Myocarditis and dilated cardiomyopathy (DCM) are often caused by viral infections and occur more frequently in men than in women, but the reasons for the sex difference remain unclear. The aim of this study was to assess whether gene changes in the heart during coxsackievirus B3 (CVB3) myocarditis in male and female BALB/c mice predicted worse DCM in males. Although myocarditis (P = 4.2 × 10(-5)) and cardiac dilation (P = 0.008) were worse in males, there was no difference in viral replication in the heart. Fibrotic remodeling genes, such as tissue inhibitor of metalloproteinase (TIMP)-1 and serpin A 3n, were upregulated in males during myocarditis rather than during DCM. Using gonadectomy and testosterone replacement, we showed that testosterone increased cardiac TIMP-1 (P = 0.04), serpin A 3n (P = 0.007), and matrix metalloproteinase (MMP)-8 (P = 0.04) during myocarditis. Testosterone increased IL-1β levels in the heart (P = 0.02), a cytokine known to regulate cardiovascular remodeling, and IL-1β in turn increased cardiac serpin A 3n mRNA (P = 0.005). We found that 39 of 118 (33%) genes identified in acute DCM patients were significantly altered in the heart during CVB3 myocarditis in mice, including serpin A 3n (3.3-fold change, P = 0.0001). Recombinant serpin A 3n treatment induced cardiac fibrosis during CVB3 myocarditis (P = 0.0008) while decreasing MMP-3 (P = 0.04) and MMP-9 (P = 0.03) levels in the heart. Thus, serpin A 3n was identified as a gene associated with fibrotic cardiac remodeling and progression to DCM in male myocarditis patients and mice.
Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR)3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3) myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL)-4-dominant T helper (Th)2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.
Ultra-miniaturized microendoscopes are vital for numerous biomedical applications. Such minimally invasive imagers allow for navigation into hard-to-reach regions and observation of deep brain activity in freely moving animals. Conventional solutions use distal microlenses. However, as lenses become smaller and less invasive, they develop greater aberrations and restricted fields of view. In addition, most of the imagers capable of variable focusing require mechanical actuation of the lens, increasing the distal complexity and weight. Here, we demonstrate a distal lens-free approach to microendoscopy enabled by computational image recovery. Our approach is entirely actuation free and uses a single pseudorandom spatial mask at the distal end of a multicore fiber. Experimentally, this lensless approach increases the space-bandwidth product, i.e., field of view divided by resolution, by threefold over a best-case lens-based system. In addition, the microendoscope demonstrates color resolved imaging and refocusing to 11 distinct depth planes from a single camera frame without any actuated parts.
We demonstrate two-dimensional imaging using illumination via a single-mode fiber with a multiply scattering tip and compressed sensing acquisition. We illuminate objects with randomly structured, but deterministic, speckle patterns produced by a coherent light source propagating through a TiO2-coated fiber tip. The coating thickness is optimized to produce speckle patterns that are highly sensitive to laser wavelength, yet repeatable. Images of the object are reconstructed from the characterized wavelength dependence of the speckle patterns and the wavelength dependence of the total light collected from the object using a single photodetector. Our imaging device is mechanically scan-free and insensitive to bending of the fiber, making it suitable for micro-endoscopy.
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