously screened for diseases and disorders with a potential microbiome etiology, and they are likely healthier than the controls in most microbiome datasets. 16S rRNA sequencing was performed on samples from a selection of stool donors at a large stool bank, OpenBiome, to characterize their gut microbial community and to compare samples across different timepoints and sequencing runs. Data description 16S rRNA sequencing was performed on 200 samples derived from 170 unique stool donations from 86 unique donors. Samples were sequenced on 11 different sequencing runs. We are making this data available because rigorously screened, likely very healthy stool donors may be useful for characterizing and understanding microbial community differences across different populations and will help shed light into the how the microbiome community promotes health and disease.

Description: Objectives Human T cell leukemia virus-1 (HTLV-1) infection may lead to one or both diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T cell leukemia lymphoma (ATLL). The complete interactions of the virus with host cells in both diseases is yet to be determined. This study aims to construct an interaction network for distinct signaling pathways in these diseases based on finding differentially expressed genes (DEGs) between HAM/TSP and ATLL. Results We identified 57 hub genes with higher criteria scores in the primary protein–protein interaction network (PPIN). The ontology-based enrichment analysis revealed following important terms: positive regulation of transcription from RNA polymerase II promoter, positive regulation of transcription from RNA polymerase II promoter involved in meiotic cell cycle and positive regulation of transcription from RNA polymerase II promoter by histone modification. The upregulated genes TNF, PIK3R1, HGF, NFKBIA, CTNNB1, ESR1, SMAD2, PPARG and downregulated genes VEGFA, TLR2, STAT3, TLR4, TP53, CHUK, SERPINE1, CREB1 and BRCA1 were commonly observed in all the three enriched terms in HAM/TSP vs. ATLL. The constructed interaction network was then visualized inside a mirrored map of signaling pathways for ATLL and HAM/TSP, so that the functions of hub genes were specified in both diseases.

Description: Objectives The emergence of colistin-resistant Enterobacteriaceae from human and animal sources is one of the major public health concerns as colistin is the last-resort antibiotic for treating infections caused by multidrug-resistant Gram-negative bacteria. We aimed to determine the prevalence of the prototype widespread colistin resistance genes (mcr-1 and mcr-2) among commensal and pathogenic Escherichia coli strains isolated from food-producing and companion animals in Iran. Results A total of 607 E. coli isolates which were previously collected from different animal sources between 2008 and 2016 used to uncover the possible presence of plasmid-mediated colistin resistance genes (mcr-1 and mcr-2) by PCR. Overall, our results could not confirm the presence of any mcr-1 or mcr-2 positive E. coli among the studied isolates. It is concluded that despite the important role of food-producing animals in transferring the antibiotic resistance, they were not the main source for carriage of mcr-1 and mcr-2 in Iran until 2016. This study suggests that the other mcr variants (mcr-3 to mcr-9) might be responsible for conferring colistin resistance in animal isolates in Iran. The possible linkage between pig farming industry and high level of mcr carriage in some countries needs to be clarified in future prospective studies.

Description: Objective To address the challenge of computational identification of cell type-specific regulatory elements on a genome-wide scale. Results We propose SeqEnhDL, a deep learning framework for classifying cell type-specific enhancers based on sequence features. DNA sequences of “strong enhancer” chromatin states in nine cell types from the ENCODE project were retrieved to build and test enhancer classifiers. For any DNA sequence, positional k-mer (k = 5, 7, 9 and 11) fold changes relative to randomly selected non-coding sequences across each nucleotide position were used as features for deep learning models. Three deep learning models were implemented, including multi-layer perceptron (MLP), Convolutional Neural Network (CNN) and Recurrent Neural Network (RNN). All models in SeqEnhDL outperform state-of-the-art enhancer classifiers (including gkm-SVM and DanQ) in distinguishing cell type-specific enhancers from randomly selected non-coding sequences. Moreover, SeqEnhDL can directly discriminate enhancers from different cell types, which has not been achieved by other enhancer classifiers. Our analysis suggests that both enhancers and their tissue-specificity can be accurately identified based on their sequence features. SeqEnhDL is publicly available at https://github.com/wyp1125/SeqEnhDL.

Description: Background Environmental factors, such as oxidative stress, have the potential to modify the epigenetic landscape of cells. We have previously shown that DNA methyltransferase (DNMT) activity can be inhibited by sublethal doses of hydrogen peroxide (H2O2). However, site-specific changes in DNA methylation and the reversibility of any changes have not been explored. Using bead chip array technology, differential methylation was assessed in Jurkat T-lymphoma cells following exposure to H2O2. Results Sublethal H2O2 exposure was associated with an initial genome-wide decrease in DNA methylation in replicating cells, which was largely corrected 72 h later. However, some alterations were conserved through subsequent cycles of cell division. Significant changes to the variability of DNA methylation were also observed both globally and at the site-specific level. Conclusions This research indicates that increased exposure to H2O2 can result in long-term alterations to DNA methylation patterns, providing a mechanism for environmental factors to have prolonged impact on gene expression.

Description: Background Tumor angiogenesis, an essential process for cancer proliferation and metastasis, has a critical role in prognostic of kidney renal clear cell carcinoma (KIRC), as well as a target in guiding treatment with antiangiogenic agents. However, tumor angiogenesis subtypes and potential epigenetic regulation mechanisms in KIRC patient remains poorly characterized. System evaluation of angiogenesis subtypes in KIRC patient might help to reveal the mechanisms of KIRC and develop more target treatments for patients. Method Ten independent tumor angiogenesis signatures were obtained from molecular signatures database (MSigDB) and gene set variation analysis was performed to calculate the angiogenesis score in silico using the Cancer Genome Atlas (TCGA) KIRC dataset. Tumor angiogenesis subtypes in 539 TCGA-KIRC patients were identified using consensus clustering analysis. The potential regulation mechanisms was studied using gene mutation, copy number variation, and differential methylation analysis (DMA). The master transcription factors (MTF) that cause the difference in tumor angiogenesis signals were completed by transcription factor enrichment analysis. Results The angiogenesis score of a prognosis related angiogenesis signature including 189 genes was significantly correlated with immune score, stroma score, hypoxia score, and vascular endothelial growth factor (VEGF) signal score in 539 TCGA KIRC patients. MMRN2, CLEC14A, ACVRL1, EFNB2, and TEK in candidate gene set showed highest correlation coefficient with angiogenesis score in TCGA-KIRC patients. In addition, all of them were associated with overall survival in both TCGA-KIRC and E-MTAB-1980 KIRC data. Clustering analysis based on 183 genes in angiogenesis signature identified two prognosis related angiogenesis subtypes in TCGA KIRC patients. Two clusters also showed different angiogenesis score, immune score, stroma score, hypoxia score, VEGF signal score, and microenvironment score. DMA identified 59,654 differential methylation sites between two clusters and part of these sites were correlated with tumor angiogenesis genes including CDH13, COL4A3, and RHOB. In addition, RFX2, SOX13, and THRA were identified as top three MTF in regulating angiogenesis signature in KIRC patients. Conclusion Our study indicate that evaluation the angiogenesis subtypes of KIRC based on angiogenesis signature with 183 genes and potential epigenetic mechanisms may help to develop more target treatments for KIRC patients.

Description: Background CP12 is a small chloroplast protein that is widespread in various photosynthetic organisms and is an actor of the redox signaling pathway involved in the regulation of the Calvin Benson Bassham (CBB) cycle. The gene encoding this protein is conserved in many diatoms, but the protein has been overlooked in these organisms, despite their ecological importance and their complex and still enigmatic evolutionary background. Methods A combination of biochemical, bioinformatics and biophysical methods including electrospray ionization-mass spectrometry, circular dichroism, nuclear magnetic resonance spectroscopy and small X ray scattering, was used to characterize a diatom CP12. Results Here, we demonstrate that CP12 is expressed in the marine diatom Thalassiosira pseudonana constitutively in dark-treated and in continuous light-treated cells as well as in all growth phases. This CP12 similarly to its homologues in other species has some features of intrinsically disorder protein family: it behaves abnormally under gel electrophoresis and size exclusion chromatography, has a high net charge and a bias amino acid composition. By contrast, unlike other known CP12 proteins that are monomers, this protein is a dimer as suggested by native electrospray ionization-mass spectrometry and small angle X-ray scattering. In addition, small angle X-ray scattering revealed that this CP12 is an elongated cylinder with kinks. Circular dichroism spectra indicated that CP12 has a high content of α-helices, and nuclear magnetic resonance spectroscopy suggested that these helices are unstable and dynamic within a millisecond timescale. Together with in silico predictions, these results suggest that T. pseudonana CP12 has both coiled coil and disordered regions. Conclusions These findings bring new insights into the large family of dynamic proteins containing disordered regions, thus increasing the diversity of known CP12 proteins. As it is a protein that is more abundant in many stresses, it is not devoted to one metabolism and in particular, it is not specific to carbon metabolism. This raises questions about the role of this protein in addition to the well-established regulation of the CBB cycle. Choregraphy of metabolism by CP12 proteins in Viridiplantae and Heterokonta. While the monomeric CP12 in Viridiplantae is involved in carbon assimilation, regulating phosphoribulokinase (PRK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) through the formation of a ternary complex, in Heterokonta studied so far, the dimeric CP12 is associated with Ferredoxin-NADP reductase (FNR) and GAPDH. The Viridiplantae CP12 can bind metal ions and can be a chaperone, the Heterokonta CP12 is more abundant in all stresses (C, N, Si, P limited conditions) and is not specific to a metabolism.

