Immunopathological Roles of Cytokines, Chemokines, Signaling Molecules, and Pattern-Recognition Receptors in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with unknown etiology affecting more than one million individuals each year. It is characterized by B- and T-cell hyperactivity and by defects in the clearance of apoptotic cells and immune complexes. Understanding the complex process involved and the interaction between various cytokines, chemokines, signaling molecules, and pattern-recognition receptors (PRRs) in the immune pathways will provide valuable information on the development of novel therapeutic targets for treating SLE. In this paper, we review the immunopathological roles of novel cytokines, chemokines, signaling molecules, PRRs, and their interactions in immunoregulatory networks and suggest how their disturbances may implicate pathological conditions in SLE

Thermal comfort and energy performance of public rental housing under typical and near-extreme weather conditions in Hong Kong

© 2017 Elsevier B.V. Building performance evaluation is crucial for sustainable urban developments. In high-density cities, occupants suffer from poor living conditions due to building overheating, especially during increasingly frequent near-extreme summer conditions caused by climate change. To represent this situation, the summer reference year weather data was employed for building simulations using DesignBuilder. This study aims to evaluate the thermal comfort and energy consumption of four typical public rental housing (PRH) building types in Hong Kong. For free-running flats, results show generally higher air temperatures in the oldest PRH type (Slab) with a compact linear building form and the most sensitive response to outdoor temperature changes for another older PRH type (Trident) with a Y-shaped design, possibly owing to its high wall conductivity. Occupants in all building types experience a ???10% increase in the proportion of discomfort hours when compared to results for typical summer conditions, but overheating is the most severe in Slab type PRH. Following an initial assessment of the cooling energy usage, a simple sensitivity test was conducted to explore the potential energy savings by various passive design strategies, including shading and reducing the exposed cooled space. A cross-shaped building form also appears to be more energy efficient. These findings, complemented by further parametric analyses, may prove useful when designing buildings for climate change

Integrating metabolomics, bionics, and culturomics to study probiotics-driven drug metabolism

Many drugs have been shown to be metabolized by the human gut microbiome, but probiotic-driven drug-metabolizing capacity is rarely explored. Here, we developed an integrated metabolomics, culturomics, and bionics framework for systematically studying probiotics-driven drug metabolism. We discovered that 75% (27/36 of the assayed drugs) were metabolized by five selected probiotics, and drugs containing nitro or azo groups were more readily metabolized. As proof-of-principle experiments, we showed that Lacticaseibacillus casei Zhang (LCZ) could metabolize racecadotril to its active products, S-acetylthiorphan and thiorphan, in monoculture, in a near-real simulated human digestion system, and in an ex vivo fecal co-culture system. However, a personalized effect was observed in the racecadotril-metabolizing activity of L. casei Zhang, depending on the individual’s host gut microbiome composition. Based on data generated by our workflow, we proposed a possible mechanism of interactions among L. casei Zhang, racecadotril, and host gut microbiome, providing practical guidance for probiotic-drug co-treatment and novel insights into precision probiotics

Dual Targeting of Antioxidant and Metabolic Enzymes to the Mitochondrion and the Apicoplast of Toxoplasma gondii

Toxoplasma gondii is an aerobic protozoan parasite that possesses mitochondrial antioxidant enzymes to safely dispose of oxygen radicals generated by cellular respiration and metabolism. As with most Apicomplexans, it also harbors a chloroplast-like organelle, the apicoplast, which hosts various biosynthetic pathways and requires antioxidant protection. Most apicoplast-resident proteins are encoded in the nuclear genome and are targeted to the organelle via a bipartite N-terminal targeting sequence. We show here that two antioxidant enzymes—a superoxide dismutase (TgSOD2) and a thioredoxin-dependent peroxidase (TgTPX1/2)—and an aconitase are dually targeted to both the apicoplast and the mitochondrion of T. gondii. In the case of TgSOD2, our results indicate that a single gene product is bimodally targeted due to an inconspicuous variation within the putative signal peptide of the organellar protein, which significantly alters its subcellular localization. Dual organellar targeting of proteins might occur frequently in Apicomplexans to serve important biological functions such as antioxidant protection and carbon metabolism

α-Syntrophin regulates ARMS localization at the neuromuscular junction and enhances EphA4 signaling in an ARMS-dependent manner

EphA4 signaling has recently been implicated in the regulation of synapse formation and plasticity. In this study, we show that ankyrin repeat-rich membrane spanning (ARMS; also known as a kinase D–interacting substrate of 220 kD), a substrate for ephrin and neurotrophin receptors, was expressed in developing muscle and was concentrated at the neuromuscular junction (NMJ). Using yeast two-hybrid screening, we identified a PDZ (PSD-95, Dlg, ZO-1) domain protein, α-syntrophin, as an ARMS-interacting protein in muscle. Overexpression of α-syntrophin induced ARMS clustering in a PDZ domain–dependent manner. Coexpression of ARMS enhanced EphA4 signaling, which was further augmented by the presence of α-syntrophin. Moreover, the ephrin-A1–induced tyrosine phosphorylation of EphA4 was reduced in C2C12 myotubes after the blockade of ARMS and α-syntrophin expression by RNA interference. Finally, α-syntrophin–null mice exhibited a disrupted localization of ARMS and EphA4 at the NMJ and a reduced expression of ARMS in muscle. Altogether, our findings suggest that ARMS may play an important role in regulating postsynaptic signal transduction through the syntrophin-mediated localization of receptor tyrosine kinases such as EphA4

A comparative study on the indoor thermal comfort and energy consumption of typical public rental housing types under near-extreme summer conditions in Hong Kong

© 2017 The Authors. Published by Elsevier Ltd. Residents of the dense urban environment in Hong Kong suffer from poor living conditions due to building overheating, especially during near-extreme summer conditions. In this study, the thermal comfort and energy performance of typical public rental housing (PRH) building types were simulated using DesignBuilder. Results show that the oldest Slab type PRH, which has a compact building form, has the highest indoor air temperature, yet the lowest cooling energy demand. On the other hand, the Trident type PRH, with the largest external wall U-value, performs the worst overall and is the most responsive to outdoor temperature changes