Intrasynovial flexor tendon lacerations of the hand are clinically problematic, typically requiring operative repair and extensive rehabilitation. The small‐molecule connective tissue growth factor ...(CTGF) mimics, oxotremorine M (Oxo‐M) and 4‐PPBP maleate (4‐PPBP), have been shown to improve tendon healing in small animal models by stimulating the expansion and differentiation of perivascular CD146+ cells. To enhance intrasynovial flexor tendon healing, small‐molecule CTGF mimics were delivered to repaired canine flexor tendons via porous sutures. In vitro studies demonstrated that Oxo‐M and 4‐PPBP retained their bioactivity and could be released from porous sutures in a sustained manner. However, in vivo delivery of the CTGF mimics did not improve intrasynovial tendon healing. Histologic analyses and expression of tenogenic, extracellular matrix, inflammation, and remodeling genes showed similar outcomes in treated and untreated repairs across two time points. Although in vitro experiments revealed that CTGF mimics stimulated robust responses in extrasynovial tendon cells, there was no response in intrasynovial tendon cells, explaining the lack of in vivo effects. The results of the current study indicate that therapeutic strategies for tendon repair must carefully consider the environment and cellular makeup of the particular tendon for improving the healing response.
The plant cytoskeleton underpins the function of a multitude of cellular mechanisms, including those associated with developmental and stress-associated signaling processes. In recent years, the ...actin cytoskeleton has been demonstrated to play a key role in plant immune signaling, including a recent demonstration that pathogens target actin filaments to block plant defense and immunity. Herein, we quantified spatial changes in host actin filament organization after infection with Pseudomonas syringae pv. tomato DC3000 (Pst DC3000), demonstrating that the type-III effector HopG1 is required for pathogen-induced changes to actin filament architecture and host disease symptom development during infection. Using a suite of pathogen effector deletion constructs, coupled with high-resolution microscopy, we found that deletion of hopG1 from Pst DC3000 resulted in a reduction in actin bundling and a concomitant increase in the density of filament arrays in Arabidopsis, both of which correlate with host disease symptom development. As a mechanism underpinning this activity, we further show that the HopG1 effector interacts with an Arabidopsis mitochondrial-localized kinesin motor protein. Kinesin mutant plants show reduced disease symptoms after pathogen infection, which can be complemented by actin-modifying agents. In total, our results support a model in which HopG1 induces changes in the organization of the actin cytoskeleton as part of its virulence function in promoting disease symptom development.
Summary
The contamination of inactivated vaccine with non‐structural proteins (NSPs) leads to a high false‐positive rate, which is a substantial barrier to accurately differentiate foot‐and‐mouth ...disease virus (FMDV)‐infected animals from vaccinated animals. To address this problem, a new chemiluminescence immunoassay (CLIA) method was developed to detect antibodies targeting the two recombinant epitope‐based proteins located in 3A and 3B. The 3Aepitp‐3Bepitp CLIA exhibited a diagnostic sensitivity of 94.0% and a diagnostic specificity of 97.5% for the detection of serum samples (naïve bovines, n = 52, vaccinated bovines, n = 422, infected bovines, n = 116) from animals with known status. The CLIA method also had a concordance rate of 88.1% with the PrioCHECK FMDV NSP ELISA based on the detection of 270 serum samples from the field. Importantly, the 3Aepitp‐3Bepitp CLIA produced no false‐positives when used to detect FMDV in samples from bovines that had been vaccinated up to five times, and it was demonstrated a low false‐positive rate when the bovines had been vaccinated up to ten (2.15%) and fifteen times (5.93%). Therefore, the 3Aepitp‐3Bepitp CLIA detects FMDV in samples from frequently vaccinated bovines with high accuracy and represents an alternative method to differentiate FMDV‐infected and vaccinated bovines.
Our aim was to investigate if the accuracy of diagnosing mild cognitive impairment (MCI) using the Mini–Mental State Examination (MMSE) and logical memory (LM) test could be enhanced by adding MRI ...data.
Data of individuals with normal cognition and MCI were obtained from the National Alzheimer Coordinating Center database (n = 386). Deep learning models trained on MRI slices were combined to generate a fused MRI model using different voting techniques to predict normal cognition versus MCI. Two multilayer perceptron (MLP) models were developed with MMSE and LM test results. Finally, the fused MRI model and the MLP models were combined using majority voting.
The fusion model was superior to the individual models alone and achieved an overall accuracy of 90.9%.