Description: Background Lysosome-associated membrane protein type 2A (LAMP-2A) is the key component of chaperone-mediated autophagy (CMA), a cargo-selective lysosomal degradation pathway. Aberrant LAMP-2A expression and CMA activation have been demonstrated in various human malignancies. The study focusing on the intrinsic role of LAMP-2A and CMA in glioblastoma (GBM), and downstream mechanism could provide valuable insight into the pathogenesis and novel therapeutic modality of GBM. Methods The levels of LAMP-2A, nuclear receptor co-repressor (N-CoR), unfolded protein response (UPR) and apoptosis were examined in clinical samples. LAMP-2A siRNA and shRNA were constructed to manipulate CMA activation. The role of CMA and downstream mechanism through degradation of N-CoR and arresting UPR mediated apoptosis were explored in GBM cells and nude mouse xenograft model. Results Elevated LAMP-2A and associated decreased N-CoR expression were observed in GBM as compared with peritumoral region and low-grade glioma. Inhibited UPR and apoptosis were observed in GBM with high LAMP-2A expression. In vitro study demonstrated co-localization and interaction between LAMP-2A and N-CoR. LAMP-2A silencing up-regulated N-CoR and aroused UPR pathway, leading to apoptosis, while N-CoR silencing led to an opposite result. In vivo study further confirmed that LAMP-2A inhibition arrested tumor growth by promoting apoptosis. Conclusions Our results demonstrated the central role of CMA in mediating N-CoR degradation and protecting GBM cells against UPR and apoptosis, and provided evidence of LAMP-2A as potential biomarker. Further research focusing on CMA with other tumorigenic process is needed and selective modulators of LAMP-2A remain to be investigated to provide a novel therapeutic strategy for GBM.

Description: Stem cells are characterized by their self-renewal and multipotency and have great potential in the therapy of various disorders. However, the blood–brain barrier (BBB) limits the application of stem cells in the therapy of neurological disorders, especially in a noninvasive way. It has been shown that small molecular substances, macromolecular proteins, and even stem cells can bypass the BBB and reach the brain parenchyma following intranasal administration. Here, we review the possible brain-entry routes of transnasal treatment, the cell types, and diseases involved in intranasal stem cell therapy, and discuss its advantages and disadvantages in the treatment of central nervous system diseases, to provide a reference for the application of intranasal stem cell therapy.

Description: Background Several studies have confirmed that mobilizing bone marrow-derived stem cells (BMSCs) ameliorates renal function loss following cisplatin-induced acute kidney injury (AKI). The aim of this study was to explore whether the combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor (AMD3100) exerts beneficial effects on renal function recovery in a model of cisplatin-induced nephrotoxicity. Methods C57BL/6J mice received intraperitoneal injections of G-CSF (200 μg/kg/day) for 5 consecutive days. On the day of the last injection, the mice received a single subcutaneous dose of AMD3100 (5 mg/kg) 1 h before cisplatin 20 mg/kg injection. Ninety-six hours after cisplatin injection, the mice were euthanized, and blood and tissue samples were collected to assess renal function and tissue damage. Cell mobilization was assessed by flow cytometry (FCM). Results Mice pretreated with G-CSF/AMD3100 exhibited longer survival and lower serum creatinine and blood urea nitrogen (BUN) levels than mice treated with only G-CSF or saline. Combinatorial G-CSF/AMD3100 treatment attenuated tissue injury and cell death, enhanced cell regeneration, and mobilized a higher number of stem cells in the peripheral blood than G-CSF or saline treatment. Furthermore, the mRNA expression of proinflammatory factors was lower, whereas that of anti-inflammatory factors was higher, in the G-CSF/AMD3100 group than in the G-CSF or saline group (all P 

Description: Objective Diversion of less urgent emergency medical services (EMS) callers to alternative primary care (PC) is much debated. Using data from the EMACROSS survey of respiratory ED patients, we aimed to characterize self-referred EMS patients, compare these with non-EMS patients, and assess scope and acceptability of a potential redirection to alternative PC. Results Of n = 292 self-referred patients, n = 99 were transported by EMS. Compared to non-EMS patients, these were older, triaged more urgently and arrived out-of-hours more frequently. The share of chronically and severely ill patients was greater. Out-of-hours ED visit, presence of a chronic pulmonary condition as well as a hospital diagnosis of respiratory failure were identified as determinants of EMS utilization in a logistic model, while consultation for access and quality motives as well as migrant status decreased the probability. EMS-transported lower urgency outpatients visiting during regular physicians’ hours were defined as potential PC cases and evaluated descriptively (n = 9). As a third was medically complex and potentially less suitable for PC, redirection potential could be estimated at only 6% of EMS cases. This would be reduced to 2% if considering patients’ judgment concerning the appropriate setting. Overall, the scope for PC diversion of respiratory EMS patients seems limited.

Description: Objective The Middle East respiratory syndrome coronavirus (MERS-CoV) is one of the zoonotic coronaviruses [Hemida Peer J 7:e7556, 2019; Hemida et al. One Health 8:100102, 2019]. The dromedary camels remained the only known animal reservoir for this virus. Several aspects of the transmission cycle of the virus between animals, including arthropod-borne infection, is still largely unknown. The main objective of the current work was to study the possibility of MERS-CoV transmission through some arthropod vectors, particularly the hard ticks. To achieve this objective, we identified a positive MERS-CoV dromedary camel herd using the commercial available real-time PCR kits. We collected some arthropods, particularly the ticks from these positive animals as well as from the animal habitats. We tested these arthropods for the presence of MERS-CoV viral RNAs. Results Our results showing the absence of any detectable MERS-CoV-RNAs in these arthropods despite these animals were actively shedding the virus in their nasal secretions. Our results are confirming for the first the failure of detection of the MERS-CoV in ticks infesting dromedary camels. Failure of the detection of MERS-CoV in ticks infesting positive naturally infected MERS-CoV camels is strongly suggesting that ticks do not play roles in the transmission of the virus among the animals and close contact humans.

Description: Introduction Renal interstitial fibrosis, an important pathological feature of kidney aging and chronic renal failure, is regulated by mesenchymal stem cells (MSCs). We have previously demonstrated low expression of miR-133b in MSC-derived extracellular vesicles (MSC-EVs) in aged rats. However, miR-133b can mediate the inhibition of epithelial-mesenchymal transition (EMT) of renal tubules induced by transforming growth factor-β1 (TGF-β1). We investigated the effect of miR-133b for the treatment of geriatric renal interstitial fibrosis and evaluated its target genes. Methods We performed real-time polymerase chain reaction to detect miR-133b expression induced during EMT of HK2 cells by TGF-β1 at different concentrations (0, 6, 8, and 10 ng/mL) and at different time points (0, 24, 48, and 72 h). The target genes of miR-133b were validated using the dual-luciferase reporter assay. In vitro experiments were performed to evaluate mRNA and protein expression of miR-133b targets, E-cadherin, α-smooth muscle actin (SMA), fibronectin, and collagen 3A1 (Col3A1), in HK2 cells transfected with miR-133b under TGF-β1 stimulation. A 24-month-old unilateral ureteral obstruction (UUO) mouse model was established and injected with transfection reagent and miR-133b into the caudal vein. The target gene of miR-133b and other parameters mentioned above such as mRNA and protein expression levels and renal interstitial fibrosis were detected at 7 and 14 days. Results miR-133b expression gradually decreased with an increase in TGF-β1 concentration and treatment time, and the miR-133b mimic downregulated connective tissue growth factor (CTGF) expression. The dual-luciferase reporter assay confirmed CTGF as a direct target of miR-133b. Transfection of the miR-133b mimic inhibited TGF-β1-induced EMT of HK2 cells; this effect was reversed by CTGF overexpression. miRNA-133b expression significantly increased (approximately 70–100 times) in mouse kidney tissues after injection of the miRNA-133b overexpression complex, which significantly alleviated renal interstitial fibrosis in mice with UUO. Conclusion miR-133b exerted targeted inhibitory effects on CTGF expression, which consequently reduced TGF-β1-induced EMT of HK2 cells and renal interstitial fibrosis in aged mice with UUO.

