Thyroid Autoimmunity as a Window to Autoimmunity: An Explanation for Sex Differences in the Prevalence of Thyroid Autoimmunity

Autoimmune thyroid diseases (AITDs), predominately Graves׳ disease and Hashimoto׳s thyroiditis, comprise the most common autoimmune diseases in humans. Both have the production of anti-thyroid antibody as an important aspect and both are much more prevalent in females, being at least 10 times more common than in males. Using these two clues, a hypothesis for the initiation of thyroid autoimmunity is proposed that helps to make the case that the thyroid is one of the most sensitive sites for autoimmunity and helps account for the prevalence and the observed sex differences in AITDs and associated diseases, such as type 1 diabetes and Latent Autoimmune Diabetes in Adults (LADA). The primary mechanisms proposed involve the underlying state of inflammation as a result of the adipokines, especially leptin, TNF-α, and IL-6, and the receptors able to recognize pathogen-associated molecular patterns (PAMP׳s) and damage-associated molecular patterns (DAMP׳s) through Toll-like receptors (TLR) and others receptors present on thyrocytes. The adipokines are produced by adipose tissue, but have hormone-like and immune modulating properties. As the levels of leptin are significantly higher in females, an explanation for the sex difference in thyroid autoimmunity emerges. The ability of the thyrocytes to participate in innate immunity through the TLR provides an adjuvant-like signal and allows for the action of other agents, such as environmental factors, viruses, bacteria, and even stress to provide the initiation step to break tolerance to thyroid self-antigens. Seeing the thyroid as one of the most sensitive sites for autoimmunity, means that for many autoimmune disorders, if autoimmunity is present, it is likely to also be present in the thyroid – and that that condition in the thyroid was probably earlier. The evidence is seen in multiple autoimmune syndrome

Combating HIV-1 by Targeting Drug Efflux Transporters on the Macrophage Reservoir

Introduction. HIV-1 eradication has not been achieved so far due to the existence of the cellular reservoir in which the virus can reside and replicate even under antiretroviral drug therapy (ART). Infected macrophages, which represent a long-term viral reservoir have been shown to lead to viral rebound independently. In response to the environmental stimuli, macrophages can be polarized into different phenotypes: the pro-inflammatory M1 and the anti-inflammatory M2. Tobacco smoking and alcohol drinking, which are prevalent among people who are living with HIV-1, have been shown to promote HIV-1 progression and decrease the efficacy of antiretroviral drugs. A commonly used macrolide antibiotic azithromycin (AZM) has been shown to shift macrophage polarization in a murine macrophage cell line. In the previous research, we found that drug efflux transporters expressed differently between macrophage phenotypes. In this dissertation, we examined the effects of CSC, ethanol exposure, and AZM on the expression and function of clinically relevant drug efflux transporters, viral suppression of antiretroviral drugs, and macrophage polarization. Methods. The human monocytic cell lines U937 and the U1 cell line, which is derived from HIV-1 infected U937, were used and polarized to the M1 and M2 macrophages. Cells with the treatment of CSC, ethanol, and AZM were harvested for downstream analysis including macrophage polarization, oxidative stress, cytokine production, transporter expression and function, and viral suppression. Cells treated with IKK-16, an inhibitor of the NF-κB signaling pathway, were harvested for the analysis of transporter expression and function. Protease inhibitor lopinavir (LPV) was used to suppress viral replication and the intracellular LPV was measured using LC-MS/MS. Results. Cigarette smoke condensate (CSC) and AZM shifted M1 macrophage polarization to M2 while having minimal effects on the M2 macrophage polarization. Inhibiting macrophage subset-specific transporters significantly increased intracellular antiretroviral drug (ARV) concentrations and drug efficacy. Neither CSC nor ethanol had any effect on the transporter inhibition-mediated viral reduction. AZM modulated the expression of major drug efflux transporters in both macrophage subsets and increased intracellular ARV concentration in M2 macrophages. NF-κB and JNK are involved in the M1 macrophage polarization shift and NF-κB was also shown to regulate major transporter expression. Conclusion. Modulating the expression and function of macrophage subset-specific transporter expression can increase intracellular ARV concentration and drug efficacy of viral suppression. Targeting subset-specific transporter may be an effective way to increase intracellular ARV concentration in the macrophage reservoir

Digital Nucleic Acid Detection Based on Microfluidic Lab-on-a-Chip Devices

Microfluidic lab-on-a-chip (LOC) technologies have been developed as a promising alternative to traditional central laboratory-based analysis approaches over several decades due to the capability of realizing miniaturized multiphase and multistep reactions. In the field of nucleic acid (NA) diagnosis, digital NA detection (dNAD) as a single-molecular-level detection is greatly attributed to the perfect combination of NA amplification and microfluidic LOC techniques. In this chapter, the principle, classification, advances, and application of dNAD will be involved. In particular, the focus will be on chip-based dNAD for giving a deep interpretation of the analysis and evaluation of digital detection. The future prospect of dNAD is also anticipated. It is sure that dNAD by means of microfluidic LOC devices as the promising technique will better serve the ambitious plan of precision medicine through absolute quantitation of NA from individuals

[(E)-10-(2,6-Dimethyl­phenyl­imino)-9-methyl-9,10-dihydro­phenanthren-9-olato]penta­methyl­dialuminum(III)

The two Al atoms in the title compound, [Al2(CH3)5(C23H20NO)], are four-coordinated in a distorted tetra­hedral environment. The coordination of one Al atom includes three methyl-C atoms and the O atom from the ligand, whereas the second Al atom is surrounded by the O atom and one N atom from the ligand as well as by two methyl-C atoms. In the ligand, the dihedral angle between the two phenyl rings in the 9,10-dihydro­phenanthren unit is 20.64 (12)°