This study is a proof of principle that multimodal fusion of models developed using MRI scans, MMSE, and LM test data is feasible and can better predict MCI.
Objectives:
Longitudinally extensive transverse myelitis (LETM) with spinal cord lesions spanning three or more vertebral segments is a key feature of neuromyelitis optica (NMO). However, the role of ...anti-aquaporin 4 (anti-AQP4) antibody, a sensitive biomarker of NMO, in the conversion of LETM to NMO remains uncertain.
Methods:
Thirty first-ever LETM patients were retrospectively analysed and divided into two groups according to the presence of anti-AQP4 antibodies.
Results:
Eighteen (60%) patients presented with anti-AQP4 antibodies. Fifteen (83.33%) anti-AQP4 (+) LETM patients converted to NMO, while only three of 12 (25%, p = 0.002) anti-AQP4 (-) LETM patients progressed to NMO, over a mean follow-up period of 5.63 years. Seven (38.89%) anti-AQP4 (+) and one (8.33%) anti-AQP4 (-) LETM patients received interferon-β1a treatment, respectively. Anti-AQP4 (+) LETM patients demonstrated a higher immunogamma globulin (IgG) index (0.68 ± 0.43 versus 0.47 ± 0.19, p = 0.018), annual relapse rate (0.72 ± 0.31 versus 0.42 ± 0.17, p = 0.01) and Kurtzke Expanded Disability Status Scale (4.28 ± 2.22 versus 2.67 ± 2.26, p = 0.031), than anti-AQP4 (-) LETM patients. In spinal magnetic resonance imaging (MRIs), more than half (58.33%) of the anti-AQP4 (+) LETM patients were observed to have central grey matter-predominant involvement in the axial view, while peripheral white matter-predominant involvement (51.85%) was the most common pattern observed in the anti-AQP4 (-) LETM patients.
Conclusion:
Anti-AQP4 (+) LETM demonstrated a high conversion rate to NMO (83.33%), suggesting that anti-AQP4 (+) LETM may represent an early, isolated syndrome of NMO spectrum disorder. The greater number of patients receiving interferon-β treatment in anti-AQP4 (+) LETM may contribute to its high annual relapse rate.
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is activated by cigarette smoke. Previously, we demonstrated that AhR is overexpressed in lung adenocarcinomas (ADs). ...In this study we observed that AhR expression is significantly correlated with nuclear RelA (a nuclear factor-κB (NFκB) subunit) and cytosolic interleukin-6 (IL-6) in 200 non-small cell lung cancer patients, especially among never smokers. Overexpression of AhR increased IL-6 expression in H1355 cells and immortalized human bronchial epithelial cells BEAS-2B. As NFκB inhibitor and knockdown RelA expression greatly reduced constitutive AhR-induced IL-6 expression, we hypothesized that AhR expression, in the absence of exogenous ligand, is able to modulate NFκB activity and subsequently upregulate IL-6 expression, thus promoting the development of lung AD. Specifically, AhR overexpression significantly increased NFκB activity, whereas interference with AhR expression significantly reduced NFκB activity and IL-6 expression in H1355 cells. We demonstrated that AhR associates with RelA in the cytosol and nucleus of human lung cells. Furthermore, AhR overexpression enhanced nuclear localization of AhR and RelA, and increased the association of AhR-RelA with the NFκB response element of the IL-6 promoter. However, p50 was not involved. Our results indicate that AhR, without exposure to a ligand, associates with RelA, which then positively modulates NFκB activity and then upregulates IL-6 expression in human lung cells. Thus we have identified a new mechanism for lung tumorigenesis in non-smokers.
B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). However, CAR-T-related tumor lysis syndrome ...(TLS) has been observed. We aimed to elucidate the incidence, clinical and laboratory characteristics, and prognosis of CAR-T cell-related TLS.
Patients (n=105) with r/r MM treated with BCMA-targeted CAR-T cell therapy were included. Patient characteristics, laboratory parameters, and clinical outcomes were assessed.