Description: Background Clinical Decision Support Systems (CDSSs) for Prescribing are one of the innovations designed to improve physician practice performance and patient outcomes by reducing prescription errors. This study was therefore conducted to examine the effects of various CDSSs on physician practice performance and patient outcomes. Methods This systematic review was carried out by searching PubMed, Embase, Web of Science, Scopus, and Cochrane Library from 2005 to 2019. The studies were independently reviewed by two researchers. Any discrepancies in the eligibility of the studies between the two researchers were then resolved by consulting the third researcher. In the next step, we performed a meta-analysis based on medication subgroups, CDSS-type subgroups, and outcome categories. Also, we provided the narrative style of the findings. In the meantime, we used a random-effects model to estimate the effects of CDSS on patient outcomes and physician practice performance with a 95% confidence interval. Q statistics and I2 were then used to calculate heterogeneity. Results On the basis of the inclusion criteria, 45 studies were qualified for analysis in this study. CDSS for prescription drugs/COPE has been used for various diseases such as cardiovascular diseases, hypertension, diabetes, gastrointestinal and respiratory diseases, AIDS, appendicitis, kidney disease, malaria, high blood potassium, and mental diseases. In the meantime, other cases such as concurrent prescribing of multiple medications for patients and their effects on the above-mentioned results have been analyzed. The study shows that in some cases the use of CDSS has beneficial effects on patient outcomes and physician practice performance (std diff in means = 0.084, 95% CI 0.067 to 0.102). It was also statistically significant for outcome categories such as those demonstrating better results for physician practice performance and patient outcomes or both. However, there was no significant difference between some other cases and traditional approaches. We assume that this may be due to the disease type, the quantity, and the type of CDSS criteria that affected the comparison. Overall, the results of this study show positive effects on performance for all forms of CDSSs. Conclusions Our results indicate that the positive effects of the CDSS can be due to factors such as user-friendliness, compliance with clinical guidelines, patient and physician cooperation, integration of electronic health records, CDSS, and pharmaceutical systems, consideration of the views of physicians in assessing the importance of CDSS alerts, and the real-time alerts in the prescription.

Description: Objective In contrast to childhood obesity, studies involving thin children are much fewer, especially in developed countries. Furthermore, most reports do not address the impact of childhood thinness on height velocity. This study investigated the prevalence of thinness and its effect on height velocity in schoolchildren in the United Arab Emirates (UAE). Weight and height were measured in 29,410 schoolchildren (50.5% females), as part of the health assessment (academic year 2014–2015). The body mass index (BMI) was classified as normal, thinness, overweight, or obese using cutoffs established by the International Obesity Task Force (IOTF), World Health Organization, and Centers for Disease Control. Results The median age was 10.2 years (range, 3–19). Using the IOTF scale, one-quarter of the children aged 4–6 years and one-third of the children aged 7–9 years were thin (BMI ≤ 18.5 kg/m2). Thinness was less prevalent (8–10%) in adolescents. Group peak height velocity was delayed 1–3 years in thin children and was higher in children with excess body fat. In conclusion thinness was the highest (25–33%) in children aged 4–9 years of age and their peak height velocity was delayed 1–3 years when compared to the other children.

Description: Objectives This study aims to investigate whether apoptosis repressor with caspase recruitment domain (ARC) could promote survival and enhance osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Materials and methods The lentivirus transfection method was used to establish ARC-overexpressing BMSCs. The CCK-8 method was used to detect cell proliferation. The BD Pharmingen™ APC Annexin V Apoptosis Detection kit was used to detect cell apoptosis. The osteogenic capacity was investigated by OCN immunofluorescence staining, ALP analysis, ARS assays, and RT-PCR analysis. Cells were seeded into calcium phosphate cement (CPC) scaffolds and then inserted subcutaneously into nude mice and the defect area of the rat calvarium. Histological analysis was conducted to evaluate the in vivo cell apoptosis and new bone formation of the ARC-overexpressing BMSCs. RNA-seq was used to detect the possible mechanism of the effect of ARC on BMSCs. Results ARC promoted BMSC proliferation and inhibited cell apoptosis. ARC enhanced BMSC osteogenic differentiation in vitro. An in vivo study revealed that ARC can inhibit BMSC apoptosis and increase new bone formation. ARC regulates BMSCs mainly by activating the Fgf-2/PI3K/Akt pathway. Conclusions The present study suggests that ARC is a powerful agent for promoting bone regeneration of BMSCs and provides a promising method for bone tissue engineering.

Description: Background Peripheral arterial disease (PAD) affects millions of people and compromises quality of life. Critical limb ischemia (CLI), which is the most advanced stage of PAD, can cause nonhealing ulcers and strong chronic pain, and it shortens the patients’ life expectancy. Cell-based angiogenic therapies are becoming a real therapeutic approach to treat CLI. Pericytes are cells that surround vascular endothelial cells to reinforce vessel integrity and regulate local blood pressure and metabolism. In the past decade, researchers also found that pericytes may function as stem or progenitor cells in the body, showing the potential to differentiate into several cell types. We investigated the gene expression profiles of pericytes during the early stages of limb ischemia, as well as the alterations in pericyte subpopulations to better understand the behavior of pericytes under ischemic conditions. Methods In this study, we used a hindlimb ischemia model to mimic CLI in C57/BL6 mice and explore the role of pericytes in regeneration. To this end, muscle pericytes were isolated at different time points after the induction of ischemia. The phenotypes and transcriptomic profiles of the pericytes isolated at these discrete time points were assessed using flow cytometry and RNA sequencing. Results Ischemia triggered proliferation and migration and upregulated the expression of myogenesis-related transcripts in pericytes. Furthermore, the transcriptomic analysis also revealed that pericytes induce or upregulate the expression of a number of cytokines with effects on endothelial cells, leukocyte chemoattraction, or the activation of inflammatory cells. Conclusions Our findings provide a database that will improve our understanding of skeletal muscle pericyte biology under ischemic conditions, which may be useful for the development of novel pericyte-based cell and gene therapies.

Description: Over recent years, mesenchymal stem/stromal cells (MSCs) and their potential biomedical applications have received much attention from the global scientific community in an increasing manner. Firstly, MSCs were successfully isolated from human bone marrow (BM), but in the next steps, they were also extracted from other sources, mostly from the umbilical cord (UC) and adipose tissue (AT). The International Society for Cellular Therapy (ISCT) has suggested minimum criteria to identify and characterize MSCs as follows: plastic adherence, surface expression of CD73, D90, CD105 in the lack of expression of CD14, CD34, CD45, and human leucocyte antigen-DR (HLA-DR), and also the capability to differentiate to multiple cell types including adipocyte, chondrocyte, or osteoblast in vitro depends on culture conditions. However, these distinct properties, including self-renewability, multipotency, and easy accessibility are just one side of the coin; another side is their huge secretome which is comprised of hundreds of mediators, cytokines, and signaling molecules and can effectively modulate the inflammatory responses and control the infiltration process that finally leads to a regulated tissue repair/healing or regeneration process. MSC-mediated immunomodulation is a direct result of a harmonic synergy of MSC-released signaling molecules (i.e., mediators, cytokines, and chemokines), the reaction of immune cells and other target cells to those molecules, and also feedback in the MSC-molecule-target cell axis. These features make MSCs a respectable and eligible therapeutic candidate to be evaluated in immune-mediated disorders, such as graft versus host diseases (GVHD), multiple sclerosis (MS), Crohn’s disease (CD), and osteoarthritis (OA), and even in immune-dysregulating infectious diseases such as the novel coronavirus disease 2019 (COVID-19). This paper discussed the therapeutic applications of MSC secretome and its biomedical aspects related to immune-mediated conditions. Sources for MSC extraction, their migration and homing properties, therapeutic molecules released by MSCs, and the pathways and molecular mechanisms possibly involved in the exceptional immunoregulatory competence of MSCs were discussed. Besides, the novel discoveries and recent findings on immunomodulatory plasticity of MSCs, clinical applications, and the methods required for their use as an effective therapeutic option in patients with immune-mediated/immune-dysregulating diseases were highlighted.

Description: Background Pharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable. Chemical compounds that modulate atrial and ventricular cell fate could be used to improve subtype-specific differentiation of endogenous or exogenously delivered progenitor cells in order to promote cardiac regeneration. Methods Transcription factor GATA4-targeted compounds that have previously shown in vivo efficacy in cardiac injury models were tested for stage-specific activation of atrial and ventricular reporter genes in differentiating pluripotent stem cells using a dual reporter assay. Chemically induced gene expression changes were characterized by qRT-PCR, global run-on sequencing (GRO-seq) and immunoblotting, and the network of cooperative proteins of GATA4 and NKX2-5 were further explored by the examination of the GATA4 and NKX2-5 interactome by BioID. Reporter gene assays were conducted to examine combinatorial effects of GATA-targeted compounds and bromodomain and extraterminal domain (BET) inhibition on chamber-specific gene expression. Results GATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression. Conclusions Collectively, these results indicate the potential for therapeutic alteration of cell fate decisions and pathological gene regulatory networks by GATA4-targeted compounds modulating chamber-specific transcriptional programs in multipotent cardiac progenitor cells and cardiomyocytes. The compound scaffolds described within this study could be used to develop regenerative strategies for myocardial regeneration.

