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Nanofiber-expanded human umbilical cord blood-derived CD34+ cell therapy has been shown to have potential applications for peripheral and myocardial ischaemic diseases. However, the efficacies of expanded CD34+ cell therapy for treating cutaneous wounds and its mechanisms of action have yet to be established. Using an excisional wound model in non-obese diabetic/severe combined immune deficient mice, we show herein that CD34+ cells accelerate the wound-healing process by enhancing collagen synthesis, and increasing fibroblast cell migration within the wound bed. Concomitantly, reduced levels of matrix metalloproteinase ( MMPs) such as MMP1, MMP3, MMP9 and MMP13 were detected in the wound beds of animals treated with CD34+ cells compared with vehicle-treated controls. CD34+ cells were found to mediate enhanced migration and proliferation of dermal fibroblast cells in vitro. Moreover, CD34+ cells secrete collagen in a serum-deprived environment. In mechanistic studies, co-culture of CD34+ cells with primary skin fibroblasts increased the expression of collagen1A1, a component of type 1 collagen, and decreased the expression of MMP1 in fibroblast cells in the presence of a proteasome inhibitor. Finally, CD34+ cell-mediated functions were transcriptionally regulated by the c-Jun N-terminal kinases pathway. Collectively, these data provide evidence of therapeutic efficacy and a novel mechanism of nanofiber-expanded CD34+ cell-mediated accelerated wound healing. [ABSTRACT FROM AUTHOR]

Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Little is known about the molecular pathways that precipitate IMT formation. Here, we report the identification of somatic mutations in UPF1, a gene that encodes an essential component of the nonsense-mediated RNA decay (NMD) pathway, in 13 of 15 pulmonary IMT samples. The majority of mutations occurred in a specific region of UPF1 and triggered UPF1 alternative splicing. Several mRNA targets of the NMD pathway were upregulated in IMT samples, indicating that the UPF1 mutations led to reduced NMD magnitude. These upregulated NMD targets included NIK mRNA, which encodes a potent activator of NF-κB. In human lung cells, UPF1 depletion increased expression of chemokine-encoding genes in a NIK-dependent manner. Elevated chemokines and IgE class switching events were observed in IMT samples, consistent with NIK upregulation in these tumors. Together, these results support a model in which UPF1 mutations downregulate NMD, leading to NIK-dependent NF-κB induction, which contributes to the immune infiltration that is characteristic of IMTs. The molecular link between the NMD pathway and IMTs has implications for the diagnosis and treatment of these tumors. [ABSTRACT FROM AUTHOR]

The subcellular localization of circular RNAs (circRNAs) is crucial for understanding their functional relevance and regulatory mechanisms. CircRNA subcellular localization exhibits variations across different cell lines, demonstrating the diversity and complexity of circRNA regulation within distinct cellular contexts. However, existing computational methods for predicting circRNA subcellular localization often ignore the importance of cell line specificity and instead train a general model on aggregated data from all cell lines. Considering the diversity and context-dependent behavior of circRNAs across different cell lines, it is imperative to develop cell line-specific models to accurately predict circRNA subcellular localization. In the study, we proposed CellCircLoc, a sequence-based deep learning model for circRNA subcellular localization prediction, which is trained for different cell lines. CellCircLoc utilizes a combination of convolutional neural networks, Transformer blocks, and bidirectional long short-term memory to capture both sequence local features and long-range dependencies within the sequences. In the Transformer blocks, CellCircLoc uses an attentive convolution mechanism to capture the importance of individual nucleotides. Extensive experiments demonstrate the effectiveness of CellCircLoc in accurately predicting circRNA subcellular localization across different cell lines, outperforming other computational models that do not consider cell line specificity. Moreover, the interpretability of CellCircLoc facilitates the discovery of important motifs associated with circRNA subcellular localization. The CellCircLoc web server is available at http://csuligroup.com:8000/cellcircloc. The source code can be obtained from https://github.com/CSUBioGroup/CellCircLoc.