Eighteen (17.1%) patients developed TLS after BCMA-targeted CAR-T cell therapy. The median time till TLS onset was 8 days. Patients with TLS had steep rise in uric acid (UA), creatinine, and lactate dehydrogenase (LDH) within 6 days following CAR-T cell infusion and presented earlier and persistent escalation of cytokines (C-reactive protein CRP, interleukin-6 IL-6, interferon-γ IFN-γ, and ferritin levels). All 18 patients had cytokine release syndrome (CRS), of which 13 (72.2%) developed grade 3-4 CRS. Three of 18 patients (16.7%) developed immune effector cell-associated neurotoxicity syndrome (ICANS): two patients with grade 1 ICANS and one with grade 2 ICANS. TLS development had a negative effect on the objective response rate (77.8% in the TLS group vs. 95.4% in the non-TLS group, p<0.01). During the median follow-up of 15.1 months, the median PFS was poorer of patients with TLS (median: 3.4 months in the TLS group vs. 14.7 months in the non-TLS group, p<0.001, hazard ratio HR=3.5 95% confidence interval CI 1.5-8.5). Also, TLS development exhibited significant effects on OS (median: 5.0 months in the TLS group vs. 39.8 months in the non-TLS group, p<0.001, hazard ratio HR=3.7 95% CI 1.3-10.3). TLS was associated with a higher tumor burden, elevated baseline creatinine and UA levels, severe CRS, pronounced CAR-T cell expansion, and corticosteroid use.
TLS is a frequently observed CAR-T therapy complication and negatively influences clinical response and prognosis. Close monitoring for TLS should be implemented during CAR-T cell therapy, especially for those at high TLS risk.
Background: It is of considerable public health importance to prevent or delay the progression of mild cognitive impairment (MCI) to more severely impaired cognitive states. This study examines the ...risk of progression from mild to severe cognitive impairment in relation to engagement in social activities while mildly impaired and the concurrence of subsequent change in engagement with MCI progression. Methods: Participants were 816 older adults with cognitively defined MCI (mean age 78.0 (standard deviation or SD = 7.4) years) from the Monongahela–Youghiogheny Healthy Aging Team (MYHAT) Study – a prospective cohort study of MCI in the community. Over three years of follow-up, 78 individuals progressed from MCI to severe cognitive impairment, while 738 did not progress. Risk of progression was estimated using discrete time survival analyses. The main predictors were standardized composite measures of the variety and frequency of engagement in social activities. Results: Lower risk of progression from mild to severe cognitive impairment was associated with both a greater level of frequency of engagement in social activities while mildly impaired (OR = 0.72, 95% CI: 0.55–0.93, p = 0.01) and also with a slower rate of decline in the variety of activities over time (OR = 0.01, 95% CI: <0.001–0.38, p = 0.02). Conclusions: Greater engagement in social activities may potentially be beneficial for preventing or delaying further cognitive decline among older adults with MCI. Alternatively, lesser engagement in social activities may be a marker of impending cognitive decline in MCI.
Microbial agents have an important role in the pathogenesis of various inflammatory eye diseases, such as uveitis and keratitis. Microbial infections of the eye such as microbial keratitis, ocular ...onchocerciasis, bacterial endophthalmitis, viral retinitis, and other infectious uveitis are unfortunately common. In addition, microbial agents have been implicated in the pathogenesis of “non-infectious” immune mediated diseases such as HLA-B27 associated acute anterior uveitis. Toll-like receptors (TLR) are a family of pattern recognition receptors that initiates rapid host innate immune response to microbial components known as pathogen associated molecular patterns, which are unique to a given class of microbes, such as lipopolysaccharide of Gram negative bacteria. Recent in vitro and in vivo studies have demonstrated the expression and function of TLRs in the eye, with significant implications for better understanding of ocular immunity and the pathogenesis of inflammatory eye diseases affecting the cornea, uvea, and retina.
Directional growth effect on magneto-mechanical properties of Fe81Al19 alloy is studied. The ideal model of heat flux for directional solidification (DS) technique is proposed, and the tuned A/L (the ...ratio of cross-sectional area and length for the ingot) and ΔT (temperature difference) are adopted to increase heat flux (q). The experimental result shows that the increase of q effectively promotes the degree of (011)100 Goss texture and therefore helps to form an oriented stripe domain structure. Large λ100 of 93.8 ppm attained for this optimized Fe81Al19 alloy prepared by DS method is very close to that of the Fe81Al19 single crystal (95.0 ppm). For the optimized DS prepared Fe81Al19 alloy, high magnetostriction sensitivity (dλ/dH) of 0.45 ppm/Oe leads to huge ΔEs/E0 of ∼10% and attractive ΔE/E0 of 8.2% at small H = 0.25 kOe. The above remarkable magneto-mechanical properties, low cost of Fe81Al19, and simple process of DS favor for applications. This work proposes an ideal model to emphasize the importance of heat flux in DS, and experimentally attains the remarkable magneto-mechanical properties for Fe81Al19 alloy prepared by DS.
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