Description: Background Patients with complex health care needs may suffer adverse outcomes from fragmented and delayed care, reducing well-being and increasing health care costs. Health reform efforts, especially those in primary care, attempt to mitigate risk of adverse outcomes by better targeting resources to those most in need. However, predicting who is susceptible to adverse outcomes, such as unplanned hospitalizations, ED visits, or other potentially avoidable expenditures, can be difficult, and providing intensive levels of resources to all patients is neither wanted nor efficient. Our objective was to understand if primary care teams can predict patient risk better than standard risk scores. Methods Six primary care practices risk stratified their entire patient population over a 2-year period, and worked to mitigate risk for those at high risk through care management and coordination. Individual patient risk scores created by the practices were collected and compared to a common risk score (Hierarchical Condition Categories) in their ability to predict future expenditures, ED visits, and hospitalizations. Accuracy of predictions, sensitivity, positive predictive values (PPV), and c-statistics were calculated for each risk scoring type. Analyses were stratified by whether the practice used intuition alone, an algorithm alone, or adjudicated an algorithmic risk score. Results In all, 40,342 patients were risk stratified. Practice scores had 38.6% agreement with HCC scores on identification of high-risk patients. For the 3,381 patients with reliable outcomes data, accuracy was high (0.71–0.88) but sensitivity and PPV were low (0.16–0.40). Practice-created scores had 0.02–0.14 lower sensitivity, specificity and PPV compared to HCC in prediction of outcomes. Practices using adjudication had, on average, .16 higher sensitivity. Conclusions Practices using simple risk stratification techniques had slightly worse accuracy in predicting common outcomes than HCC, but adjudication improved prediction.

Description: Introduction The potential of regenerative medicine to improve human health has led to the rapid expansion of stem cell clinics throughout the world with varying levels of regulation and oversight. This has led to a market ripe for stem cell tourism, with Tijuana, Mexico, as a major destination. In this study, we characterize the online marketing, intervention details, pricing of services, and assess potential safety risks through web surveillance of regenerative medicine clinics marketing services in Tijuana. Methods We conducted structured online search queries from March to April 2019 using 296 search terms in English and Spanish on two search engines (Google and Bing) to identify websites engaged in direct-to-consumer advertising of regenerative medicine services. We performed content analysis to characterize three categories of interest: online presence, tokens of scientific legitimacy, and intervention details. Results Our structured online searches resulted in 110 unique websites located in Tijuana corresponding to 76 confirmed locations. These clinics’ online presence consisted of direct-to-consumer advertising mainly through a dedicated website (94.5%) or Facebook page (65.5%). The vast majority of these websites (99.1%) did not mention any affiliation to an academic institutions or other overt tokens of scientific legitimacy. Most clinics claimed autologous tissue was the source of treatments (67.3%) and generally did not specify route of administration. Additionally, of the Tijuana clinics identified, 13 claimed licensing, though only 1 matched with available licensing information. Conclusions Regenerative medicine clinics in Tijuana have a significant online presence using direct-to-consumer advertising to attract stem-cell tourism clientele in a bustling border region between Mexico and the USA. This study adds to existing literature evidencing the unregulated nature of online stem cell offerings and provides further evidence of the need for regulatory harmonization, particularly to address stem cell services being offered online across borders.

Description: Background Neural stem cell (NSC) therapy remains one of the most potential approaches for the treatment of neurological disorders. The discovery of human induced pluripotent stem cells (hiPSCs) and the establishment of hiPSC-derived human neural stem cells (hiNSCs) have revolutionized the technique of cell therapy. Meanwhile, it is often required that NSCs are stored and transported to a long distance for research or treatment purposes. Although high survival rates could be maintained, conventional methods for cell transportation (dry ice or liquid nitrogen) are inconvenient and expensive. Therefore, the establishment of a safe, affordable, and low-cost strategy to store and transport easily accessible hiPSCs and hiNSCs, with characteristics that match fetal hNSCs, is incredibly urgent. Methods We reprogrammed human urinary cells to iPSCs using a non-integrating, virus-free technique and differentiated the iPSCs toward iNSCs/neurospheres and neurons, under Good Manufacturing Practice (GMP)-compatible conditions. The pluripotency of iPSCs and iNSCs was characterized by a series of classical methods (surface markers, karyotype analysis, and in vitro as well as in vivo differentiation capabilities, etc.). Results Here, our results showed that we successfully generated hiNSCs/neurospheres from more available, non-invasive, and more acceptable urinary cells by a virus-free technique. Next, we demonstrated that the iNSCs differentiated into mature cerebral cortical neurons and neural networks. Interestingly, hiNSCs survived longer as neurospheres at ambient temperature (AT) than those cultured in a monolayer. Within 7 days approximately, the neural viability remained at 〉 80%, while hiNSCs cultured in a monolayer died almost immediately. Neurospheres exposed to AT that were placed under standard culture conditions (37 °C, 5% CO2) recovered their typical morphology, and retained their proliferation and differentiation abilities. Conclusions In this study, we provided a simple method for the storage of NSCs as neurospheres at AT as an alternative method to more costly and inconvenient traditional methods of cryopreservation. This will enable hiNSCs to be transported over long distances at AT and facilitate the therapeutic application of NSCs as neurospheres without any further treatment.

Description: Background The Ministry of Health in Saudi Arabia is expanding the country’s telemedicine services by using advanced technology in health services. In doing so, an e-health application (app), Seha, was introduced in 2018 that allows individuals to have face-to-face visual medical consultations with their doctors on their smartphones. Objective This study evaluated the effectiveness of the app in improving healthcare delivery by ensuring patient satisfaction with the care given, increasing access to care, and improving efficiency in the healthcare system. Methods A cross-sectional study design was used to assess the perceptions of users of the Seha app and non-users who continued with traditional health services. The data were collected using an online survey via Google Forms between June 2020 and September 2020. Independent t tests and chi-square (χ2) tests were conducted to answer the research questions. Results There was a significant difference between users and non-users in terms of ease of access to health services (t =  − 9.38, p 

Description: Objective The objectives of this study were to investigate the antifungal susceptibility and genetic diversity of Candida albicans isolated from HIV+ patients with oropharyngeal candidiasis. A total of 50 C. albicans isolates were cultured on Sabouraud glucose agar containing chloramophenicol. The antifungal susceptibility of the isolates against fluconazole, clotrimazole, nystatin, amphotericin B, ketoconazole and flucytosine was assessed using disc diffusion method. The genetic diversity of C. albicans isolates was determined using random amplified polymorphic DNA marker. Results The inhibition zones ranged from 4 ± 1.8 to 40 ± 3.8 mm for fluconazole, 7 ± 1.0 to 37 ± 1.8 mm for ketoconazole, 14 ± 0.8 to24 ± 0.8 mm for amphotericin B, 25 ± 0.0 to 33 ± 0.0 mm for nystatin and 7 ± 4.2 to 40 ± 0.0 mm for clotrimazole. At 90% similarity, three distinct groups were observed. The smallest cluster composed of 3 isolates, whereas the largest one composed of 17 isolates. 32% (16/50), 28% (14/50) and 14% (7/50) were resistant to fluconazole, ketoconazole and clotrimazole, respectively.

Description: Therapy resistance is a major problem when treating cancer patients as cancer cells develop mechanisms that counteract the effect of therapeutic compounds, leading to fit and more aggressive clones that contribute to poor prognosis. Therapy resistance can be both intrinsic and/or acquired. These are multifactorial events, and some are related to factors including adaptations in cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), deregulation of key signaling pathways, drug efflux through ABC transporters, acquired mutations, evading apoptosis, and activation of DNA damage response among others. Among these factors, CSCs represent the major source of therapy resistance. CSCs are a subset of tumor cells that are capable of self-renewal and multilineage progenitor expansion that are known to be intrinsically resistant to anticancer treatments. Multiple clones of CSCs pre-exist, and some can adopt and expand easily to changes in the tumor microenvironment (TME) and/or in response to radio- and chemotherapy. A combination of both intrinsic and extrinsic factors contributes to CSC-mediated therapy resistance. In this review, we will focus on CSCs and therapy resistance as well as suggest strategies to eliminate CSCs and, therefore, overcome resistance.

Description: Objective The evaluation of physical activity for chronic hemodialysis patients is a new approach for patient global care. The objective of this work is to evaluate the physical activity in chronic hemodialysis patients and identify the risk factors associated with reduced physical activity. This is a prospective study for 6 months including 150 chronic hemodialysis patients in the Guelmim-Oued Noun Regionin Moroccan Sahara. We use Baecke's survey, translated and validated in Arabic local language. The socio-demographic, clinical, and biological data were completed during the interrogation and from the medical records of the patients. Results The mean age of our patients was 54.6 ± 16.4 years, with male predominance (59%). Most patients have a low education level and 60% were illiterate. Hypertension was found in 54% of our patients, diabetes in 39%, and cardiovascular disease in 10% of patients. Low Physical activity was associated with gender (OR = 4.05), age (OR = 1.03) and high education level (OR = 0.2). Our work has met the various pre-established objectives, however other more specific studies must be conducted to better characterize the profile of physical activity in chronic hemodialysis patients.

