Background/Aims: Spine and spinal cord pathologies and associated neuropathic pain are among the most complex medical disorders to treat. While rodent models are widely used in spine and spinal cord research and have provided valuable insight into pathophysiological mechanisms, these models offer limited translatability. Thus, studies in rodent models have not led to the development of clinically effective therapies. More recently, swine has become a favored model for spine research because of the high congruency of the species to humans with respect to spine and spinal cord anatomy, vasculature, and immune responses. However, conventional breeds of swine commonly used in these studies present practical and translational hurdles due to their rapid growth toward weights well above those of humans. Methods: In the current study, we evaluated the suitability of a human-sized breed of swine developed at the University of Wisconsin-Madison, the Wisconsin Miniature SwineTM (WMSTM), in the context of thoracic spine morphometry for use in research to overcome limitations of conventional swine breeds. The morphometry of thoracic vertebrae (T1–T15) of 5–6 months-old WMS was analyzed and compared to published values of human and conventional swine spines. Results: The key finding of this study is that WMS spine more closely models the human spine for many of the measured vertebrae parameters, while being similar to conventional swine in respect to the other parameters. Conclusion: WMS provides an improvement over conventional swine for use in translational spinal cord injury studies, particularly long-term ones, because of its slower rate of growth and its maximum growth being limited to human weight and size.
Aims Congenital heart disease (CHD) is the most common genetic birth defect, which has considerable morbidity and mortality. We focused on deciphering key regulators that govern cardiac progenitors and cardiogenesis. FOXK1 is a forkhead/winged helix transcription factor known to regulate cell cycle kinetics and is restricted to mesodermal progenitors, somites and the heart. In the present study, we define an essential role for FOXK1 during cardiovascular development. Methods & Results We used the mouse embryoid body system to differentiate control and Foxk1 KO ESCs into mesodermal, cardiac progenitor cells and mature cardiac cells. Using flow cytometry, immunohistochemistry, cardiac beating, transcriptional and ChIP qPCR assays, bulk RNAseq and ATACseq analyses, FOXK1 was observed to be an important regulator of cardiogenesis. Flow cytometry analyses revealed perturbed cardiogenesis in Foxk1 KO EBs. Bulk RNAseq analysis at two developmental stages showed a significant reduction of the cardiac molecular program in Foxk1 KO EBs compared to the control EBs. ATACseq analysis during EB differentiation demonstrated that the chromatin landscape nearby known important regulators of cardiogenesis was significantly relaxed in control EBs compared to Foxk1 KO EBs. Furthermore, we demonstrated that in the absence of FOXK1, cardiac differentiation was markedly impaired by assaying for cTnT expression and cardiac contractility. We demonstrate that FOXK1 is an important regulator of cardiogenesis by repressing the Wnt/β-catenin signaling pathway and thereby promoting differentiation. Conclusions These results identify FOXK1 as an essential transcriptional and epigenetic regulator of cardiovascular development. Mechanistically, FOXK1 represses Wnt signaling to promote the development of cardiac progenitor cells. Translational perspective Congenital heart disease is the most common birth defect. Deciphering the networks that govern cardiomyocyte specification, proliferation and differentiation will provide insights regarding therapeutic interventions for cardiovascular disease. The winged helix/forkhead family of transcription factors have been shown to have critical roles in epigenetics, organogenesis, cellular proliferation and differentiation. FOXK1 is an important transcription factor that regulates cardiovascular development through the Wnt signaling pathway. This FOXK1-Wnt pathway defines a network that may be therapeutically targeted to promote cardiogenesis.
There are several techniques of monitoring essential tremors, but there is not yet a standard method developed for the field. A quantitative way to track effects of medication and/or lifestyle treatment would be beneficial for future research in prevention or regression of essential tremors. The two methods evaluated are acoustic tremor monitoring (ATM) and rhythmic spirals (RS). The novel ATM measurement quantifies frequency and amplitude quickly and cost effectively. The tremor patient holds a microphone close to a speaker playing a single frequency tone. The Doppler Effect caused by the shaking microphone distorts the sound recording, and the encoded tremor information can be retrieved by using the Fast-Fourier Transform algorithm. The second method, RS, can be used by patients at home to measure frequency. The RS method is similar to the classic Archimedes spirals, but uses a different form and is timed which allows for the calculation of tremor frequency. The RS and ATM methods produce statistically similar frequency measurements, although ATM has greater precision. KEYWORDS: Essential Tremors, Archimedes Spiral, Accelerometry, Spiral Analysis, Acoustic Tremor Monitoring, Rhythmic Spirals.
Background: Congenital heart disease (CHD) is the most common genetic birth defect and has considerable morbidity and mortality. Therefore, it is essential to define the mechanisms governing the specification and differentiation of mesodermal and cardiac progenitors to develop targeted therapies for CHD. FOXK1 is a forkhead/winged helix transcription factor known to regulate cell cycle kinetics, myogenic stem cell proliferation and tumorigenesis. During development, FOXK1 expression is restricted to mesodermal progenitors, somites and the heart. The role for FOXK1 in the developing heart is unknown and warrants investigation. In the present study, we describe a novel role for FOXK1 as an essential regulator of cardiovascular development. Approach and Results: We used a mouse embryoid body (EB) system to differentiate WT and Foxk1 null ESCs into mesodermal and cardiac progenitor cells. Flow cytometry analysis for FLK1+PDGFRa+ showed that in the absence of FOXK1, the cardiac lineage was significantly affected. Bulk RNAseq analysis of D3 and D5 EBs showed a significant induction of the cardiac molecular program in WT EBs compared to the Foxk1 null EBs. Since forkhead transcription factors have been shown to be important epigenetic regulators (i.e. pioneer factors), we performed ATACseq of D3 and D5 EBs, which showed that the chromatin landscape nearby known important regulators of cardiogenesis (Isl1, Gata4, Hand1, Hand2, etc.) was significantly relaxed in WT EBs compared to Foxk1 null EBs. Furthermore, we demonstrated that in the absence of Foxk1 , cardiac differentiation was markedly impaired by assaying for cTnT expression and cardiac contractility which was essentially absent in Foxk1 null EBs compared to WT EBs at D10 of differentiation. Additionally, using transcriptional, Co-IP and pulldown assays we demonstrated that FOXK1 is an important regulator of Notch and Wnt/β-catenin signaling pathways during cardiogenesis. These results were further supported as the Foxk1 null embryo was lethal at E9.5 and had perturbed heart development. Conclusions: These results identify FOXK1 as an essential transcriptional and epigenetic regulator of cardiovascular development using EB assays and gene disruption technologies.
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