Ralstonia solanacearum causes lethal bacterial wilt diseases in numerous crops, resulting in considerable yield losses. Harnessing genetic resistance is desirable for safeguarding plants against phytopathogens. However, genetic resources resistant to bacterial wilt are limited in crops. RipE1, a conserved type Ⅲ effector with cysteine protease activity, is recognized in Nicotiana benthamiana and Arabidopsis (Arabidopsis thaliana). Here, using a virus-induced gene silencing approach, we identified the gene encoding N. benthamiana homologue of Ptr1 (NbPtr1a), a coiled-coil nucleotide-binding leucine-rich repeat receptor (NLR) recognizing RipE1. Silencing or editing NbPtr1a completely abolished RipE1-induced cell death, indicating recognition of RipE1 by NbPtr1a. Genetic complementation confirmed this recognition, which is conserved across multiple solanaceous plants. Expression of RipE1 in planta or within pathogenic bacteria promoted pathogen colonization of Nbptr1a mutant plants, demonstrating its virulence function independent of NLR recognition. Silencing NbRIN4 enhanced RipE1-induced cell death, while expressing NbRIN4 inhibited it, suggesting that NbRIN4 is involved in recognition of NbPtr1a-RipE1. Furthermore, RipE1 associated with and cleaved NbRIN4, AtRIN4, and tomato (Solanum lycopersicum) SlRIN4 proteins through its cysteine protease activity. Silencing NbRIN4 in Nbptr1a mutants did not prevent RipE1 from promoting pathogen colonization, suggesting that NbRIN4 is not the primary target for RipE1-mediated virulence. Additionally, NbRIN4 suppressed self-association of the coiled-coil domain of NbPtr1a, which is critical for NbPtr1a-mediated cell death and resistance. Finally, we demonstrated that activation of NbPtr1a requires RipE1-mediated elimination of NbRIN4. Given the conserved nature of RipE1, Ptr1 holds great potential for protecting crops from diverse R. solanacearum strains and other distinct pathogens., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Tendon injuries are widespread and chronic disorders of the musculoskeletal system, frequently caused by overload of the tendons. Currently, the most common treatment for tendon injuries is "cell-free therapy", of which exosomes, which can treat a host of diseases, including immune disorders, musculoskeletal injuries and cardiovascular diseases, are one kind. Among the many sources of exosomes, adipose-derived stem cell exosomes (ASC-Exos) have better efficacy. This is attributed not only to the ease of isolation of adipose tissue, but also to the high differentiation capacity of ASCs, their greater paracrine function, and immunomodulatory capacity compared to other exosomes. ASC-Exos promote tendon repair by four mechanisms: promoting angiogenesis under hypoxic conditions, reducing the inflammatory response, promoting tendon cell migration and proliferation, and accelerating collagen synthesis, thus accelerating tendon healing. This review focuses on describing studies of preclinical experiments with various exosomes, the characteristics of ASC-Exos and their mechanisms of action in tendon healing, as well as elaborating the limitations of ASC-Exos in clinical applications., (© 2022. The Author(s).)

Background: The coronavirus disease 2019 (COVID-19) pandemic has posed a significant influence on public mental health. Current efforts focus on alleviating the impacts of the disease on public health and the economy, with the psychological effects due to COVID-19 relatively ignored. In this research, we are interested in exploring the quantitative characterization of the pandemic impact on public mental health by studying an online survey dataset of the United States., Methods: The analyses are conducted based on a large scale of online mental health-related survey study in the United States, conducted over 12 consecutive weeks from April 23, 2020 to July 21, 2020. We are interested in examining the risk factors that have a significant impact on mental health as well as in their estimated effects over time. We employ the multiple imputation by chained equations (MICE) method to deal with missing values and take logistic regression with the least absolute shrinkage and selection operator (Lasso) method to identify risk factors for mental health., Results: Our analysis shows that risk predictors for an individual to experience mental health issues include the pandemic situation of the State where the individual resides, age, gender, race, marital status, health conditions, the number of household members, employment status, the level of confidence of the future food affordability, availability of health insurance, mortgage status, and the information of kids enrolling in school. The effects of most of the predictors seem to change over time though the degree varies for different risk factors. The effects of risk factors, such as States and gender show noticeable change over time, whereas the factor age exhibits seemingly unchanged effects over time., Conclusions: The analysis results unveil evidence-based findings to identify the groups who are psychologically vulnerable to the COVID-19 pandemic. This study provides helpful evidence for assisting healthcare providers and policymakers to take steps for mitigating the pandemic effects on public mental health, especially in boosting public health care, improving public confidence in future food conditions, and creating more job opportunities., Trial Registration: This article does not report the results of a health care intervention on human participants., (© 2022. The Author(s).)