Description: Background Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Nevertheless, the mechanisms underlying these observations are not well known. Direct cell contact, soluble factor production, and turning antigen-presenting cells into tolerogenic phenotypes, have been proposed to be among possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion and activity. We and others demonstrated that adult bone marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ helper and CD8+ cytotoxic T cells but also indirectly through the induction of T regs. In parallel, we demonstrated that fetal liver (FL)-MSCs demonstrates much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs. Methods MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation, and their proliferation potential. Using different in vitro combinations, we performed co-cultures of FL- or BM-MSCs and murine CD3+CD25−T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results We demonstrated that although both types of MSC display similar cell surface phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs. Conclusions These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

Description: Background Human periodontal ligament stem cells (hPDLSCs) are ideal seed cells for periodontal regeneration. A greater understanding of the dynamic protein profiles during osteogenic differentiation contributed to the improvement of periodontal regeneration tissue engineering. Methods Tandem Mass Tag quantitative proteomics was utilized to reveal the temporal protein expression pattern during osteogenic differentiation of hPDLSCs on days 0, 3, 7 and 14. Differentially expressed proteins (DEPs) were clustered and functional annotated by Gene Ontology (GO) terms. Pathway enrichment analysis was performed based on the Kyoto Encyclopedia of Genes and Genomes database, followed by the predicted activation using Ingenuity Pathway Analysis software. Interaction networks of redox-sensitive signalling pathways and oxidative phosphorylation (OXPHOS) were conducted and the hub protein SOD2 was validated with western blotting. Results A total of 1024 DEPs were identified and clustered in 5 distinctive clusters representing dynamic tendencies. The GO enrichment results indicated that proteins with different tendencies show different functions. Pathway enrichment analysis found that OXPHOS was significantly involved, which further predicted continuous activation. Redox-sensitive signalling pathways with dynamic activation status showed associations with OXPHOS to various degrees, especially the sirtuin signalling pathway. SOD2, an important component of the sirtuin pathway, displays a persistent increase during osteogenesis. Data are available via ProteomeXchange with identifier PXD020908. Conclusion This is the first in-depth dynamic proteomic analysis of osteogenic differentiation of hPDLSCs. It demonstrated a dynamic regulatory mechanism of hPDLSC osteogenesis and might provide a new perspective for research on periodontal regeneration. Graphical abstract

Description: Background Previous reports have identified that human bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) with their cargo microRNAs (miRNAs) are a promising therapeutic approach for the treatment of idiopathic pulmonary fibrosis (IPF). Therefore, we explored whether delivery of microRNA-186 (miR-186), a downregulated miRNA in IPF, by BMSC EVs could interfere with the progression of IPF in a murine model. Methods In a co-culture system, we assessed whether BMSC-EVs modulated the activation of fibroblasts. We established a mouse model of PF to evaluate the in vivo therapeutic effects of BMSC-EVs and determined miR-186 expression in BMSC-EVs by polymerase chain reaction. Using a loss-of-function approach, we examined how miR-186 delivered by BMSC-EVs affected fibroblasts. The putative relationship between miR-186 and SRY-related HMG box transcription factor 4 (SOX4) was tested using luciferase assay. Next, we investigated whether EV-miR-186 affected fibroblast activation and PF by targeting SOX4 and its downstream gene, Dickkopf-1 (DKK1). Results BMSC-EVs suppressed lung fibroblast activation and delayed IPF progression in mice. miR-186 was downregulated in IPF but enriched in the BMSC-EVs. miR-186 delivered by BMSC-EVs could suppress fibroblast activation. Furthermore, miR-186 reduced the expression of SOX4, a target gene of miR-186, and hence suppressed the expression of DKK1. Finally, EV-delivered miR-186 impaired fibroblast activation and alleviated PF via downregulation of SOX4 and DKK1. Conclusion In conclusion, miR-186 delivered by BMSC-EVs suppressed SOX4 and DKK1 expression, thereby blocking fibroblast activation and ameliorating IPF, thus presenting a novel therapeutic target for IPF.

Description: Background Protein tyrosine phosphatase 1B (PTP1B) is one of the major negative regulators of leptin and insulin signaling, and has been strongly implicated in insulin resistance development in the course of obesity and metabolic syndrome conditions; however, its exact role in controlling adipose tissue biogenesis is still poorly understood. Objectives This investigation aimed to elucidate whether selective inhibition of PTP1B using MSI-1436 compound may improve and restore the defective adipogenicity of ASCs isolated from EMS-affected horses. Methods Equine ASC EMS cells were cultured under adipogenic conditions in the presence of PTP1B inhibitor and were subsequently tested for expression of the main adipogenic-related genes using RT-qPCR, changes in free fatty acid profiles by means of GC-MS technique, and for mitochondrial dynamics improvement through the analysis of mitochondrial transmembrane potential and oxidative stress. Results Selective inhibition of PTP1B in equine ASC EMS cells improved substantially adipogenic differentiation by promoting cellular proliferation and normalizing expression of C/EBPalpha, PPARγ, and Adipoq markers that are critical for proper adipogenesis. Levels of secreted adiponectin and PPARγ were also shown to be increased in MSI-1436-conditioned cells, while total leptin levels markedly dropped under the same conditions. Moreover, MSI-1436 treatment enabled the regulation of metabolic-related transcripts that are crosslink to adipogenesis, namely Akt1, Akt2, and SHBG. The obtained results demonstrated also an obvious reduction in intracellular accumulated ROS and NO, as well as mitigated ER stress through the downregulation of Chop, Perk, Atf6, Ire1, and Xbp1 transcripts upon PTP1B inhibition. Furthermore, general fluctuations in FFA composition of all differentiated groups have been highlighted, where palmitic acid, palmitoleic acid, stearic acid, and linolelaidic acid that are known to be associated with the development of metabolic disorders were found to be normalized upon PTP1B inhibition during adipogenic differentiation. Conclusion The presented data provides the evidence that the use of PTP1B inhibitor may be successful in controlling and enhancing adipogenic differentiation of impaired equine ASCs affected by metabolic syndrome, and thus offers new insights for the management of obesity through the regulation of adipose tissue dynamics. Graphical abstract

Description: Background Skin wounds in diabetic patients hardly recover. Accumulating evidence has shown that mammalian target of rapamycin (mTOR) pathway and myeloid-derived suppressor cells (MDSCs) are involved in inflammatory-related response. INK128 is a novel mTOR kinase inhibitor in clinical development. However, the exact roles of MDSCs and INK128 in healing wound of diabetic patients are unclear. Methods Mice models of normal, diabetic, and diabetic+INK128 were constructed. Bone marrow (BM)-derived macrophages and RAW264.7 cell line co-cultured with MDSCs, which were induced at different conditions. Flow cytometry, western blot, quantitative real-time PCR, and immunohistochemical analysis were performed. Results Diabetic mice (DM) had a slower recovery rate, thinner epidermis and dermis, and less blood vessels than those of normal mice. MDSCs were abnormally accumulated in DM, mTOR was activated in MDSCs of DM, and the cells were treated with high glucose. Moreover, mTOR signaling inhibitor INK128 could promote wound healing through reducing the MDSCs. MDSC function was disordered in DM and high-glucose environments, while INK128 could help retrieve their function. Furthermore, high glucose and other factors in DM could promote M-MDSC differentiation to M1 pro-inflammatory macrophage cells, thus inhibiting wound healing. The differentiation, which was dependent on mTOR signaling, could be reversed by INK128. Conclusion INK128 is potential to be developed as a clinical strategy to promote wound healing of diabetic patients.

Description: Background Retina diseases may lead to blindness as they often afflict both eyes. Stem cell transplantation into the affected eye(s) is a promising therapeutic strategy for certain retinal diseases. Human peripheral blood mononuclear cells (hPBMCs) are a good source of stem cells, but it is unclear whether pre-induced hPBMCs can migrate from the injected eye to the contralateral eye for bilateral treatment. We examine the possibility of bilateral cell transplantation from unilateral cell injection. Methods One hundred and sixty-one 3-month-old retinal degeneration 1 (rd1) mice were divided randomly into 3 groups: an untreated group (n = 45), a control group receiving serum-free Dulbecco’s modified Eagle’s medium (DMEM) injection into the right subretina (n = 45), and a treatment group receiving injection of pre-induced hPBMCs into the right subretina (n = 71). Both eyes were examined by full-field electroretinogram (ERG), immunofluorescence, flow cytometry, and quantitative real-time polymerase chain reaction (qRT-PCR) at 1 and 3 months post-injection. Results At both 1 and 3 months post-injection, labeled pre-induced hPBMCs were observed in the retinal inner nuclear layer of the contralateral (left untreated) eye as well as the treated eye as evidenced by immunofluorescence staining for a human antigen. Flow cytometry of fluorescently label cells and qRT-PCR of hPBMCs genes confirmed that transplanted hPBMCs migrated from the treated to the contralateral untreated eye and remained viable for up to 3 months. Further, full-field ERG showed clear light-evoked a and b waves in both treated and untreated eyes at 3 months post-transplantation. Labeled pre-induced hPBMCs were also observed in the contralateral optic nerve but not in the blood circulation, suggesting migration via the optic chiasm. Conclusion It may be possible to treat binocular eye diseases by unilateral stem cell injection. Graphical abstract

