Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.
Background and Aims Ileal strictures are the major indication for resective surgery in Crohn’s disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. Methods Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. Results 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). Conclusion An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders, however, we still lack fundamental knowledge about meningeal biology. Here, we utilized high-throughput RNA sequencing (RNA-seq) techniques to investigate the transcriptional response of the meninges to traumatic brain injury (TBI) and aging in the sub-acute and chronic time frames. Using single-cell RNA sequencing (scRNA-seq), we first explored how mild TBI affects the cellular and transcriptional landscape in the meninges in young mice at one-week post-injury. Then, using bulk RNA-seq, we assessed the differential long-term outcomes between young and aged mice following TBI. In our scRNA-seq studies, we highlight injury-related changes in differential gene expression seen in major meningeal cell populations including macrophages, fibroblasts, and adaptive immune cells. We found that TBI leads to an upregulation of type I interferon (IFN) signature genes in macrophages and a controlled upregulation of inflammatory-related genes in the fibroblast and adaptive immune cell populations. For reasons that remain poorly understood, even mild injuries in the elderly can lead to cognitive decline and devastating neuropathology. To better understand the differential outcomes between the young and the elderly following brain injury, we performed bulk RNA-seq on young and aged meninges 1.5 months after TBI. Notably, we found that aging alone induced upregulation of meningeal genes involved in antibody production by B cells and type I IFN signaling. Following injury, the meningeal transcriptome had largely returned to its pre-injury signature in young mice. In stark contrast, aged TBI mice still exhibited upregulation of immune-related genes and downregulation of genes involved in extracellular matrix remodeling. Overall, these findings illustrate the dynamic transcriptional response of the meninges to mild head trauma in youth and aging.
Background Facial rejuvenation procedures are common in plastic surgery. Objectives The aim of this study was to report the 50 most cited articles in the field of aesthetic facial rejuvenation surgery and provide a simple educational resource for plastic surgeons. Methods The authors utilized the Web of Science Citation Index to identify the 50 most cited articles related to surgery for facial rejuvenation published from 1950 to 2019. Articles were classified according to their level of evidence, type of study, country of publication, and topic of interest: facelift, blepharoplasty, brow lift, neck lift, or combined areas. Results The mean number of citations per article was 137, and the majority of articles (n = 19) were published between 1990 and 1999. The most prevalent topic was facelift surgery (n = 24), followed by articles discussing combined procedures (n = 13), blepharoplasty (n = 6), brow lift (n = 4), and neck lift (n = 3). Most of the articles were classified as clinical (n = 26), followed by basic science studies (n = 12) and review articles (n = 12). Among the articles amenable to grading level of evidence (n = 26), most (n = 24) presented their findings utilizing level IV evidence. The nation of origin for most of the articles (n = 41) was the United States. Conclusions Articles addressing facelift surgery represented the largest proportion of peer-reviewed landmark publications in aesthetic facial surgery research. A simple educational resource is presented to encourage the appreciation of the research in this field.
Background Aesthetic facial surgeries historically rely on subjective analysis in determining success; this limits objective comparison of surgical outcomes. Objectives This case study exemplifies the use of an artificial intelligence software on objectively analyzing facial rejuvenation techniques with the aim of reducing subjective bias. Methods Retrospectively, all patients who underwent facial rejuvenation surgery with concomitant procedures from 2015-2017 were included (n = 32). Patients were categorized in Groups A-C: Group A -10 superficial musculoaponeurotic system (SMAS) plication facelift (n = 10), Group B - SMASectomy facelift (n = 7), and Group C - high SMAS facelift (n = 15). Neutral repose images pre- and post-operatively (average >3 months) were analyzed using artificial intelligence for emotion and action unit alterations. Results Postoperatively, Group A experienced a decrease in happiness by 0.84% and a decrease in anger by 6.87% (P>>0.1). Group B had an increase in happiness by 0.77% and an increase in anger by 1.91% (P>>0.1). Both Group A and B did not show any discernable action unit patterns. In Group C, the lip corner puller AU increased in average intensity from 0% to 18.7%. This correlated with an average increase in detected happiness from 1.03% to 13.17% (p = 0.008). Conversely, the average detected anger decreased from 14.66% to 0.63% (p = 0.032). Conclusions This study provides the first proof of concept for the use of a machine learning software application to objectively assess various aesthetic surgical outcomes in facial rejuvenation. Due to limitations in patient heterogeneity, this study does not claim one technique’s superiority but serve as a concept foundation for future investigation.
Recent advances have highlighted the importance of several innate immune receptors expressed by microglia in Alzheimer’s disease (AD). In particular, mounting evidence from AD patients and experimental models indicates pivotal roles for TREM2, CD33, and CD22 in neurodegenerative disease progression. While there is growing interest in targeting these microglial receptors to treat AD, we still lack knowledge of the downstream signaling molecules used by these receptors to orchestrate immune responses in AD. Notably, TREM2, CD33, and CD22 have been described to influence signaling associated with the intracellular adaptor molecule CARD9 to mount downstream immune responses outside of the brain. However, the role of CARD9 in AD remains poorly understood. Here, we show that genetic ablation of CARD9 in the 5xFAD mouse model of AD results in exacerbated amyloid beta (Aβ) deposition, increased neuronal loss, worsened cognitive deficits, and alterations in microglial responses. We further show that pharmacological activation of CARD9 promotes improved clearance of Aβ deposits from the brains of 5xFAD mice. These results help to establish CARD9 as a key intracellular innate immune signaling molecule that regulates Aβ-mediated disease and microglial responses. Moreover, these findings suggest that targeting CARD9 might offer a strategy to improve Aβ clearance in AD.
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