In our study, older velopharyngeal insufficiency (posterior velopharyngeal insufficiency) patients were defined as those older than 6 years of age. This study aimed to evaluate the abnormal acoustic features of older velopharyngeal insufficiency patients before and after posterior pharyngeal flap surgery. A retrospective medical record review was conducted for patients aged 6 years and older, who underwent posterior pharyngeal flap surgery between November 2011 and March 2015. The audio records of patients were evaluated before and after surgery. Spectral analysis was conducted by the Computer Speech Lab (CSL)-4150B acoustic system with the following input data: The vowel /i/, unaspirated plosive /b/, aspirated plosives /p/, aspirated fricatives /s/ and /x/, unaspirated affricates /j/ and /z/, and aspirated affricates /c/ and /q/. The patients were followed up for 3 months. Speech outcome was evaluated by comparing the postoperatively phonetic data with preoperative data. Subjective and objective analyses showed significant differences in the sonogram, formant, and speech articulation before and after the posterior pharyngeal flap surgery. However, the sampled patients could not be considered to have a high speech articulation (<85%) as the normal value was above or equal to 96%. Our results showed that pharyngeal flap surgery could correct the speech function of older patients with posterior velopharyngeal insufficiency to some extent. Owing to the original errors in pronunciation patterns, pathological speech articulation still existed, and speech treatment is required in the future.

Photon counting CT (PCCT) is an x-ray imaging technique that has undergone great development in the past decade. PCCT has the potential to improve dose efficiency and low-dose performance. In this paper, we propose a statistics-based iterative algorithm to perform a direct reconstruction of material-decomposed images. Compared with the conventional sinogram-based decomposition method which has degraded performance in low-dose scenarios, the multi-energy alternating minimization algorithm for photon counting CT (MEAM-PCCT) can generate accurate material-decomposed image with much smaller biases.

The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain. We demonstrate the ability of anti-CD19-AbTCR-T cells to trigger antigen-specific cytokine production, degranulation, and killing of CD19-positive cancer cells in vitro and in xenograft mouse models. By using the same anti-CD19 binding moiety on an AbTCR compared to a CAR platform, we demonstrate that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3ζ CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype. Moreover, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019, our anti-CD19-AbTCR shows less cytokine release and comparable tumor inhibition in a patient-derived xenograft leukemia model., Competing Interests: Y.X., Z.Y., L.H.H., P.Z., L.L., B.Z., S.G., J.L., J.F.M., V.W.C., H.L., and C.L. are employees of and have equity ownership and/or stock options in Eureka Therapeutics, Inc. S.A.G. is a scientific advisor to Eureka Therapeutics with stock options in the company. D.M.B. is a consultant to Eureka Therapeutics. Other associations: S.A.G. has received research and/or clinical trial support from Novartis, Servier and Kite. He consults for, has participated in ad boards, or serves on study steering committees or scientific advisory boards for the following companies: Novartis, Adaptimmune, TCR2, Juno, GlaxoSmithKline, Cellectis, Vertex, Roche and Janssen. He is listed on a patent related to toxicity management in cell therapy managed by University of Pennsylvania and CHOP policies.

Background: Understanding how landscape factors, including suites of geographic and environmental variables, and both historical and contemporary ecological and evolutionary processes shape the distribution of genetic diversity is a primary goal of landscape and conservation genetics and may be particularly consequential for species involved in ecological restoration. In this study, we examine the factors that shape the distribution of genetic variation in a leguminous shrub (Caragana microphylla) important for restoration efforts on the Mongolian Plateau in China. This region houses several major bioclimatic gradients, and C. microphylla is an important restoration species because it stabilizes soils and prevents advancing desertification on the Inner Mongolia Plateau caused by ongoing climate change., Results: We assembled an expansive genomic dataset, consisting of 22 microsatellite loci, four cpDNA regions, and 5788 genome-wide SNPs from ten populations of C. microphylla. We then applied ecological niche modelling and linear and non-linear regression techniques to investigate the historical and contemporary forces that explain patterns of genetic diversity and population structure in C. microphylla on the Inner Mongolia Plateau. We found strong evidence that both geographic and environmental heterogeneity contribute to genetic differentiation and that the spatial distribution of genetic diversity in C. microphylla appears to result partly from the presence of a glacial refugium at the southwestern edge of its current range., Conclusions: These results suggest that geographic, environmental, and historical factors have all contributed to spatial genetic variation in this ecologically important species. These results should guide restoration plans to sustain genetic diversity during plant translocations.

Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Little is known about the molecular pathways that precipitate IMT formation. Here, we report the identification of somatic mutations in UPF1, a gene that encodes an essential component of the nonsense-mediated RNA decay (NMD) pathway, in 13 of 15 pulmonary IMT samples. The majority of mutations occurred in a specific region of UPF1 and triggered UPF1 alternative splicing. Several mRNA targets of the NMD pathway were upregulated in IMT samples, indicating that the UPF1 mutations led to reduced NMD magnitude. These upregulated NMD targets included NIK mRNA, which encodes a potent activator of NF-κB. In human lung cells, UPF1 depletion increased expression of chemokine-encoding genes in a NIK-dependent manner. Elevated chemokines and IgE class switching events were observed in IMT samples, consistent with NIK upregulation in these tumors. Together, these results support a model in which UPF1 mutations downregulate NMD, leading to NIK-dependent NF-κB induction, which contributes to the immune infiltration that is characteristic of IMTs. The molecular link between the NMD pathway and IMTs has implications for the diagnosis and treatment of these tumors.

Despite recent advances in cardiovascular medicine, ischemic diseases remain a major cause of morbidity and mortality. Although stem cell-based therapies for the treatment of ischemic diseases show great promise, limited availability of biologically functional stem cells mired the application of stem cell-based therapies. Previously, we reported a PES-nanofiber based ex vivo stem cell expansion technology, which supports expansion of human umbilical cord blood (UCB)-derived CD133(+)/CD34(+) progenitor cells ∼225 fold. Herein, we show that using similar technology and subsequent re-expansion methods, we can achieve ∼5 million-fold yields within 24 days of the initial seeding. Interestingly, stem cell phenotype was preserved during the course of the multiple expansions. The high level of the stem cell homing receptor, CXCR4 was expressed in the primary expansion cells, and was maintained throughout the course of re-expansions. In addition, re-expanded cells preserved their multi-potential differential capabilities in vitro, such as, endothelial and smooth muscle lineages. Moreover, biological functionality of the re-expanded cells was preserved and was confirmed by a murine hind limb ischemia model for revascularization. These cells could also be genetically modified for enhanced vasculogenesis. Immunohistochemical evidences support enhanced expression of angiogenic factors responsible for this enhanced neovascularization. These data further confirms that nanofiber-based ex-vivo expansion technology can generate sufficient numbers of biologically functional stem cells for potential clinical applications., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Because of their ability for self-renewal and neural differentiation, stem cells are believed to be ideal for cell replacement therapy in Parkinson's disease (PD). Nanofiber-expanded human umbilical cord hematopoietic stem cells (HUHSCs) are advantageous to other stem cells as they provide a source of unlimited stem cell production for clinical application. In this study, we investigated whether 1. nanofiber-expanded HUHSCs are capable of neural differentiation in vitro, and 2. they could improve dopaminergic neuron morphology in the caudate/putamen (CPu) and substantia nigra pars compacta (SNc) of the MPTP-mouse model of PD. When cultured under neural differentiation conditions, nanofiber-expanded HUHSCs were able to undergo neural differentiation in vitro, as determined by gene and protein expression of neural markers such as MAP2, NeuN, HuC, GFAP and Oligo2. Thirty days after a single intracardioventricular injection of HUHSCs to MPTP-mice there was a significant recovery of tyrosine hydroxylase (TH) immunostaining in CPu. There was an increase in the size and staining density of TH+ cells in SNc, while their number was unchanged.

Despite recent advances in cardiovascular medicine, ischemic heart disease remains the major cause of death in the United States and abroad. Cell-based therapy for degenerative diseases like myocardial ischemia using stem cells is currently under serious investigation. Various types of stem cells are being considered to be candidates for cell transplantation in cell-based therapy. Hematopoietic stem cells are one of the most promising cell types as several studies demonstrated their ability to improve ischemic cardiac functions by enhancing neovascularization and by reducing the total size of scar tissue. However, in order to procure sufficient numbers of functional stem cells, ex-vivo expansion technology became critically important. In this review, we focus on the state-of-the-art ex-vivo technology for the expansion of hematopoietic stem cells, and the underlying mechanisms regulating stem cell self-renewal as well as differentiation.