Description: Background Brown adipocytes (BAs) are major components of brown adipose tissue (BAT), which is involved in blood pressure regulation. BAs are derived from multiple progenitors, including PDGFRα+ adipose-derived stem cells (ASCs). Skin-derived mesenchymal stem cells (S-MSCs) have the capacity to differentiate into adipocytes; however, their ability to differentiate into BAs remains unexplored. We aim to study the ability and regulatory mechanism of the differentiation of S-MSCs into BAs and the direct role of BAT in blood pressure regulation. Methods Protein expression was measured by flow cytometry or Western blotting, and gene mRNA levels were quantified by real-time quantitative PCR (RT-PCR). To induce the differentiation of S-MSCs into BAs, S-MSCs were stimulated with a brown adipogenic cocktail comprising insulin, IBMX, dexamethasone, triiodothyronine (T3), and rosiglitazone for the indicated periods. The oxygen consumption rate (OCR) was measured with an XF24 Extracellular Flux Analyzer. Mitochondrial mass was determined by flow cytometry and fluorescence staining. Hypertension was induced in WT mice by infusion of angiotensin II (Ang II), and systolic blood pressure (SBP) was measured using a tail cuff. Interscapular brown adipose tissue (iBAT)-deficient mice were generated by surgical removal of the iBAT depot, after which the animals were allowed to recover for 6 days. Aortic, iBAT, and heart tissue sections were analyzed by hematoxylin and eosin (HE) staining. Results We found that in vitro, S-MSCs isolated from the mouse dermis expressed the stem cell markers CD90/105 and PDGFRα and readily differentiated into BAs. Mitochondrial biogenesis and oxygen consumption were markedly increased during differentiation of S-MSCs into BAs. In vivo, iBAT was converted to white adipose tissue (WAT) in Ang II-induced hypertensive mice. We assessed the direct role of BAT in blood pressure (BP) regulation by using iBAT-deficient mice (generated by surgical removal of iBAT) and C57BL/6 (wild-type (WT)) mice and found that Ang II-induced BP elevation and vascular damage were markedly aggravated in iBAT-deficient mice compared with WT mice. Conclusions This study demonstrates that PDGFRα+ S-MSCs are able to differentiate into BAs and that this differentiation is regulated by mitochondrial activity. We also show that BAT plays a direct role in ameliorating Ang II-induced hypertension. The therapeutic potential of BAT for the prevention of hypertension-induced organ remodeling thus warrants further investigation. Graphical abstract. Schematic of the in vitro differentiation of PDGFRα+ S-MSCs into BAs via a process regulated by mitochondrial activity. BAT plays a direct role in Ang II-induced hypertension and target organ remodeling

Description: Background The objective was to explore the therapeutic effect of autologous adipose-derived stem cells (ADSCs) combined with ShakeGel™3D transplantation to activate the BMP7-Smad5 signaling pathway to treat intrauterine adhesions (IUA). Methods Autologous ADSCs were isolated and then merged with ShakeGel™3D. The IUA model was established by mechanical injury. The third generation of autologous ADSCs was injected directly into the uterus in combination with ShakeGel™3D. After 7 days of treatment, endometrial morphology, number of endometrial glands, endometrial fibrosis area, and fibrosis biomarker analysis by RT-PCR and IHC were examined. BMP7 and phosphorylation of Smad5 were also detected, and the recovery of infertility function in treated mice was evaluated. Results Fluorescence-activated cell sorting (FACS) showed that autologous ADSCs expressed CD105 (99.1%), CD29 (99.6%), and CD73 (98.9%). Autologous ADSCs could still maintain a good growth state in ShakeGel™3D. Histological examination revealed that the number of endometrial glands increased significantly, and the area of fibrosis decreased. At the same time, the expression of BMP7 and Smad5 in the ADSCs + Gel group was significantly upregulated, and the final reproductive function of this group was partly recovered. Conclusions Autologous ADSCs can be used in combination with ShakeGel™3D to maintain functionality and create a viable three-dimensional growth environment. The combined transplantation of autologous ADSCs and ShakeGel™3D promotes the recovery of damaged endometrial tissue by increasing BMP7-Smad5 signal transduction, resulting in endometrium thickening, increased number of glands, and decreased fibrosis, leading to restoration of partial fertility.

Description: Background Osteoporosis (OP) is a metabolic bone disease due to the imbalance of osteogenesis and bone resorption, in which, bone marrow mesenchymal stem cells (BMSCs) have a significant effect as the seed cells. Recent research has shown the function of Morusin on inhibiting osteoclast differentiation in vitro. However, whether Morusin can regulate the osteogenic differentiation in addition to the proliferation of BMSCs remains unclear. Methods BMSCs were isolated from 4-week-old Wistar rats and then treated with different concentrations of Morusin for 3, 5, 7, and 14 days. The proliferation of BMSCs was detected by MTT assay. The effect of Morusin on osteogenic differentiation of BMSCs was detected by RT-qPCR, Western blotting, ALP, and Alizarin Red staining. The effect of Morusin on Wnt/β-catenin signaling pathway was analyzed by RT-qPCR, Western blotting, and immunofluorescence. Finally, in the ovariectomy-induced osteoporosis model, the anti-osteoporosis activity of Morusin was determined by micro-CT, HE, and immunohistochemistry. Results The results showed the function of 2.5–10 μM Morusin in the promotion of the proliferation in addition to osteogenic differentiation of BMSCs. Moreover, it also has an impact in activating the Wnt/β-catenin signaling pathway via inhibition of β-catenin phosphorylation as well as promotion of its nuclear translocation. Upon Dickkopf-related protein-1 (DKK-1, an inhibitor of the Wnt/β-catenin signaling pathway) was added to the Morusin, Morusin had a decreased stimulatory osteogenic effect on BMSCs. Finally, in the rat OP model, we found that Morusin could also exert anti-osteoporosis activity in vivo. Conclusions This study indicates the ability of Morusin in the promotion of osteogenic differentiation of BMSCs via the activation of Wnt/β-catenin signaling pathway and also shows the potential of Morusin to be an agent for osteoporosis treatment.

Description: Background Cellular therapy based on mesenchymal stem cells (MSCs) is a promising novel therapeutic strategy for the osteonecrosis of the femoral head (ONFH), which is gradually becoming popular, particularly for early-stage ONFH. Nonetheless, the MSC-based therapy is challenging due to certain limitations, such as limited self-renewal capability of cells, availability of donor MSCs, and the costs involved in donor screening. As an alternative approach, MSCs derived from induced pluripotent stem cells (iPSCs), which may lead to further standardized-cell preparations. Methods In the present study, the bone marrow samples of patients with ONFH (n = 16) and patients with the fracture of the femoral neck (n = 12) were obtained during operation. The bone marrow-derived MSCs (BMSCs) were isolated by density gradient centrifugation. BMSCs of ONFH patients (ONFH-BMSCs) were reprogrammed to iPSCs, following which the iPSCs were differentiated into MSCs (iPSC-MSCs). Forty adult male rats were randomly divided into following groups (n = 10 per group): (a) normal control group, (b) methylprednisolone (MPS) group, (c) MPS + BMSCs treated group, and (d) MPS + iPSC-MSC-treated group. Eight weeks after the establishment of the ONFH model, rats in BMSC-treated group and iPSC-MSC-treated group were implanted with BMSCs and iPSC-MSCs through intrabone marrow injection. Bone repair of the femoral head necrosis area was analyzed after MSC transplantation. Results The morphology, immunophenotype, in vitro differentiation potential, and DNA methylation patterns of iPSC-MSCs were similar to those of normal BMSCs, while the proliferation of iPSC-MSCs was higher and no tumorigenic ability was exhibited. Furthermore, comparing the effectiveness of iPSC-MSCs and the normal BMSCs in an ONFH rat model revealed that the iPSC-MSCs was equivalent to normal BMSCs in preventing bone loss and promoting bone repair in the necrosis region of the femoral head. Conclusion Reprogramming can reverse the abnormal proliferation, differentiation, and DNA methylation patterns of ONFH-BMSCs. Transplantation of iPSC-MSCs could effectively promote bone repair and angiogenesis in the necrosis area of the femoral head.

Description: Background Premature ovarian insufficiency (POI) is one of the major causes of infertility. We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) effectively improved ovarian function in a murine model of POI. Recent studies indicated that mesenchymal stem cell-derived exosomes were important components in tissue repair. In this study, we investigated the therapeutic effects of MenSCs-derived exosomes (MenSCs-Exos) in a rat model of POI and its mechanism in restoring ovulation. Methods Ovaries of 4.5-day-old Sprague Dawley rats (SD rats) were cultured in vitro to evaluate the effects of MenSCs-Exos exposure on early follicle development. Furthermore, POI in rats was induced by intraperitoneal administration of 4-vinylcyclohexene diepoxide (VCD). Forty-eight POI rats were randomly assigned to four groups, each receiving a different treatment: PBS, MenSCs, MenSCs-Exos, and Exo-free culture supernatant of MenSCs. Estrous cyclicity, ovarian morphology, follicle dynamics, serum hormones, pregnancy outcomes, and molecular changes were investigated. Results Exposure to MenSCs-Exos promoted the proliferation of granulosa cells in primordial and primary follicles in vitro and increased the expression of early follicle markers Deleted In Azoospermia Like (DAZL) and Forkhead Box L2 (FOXL2) while inhibiting follicle apoptosis. In vivo, MenSCs-Exos transplantation effectively promoted follicle development in the rat model of POI and restored the estrous cyclicity and serum sex hormone levels, followed by improving the live birth outcome. In addition, transplantation of MenSCs-Exos regulated the composition of the ovarian extracellular matrix and accelerated the recruitment of dormant follicles in the ovarian cortex and increased proliferation of granulosa cells in these follicles. Conclusion MenSCs-Exos markedly promoted follicle development in vitro and in vivo and restored fertility in POI rats, suggesting a restorative effect on ovarian functions. The therapeutic effect of MenSCs-Exos transplantation was sustainable, consistent with that of MenSCs transplantation. Our results suggested that MenSCs-Exos transplantation may be a promising cell-free bioresource in the treatment of POI.

Description: Background The asthma-related airway wall remodeling is associated i.a. with a damage of bronchial epithelium and subepithelial fibrosis. Functional interactions between human bronchial epithelial cells and human bronchial fibroblasts are known as the epithelial-mesenchymal trophic unit (EMTU) and are necessary for a proper functioning of lung tissue. However, a high concentration of the transforming growth factor-β1 (TGF-β1) in the asthmatic bronchi drives the structural disintegrity of epithelium with the epithelial-to-mesenchymal transition (EMT) of the bronchial epithelial cells, and of subepithelial fibrosis with the fibroblast-to-myofibroblast transition (FMT) of the bronchial fibroblasts. Since previous reports indicate different intrinsic properties of the human bronchial epithelial cells and human bronchial fibroblasts which affect their EMT/FMT potential beetween cells derived from asthmatic and non-asthmatic patients, cultured separatelly in vitro, we were interested to see whether corresponding effects could be obtained in a co-culture of the bronchial epithelial cells and bronchial fibroblasts. In this study, we investigate the effects of the TGF-β1 on the EMT markers of the bronchial epithelial cells cultured in the air-liquid-interface and effectiveness of FMT in the bronchial fibroblast populations in the EMTU models. Results Our results show that the asthmatic co-cultures are more sensitive to the TGF-β1 than the non-asthmatic ones, which is associated with a higher potential of the asthmatic bronchial cells for a profibrotic response, analogously to be observed in '2D' cultures. They also indicate a noticeable impact of human bronchial epithelial cells on the TGF-β1-induced FMT, stronger in the asthmatic bronchial fibroblast populations in comparison to the non-asthmatic ones. Moreover, our results suggest the protective effects of fibroblasts on the structure of the TGF-β1–exposed mucociliary differentiated bronchial epithelial cells and their EMT potential. Conclusions Our data are the first to demonstrate a protective effect of the human bronchial fibroblasts on the properties of the human bronchial epithelial cells, which suggests that intrinsic properties of not only epithelium but also subepithelial fibroblasts affect a proper condition and function of the EMTU in both normal and asthmatic individuals.

Description: Background Poor balance has been cited as one of the key causal factors of falls. Timely detection of balance impairment can help identify the elderly prone to falls and also trigger early interventions to prevent them. The goal of this study was to develop a surrogate approach for assessing elderly’s functional balance based on Short Form Berg Balance Scale (SFBBS) score. Methods Data were collected from a waist-mounted tri-axial accelerometer while participants performed a timed up and go test. Clinically relevant variables were extracted from the segmented accelerometer signals for fitting SFBBS predictive models. Regularized regression together with random-shuffle-split cross-validation was used to facilitate the development of the predictive models for automatic balance estimation. Results Eighty-five community-dwelling older adults (72.12 ± 6.99 year) participated in our study. Our results demonstrated that combined clinical and sensor-based variables, together with regularized regression and cross-validation, achieved moderate-high predictive accuracy of SFBBS scores (mean MAE = 2.01 and mean RMSE = 2.55). Step length, gender, gait speed and linear acceleration variables describe the motor coordination were identified as significantly contributed variables of balance estimation. The predictive model also showed moderate-high discriminations in classifying the risk levels in the performance of three balance assessment motions in terms of AUC values of 0.72, 0.79 and 0.76 respectively. Conclusions The study presented a feasible option for quantitatively accurate, objectively measured, and unobtrusively collected functional balance assessment at the point-of-care or home environment. It also provided clinicians and elderly with stable and sensitive biomarkers for long-term monitoring of functional balance.

Description: Objective The application of molecular graphics software as a simple and free alternative to molecular model sets for introductory-level chemistry learners is presented. Results Based on either Avogadro or IQmol, we proposed four sets of tasks for students, building basic molecular geometries, visualizing orbitals and densities, predicting polarity of molecules and matching 3D structures with bond-line structures. These topics are typically covered in general chemistry for first-year undergraduate students. Detailed step-by-step procedures are provided for all tasks for both programs so that instructors and students can adopt one of the two programs in their teaching and learning as an alternative to molecular model sets.

Description: Background The electronic health record (EHR) holds the prospect of providing more complete and timely access to clinical information for biomedical research, quality assessments, and quality improvement compared to other data sources, such as administrative claims. In this study, we sought to assess the completeness and timeliness of structured diagnoses in the EHR compared to computed diagnoses for hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM). Methods We determined the amount of time for a structured diagnosis to be recorded in the EHR from when an equivalent diagnosis could be computed from other structured data elements, such as vital signs and laboratory results. We used EHR data for encounters from January 1, 2012 through February 10, 2019 from an academic health system. Diagnoses for HTN, HLD, and DM were computed for patients with at least two observations above threshold separated by at least 30 days, where the thresholds were outpatient blood pressure of ≥ 140/90 mmHg, any low-density lipoprotein ≥ 130 mg/dl, or any hemoglobin A1c ≥ 6.5%, respectively. The primary measure was the length of time between the computed diagnosis and the time at which a structured diagnosis could be identified within the EHR history or problem list. Results We found that 39.8% of those with HTN, 21.6% with HLD, and 5.2% with DM did not receive a corresponding structured diagnosis recorded in the EHR. For those who received a structured diagnosis, a mean of 389, 198, and 166 days elapsed before the patient had the corresponding diagnosis of HTN, HLD, or DM, respectively, recorded in the EHR. Conclusions We found a marked temporal delay between when a diagnosis can be computed or inferred and when an equivalent structured diagnosis is recorded within the EHR. These findings demonstrate the continued need for additional study of the EHR to avoid bias when using observational data and reinforce the need for computational approaches to identify clinical phenotypes.

Description: Background Data from clinical registries may be linked to gain additional insights into disease processes, risk factors and outcomes. Identifying information varies from full names, addresses and unique identification codes to statistical linkage keys to no direct identifying information at all. A number of databases in Australia contain the statistical linkage key 581 (SLK-581). Our aim was to investigate the ability to link data using SLK-581 between two national databases, and to compare this linkage to that achieved with direct identifiers or other non-identifying variables. Methods The Australian and New Zealand Society of Cardiothoracic Surgeons database (ANZSCTS-CSD) contains fully identified data. The Australian and New Zealand Intensive Care Society database (ANZICS-APD) contains non-identified data together with SLK-581. Identifying data is removed at participating hospitals prior to central collation and storage. We used the local hospital ANZICS-APD data at a large single tertiary centre prior to deidentification and linked this to ANZSCTS-CSD data. We compared linkage using SLK-581 to linkage using non-identifying variables (dates of admission and discharge, age and sex) and linkage using a complete set of unique identifiers. We compared the rate of match, rate of mismatch and clinical characteristics between unmatched patients using the different methods. Results There were 1283 patients eligible for matching in the ANZSCTS-CSD. 1242 were matched using unique identifiers. Using non-identifying variables 1151/1242 (92.6%) patients were matched. Using SLK-581, 1202/1242 (96.7%) patients were matched. The addition of non-identifying data to SLK-581 provided few additional patients (1211/1242, 97.5%). Patients who did not match were younger, had a higher mortality risk and more non-standard procedures vs matched patients. The differences between unmatched patients using different matching strategies were small. Conclusion All strategies provided an acceptable linkage. SLK-581 improved the linkage compared to non-identifying variables, but was not as successful as direct identifiers. SLK-581 may be used to improve linkage between national registries where identifying information is not available or cannot be released.

Description: Objectives Annually, 1.2 million humans are stung by scorpions and severely affected by their venom. Some of the scorpion species of medical importance have a similar morphology to species with low toxicity. To establish diagnostic tools for surveying scorpions, the current study was conducted to generate three mitochondrial markers, Cytochrome Oxidase I (COI gene), 12S rDNA and 16S rDNA for six species of medically important Iranian scorpions: Androctonus crassicauda, Hottentotta saulcyi, Mesobuthus caucasicus, M. eupeus, Odontobuthus doriae, and Scorpio maurus. Results Phylogenetic analyses of the obtained sequences corroborated the morphological identification. For the first time, 12S rDNA sequences are reported from Androctonus crassicauda, Hottentotta saulcyi, Mesobuthus caucasicus and M. eupeus and also the 16S rDNA sequence from Hottentotta saulcyi. We conclude that the mitochondrial markers are useful for species determination among these medically important species of scorpions.

Description: Objective Currently, next generation sequencing (NGS) is widely used to decode potential novel or variant pathogens both in emergent outbreaks and in routine clinical practice. However, the efficient identification of novel or diverged pathogenomic compositions remains a big challenge. It is especially true for short DNA sequence fragments from NGS, since sequence similarity searching is vulnerable to false negatives or false positives, as is mismatching or matching with unrelated proteins. Therefore, this study aimed to establish a bioinformatics approach that can generate unique motif sequences for profiling searching, resulting in high specificity and sensitivity. Results In this study, we introduced a Shortest Unique Representative Hidden Markov Model (HMM) approach to identify bacterial toxin, virulence factor (VF), and antimicrobial resistance (AR) in short sequence reads. We first construct unique representative domain sequences of toxin genes, VFs, and ARs to avoid potential false positives, and then to use HMM models to accurately identify potential toxin, VF, and AR fragments. The benchmark shows this approach can achieve relatively high specificity and sensitivity if the appropriate cutoff value is applied. Our approach can be used to recognize the protein sequences of known toxins and pathogens, identifies their common characteristics and then searches for similar sequences in other organisms.

Description: Objective The Sumatran rhinoceros is critically endangered, with fewer than 100 individuals surviving across its current range. Accurate census estimates of the remaining populations are essential for development and implementation of conservation plans. In order to enable molecular censusing, we here develop microsatellite markers with amplicon sizes of short length, appropriate for non-invasive fecal sampling. Results Due to limited sample quantity and potential lack of genome-wide diversity, Illumina sequence reads were generated from two Sumatran rhinoceros samples. Genomic screening identified reads with short tandem repeats and loci that were polymorphic within the dataset. Twenty-nine novel polymorphic microsatellite markers were characterized (A = 2.4; HO = 0.30). These were sufficient to distinguish among individuals (PID 

Description: This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13104-021-05537-4

Description: Objective Environmental surfaces may serve as potential reservoirs for nosocomial pathogens and facilitate transmissions via contact depending on its tenacity. This study provides data on survival kinetics of the most important nosocomial bacteria on a panel of commonly used surfaces. Type strains of S. aureus, K. pneumoniae, P. aeruginosa, A. baumannii, S. marcescens, E. faecium, E. coli, and E. cloacae were suspended in 0.9% NaCl solution at a McFarland of 1 and got then plated via cotton swabs either on glass, polyvinyl chloride, stainless steel, or aluminum. Surfaces were stored at regular ambient temperature and humidity to simulate routine daycare conditions. Sampling was performed by contact plates for a time period of four weeks. Results The longest survival was observed for A. baumannii and E. faecium on all materials (at least four weeks). S. aureus remained viable for at least one week. Gram negative species other than A. baumannii were usually inactivated in less than two days. Nosocomial transmission of the above mentioned bacteria may easily occur if no appropriate infection control measures are applied on a regular daily basis. This might be of particular importance when dealing with outbreaks of A. baumannii and E. faecium.

Description: Background The bone marrow mesenchymal stem cell (BMSCs)-derived extracellular vesicles (EVs) open up a new avenue for ulcerative colitis (UC) treatment recently, but they are not selectively enriched in targeted tissues. EphB2, a cell-to-cell signaling receptor, is identified as a regulator for inflammatory response, immune homeostasis and cell migration. In this study, we investigated the therapeutic potential and underlying mechanism for EphB2 over-expressing BMSCs derived EVs (EphB2-EVs) in the treatment of UC. Methods BMSCs and EVs were obtained and characterized by a series of experiments. Lentivirus vector encoding EphB2 was transfected into BMSCs and verified by qRT-PCR. We analyzed the EphB2-EVs ability of colonic targeting in a DSS-induced colitis model by using confocal microscope and WB. The protective effect of EphB2-EVs in vivo was systematically evaluated by using a series of function experiments. Results We successfully constructed EphB2-overexpressing BMSCs derived EVs (EphB2-EVs). Overexpression of EphB2 significantly enhanced the homing of EVs to the damaged colon. In addition, EphB2-EVs were effective to attenuate inflammation in intestinal mucosa and restore the damaged colon tissue by inhibiting the release of proinflammatory cytokines and upregulating the anti-inflammatory mediators. EphB2-EVs effectively reduced the oxidative stress and repaired the intestinal mucosal barrier in the UC rats. Moreover, EphB2-EVs demonstrated a robust immunomodulatory effect to restore immune homeostasis via modulating Th17/Treg balance and restraining STAT3 activation. Conclusions Our results suggest that EphB2-EVs have high colonic targeting ability and could mitigate DSS-induced colitis via maintaining colonic immune homeostasis. These findings provide an effective therapeutic strategy for UC treatment in clinic.

Description: Background Severe peripheral nerve injury significantly affects patients’ quality of life and induces neuropathic pain. Neural crest stem cells (NCSCs) exhibit several attractive characteristics for cell-based therapies following peripheral nerve injury. Here, we investigate the therapeutic effect of NCSC therapy and associated changes in the spinal cord in a sciatic nerve transection (SNT) model. Methods Complex sciatic nerve gap injuries in rats were repaired with cell-free and cell-laden nerve scaffolds for 12 weeks (scaffold and NCSC groups, respectively). Catwalk gait analysis was used to assess the motor function recovery. The mechanical withdrawal threshold and thermal withdrawal latency were used to assess the development of neuropathic pain. Activation of glial cells was examined by immunofluorescence analyses. Spinal levels of extracellular signal-regulated kinase (ERK), NF-κB P65, brain-derived neurotrophic factor (BDNF), growth-associated protein (GAP)-43, calcitonin gene-related peptide (CGRP), and inflammation factors were calculated by western blot analysis. Results Catwalk gait analysis showed that animals in the NCSC group exhibited a higher stand index and Max intensity At (%) relative to those that received the cell-free scaffold (scaffold group) (p 

Description: Background Acute lung injury (ALI) and in its severe form, acute respiratory distress syndrome (ARDS), results in increased pulmonary vascular inflammation and permeability and is a major cause of mortality in many critically ill patients. Although cell-based therapies have shown promise in experimental ALI, strategies are needed to enhance the potency of mesenchymal stem cells (MSCs) to develop more effective treatments. Genetic modification of MSCs has been demonstrated to significantly improve the therapeutic benefits of these cells; however, the optimal vector for gene transfer is not clear. Given the acute nature of ARDS, transient transfection is desirable to avoid off-target effects of long-term transgene expression, as well as the potential adverse consequences of genomic integration. Methods Here, we explored whether a minicircle DNA (MC) vector containing human angiopoietin 1 (MC-ANGPT1) can provide a more effective platform for gene-enhanced MSC therapy of ALI/ARDS. Results At 24 h after transfection, nuclear-targeted electroporation using an MC-ANGPT1 vector resulted in a 3.7-fold greater increase in human ANGPT1 protein in MSC conditioned media compared to the use of a plasmid ANGPT1 (pANGPT1) vector (2048 ± 567 pg/mL vs. 552.1 ± 33.5 pg/mL). In the lipopolysaccharide (LPS)-induced ALI model, administration of pANGPT1 transfected MSCs significantly reduced bronchoalveolar lavage (BAL) neutrophil counts by 57%, while MC-ANGPT1 transfected MSCs reduced it by 71% (p 

Description: Background This commentary assesses critically the published article in the Health Economics Review. 2020; 10 (1), 1–9. It explains the effects of health expenditure on infant mortality in sub-Saharan Africa using a panel data analysis (i.e. random effects) over the year 2000–2015 extracted from the World Bank Development Indicators. The paper is well written and deserve careful attention. Main text The main reasons for inaccurate estimates observed in this paper are due to endogeneity issue with random effects panel estimators. It occurs when two or more variables simultaneously affect/cause each other. In this paper, the presence of endogeneity bias (i.e. education, health, health care expenditures and real GDP per capita variables) and its omitted variable bias leads to inaccurate estimates and conclusion. Random effects model require strict exogeneity of regressors. Moreover, frequentist/classic estimation (i.e. random effects) relies on sampling size and likelihood of the data in a specified model without considering other kinds of uncertainty. Conclusion This comment argues future studies on health expenditures versus health outcomes (i.e. infant, under-five and neonates mortality) to use either dynamic panel (i.e. system Generalized Method of Moments, GMM) to control endogeneity issues among health (infant or neonates mortality), GDP per capita, education and health expenditures variables or adopting Bayesian framework to adjust uncertainty (i.e. confounding, measurement errors and endogeneity of variables) within a range of probability distribution.