Equilibrative nucleoside transporter 3 supports microglial functions and protects against the progression of Huntington's disease in the mouse model.

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by involuntary movements, cognitive deficits, and psychiatric symptoms. Currently, there is no cure, and only limited treatments are available to manage the symptoms and to slow down the disease's progression. The molecular and cellular mechanisms of HD's pathogenesis are complex, involving immune cell activation, altered protein turnover, and disturbance in brain energy homeostasis. Microglia have been known to play a dual role in HD, contributing to neurodegeneration through inflammation but also enacting neuroprotective effects by clearing mHTT aggregates. However, little is known about the contribution of microglial metabolism to HD progression. This study explores the impact of a microglial metabolite transporter, equilibrative nucleoside transporter 3 (ENT3), in HD. Known as a lysosomal membrane transporter protein, ENT3 is highly enriched in microglia, with its expression correlated with HD severity. Using the R6/2 ENT3-/- mouse model, we found that the deletion of ENT3 increases microglia numbers yet worsens HD progression, leading to mHTT accumulation, cell death, and disturbed energy metabolism. These results suggest that the delicate balance between microglial metabolism and function is crucial for maintaining brain homeostasis and that ENT3 has a protective role in ameliorating neurodegenerative processes.

INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control.

The immune synapse, a highly organized structure formed at the interface between T lymphocytes and antigen-presenting cells (APCs), is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares similarities with the primary cilium, a sensory organelle in eukaryotic cells, although the roles of ciliary proteins on the immune synapse remain elusive. Here, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, is enriched at the immune synapse in Jurkat T-cells during superantigen-mediated conjugation or antibody-mediated crosslinking of TCR complexes, and forms a complex with CD3ζ, ZAP-70, and Lck. Silencing INPP5E in Jurkat T-cells impairs the polarized distribution of CD3ζ at the immune synapse and correlates with a failure of PI(4,5)P2 clearance at the center of the synapse. Moreover, INPP5E silencing decreases proximal TCR signaling, including phosphorylation of CD3ζ and ZAP-70, and ultimately attenuates IL-2 secretion. Our results suggest that INPP5E is a new player in phosphoinositide manipulation at the synapse, controlling the TCR signaling cascade.

Protocol for standardized intrathymic injection in mice.

Currently available intrathymic injection techniques cause postoperative complications or difficulties in equipment acquisition. Here, we describe a standardized intrathymic injection protocol that requires only basic equipment with a minimally invasive procedure. We detail steps to identify injection sites for intrathymic delivery. We then describe how to visualize a successful intrathymic injection by including Indian ink in the injected solution. For complete details on the use and execution of this protocol, please refer to Tsai et al. (2022).1.

IFN-stimulated metabolite transporter ENT3 facilitates viral genome release.

An increasing amount of evidence emphasizes the role of metabolic reprogramming in immune cells to fight infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that the expression of equilibrative nucleoside transporter 3 (ENT3, encoded by solute carrier family 29 member 3, Slc29a3) is part of the innate immune response, which is rapidly upregulated upon pathogen invasion. The transcription of Slc29a3 is directly regulated by type I interferon-induced signaling, demonstrating that this metabolite transporter is an interferon-stimulated gene (ISG). Suprisingly, we unveil that several viruses, including SARS-CoV-2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of Slc29a3 expression is sufficient to significantly decrease viral replication in vitro and in vivo. Our study reveals that ENT3 is a pro-viral ISG co-opted by some viruses to gain a survival advantage.

Multiomics reveal the central role of pentose phosphate pathway in resident thymic macrophages to cope with efferocytosis-associated stress.

Tissue-resident macrophages (TRMs) are heterogeneous cell populations found throughout the body. Depending on their location, they perform diverse functions maintaining tissue homeostasis and providing immune surveillance. To survive and function within, TRMs adapt metabolically to the distinct microenvironments. However, little is known about the metabolic signatures of TRMs. The thymus provides a nurturing milieu for developing thymocytes yet efficiently removes those that fail the selection, relying on the resident thymic macrophages (TMφs). This study harnesses multiomics analyses to characterize TMφs and unveils their metabolic features. We find that the pentose phosphate pathway (PPP) is preferentially activated in TMφs, responding to the reduction-oxidation demands associated with the efferocytosis of dying thymocytes. The blockade of PPP in Mφs leads to decreased efferocytosis, which can be rescued by reactive oxygen species (ROS) scavengers. Our study reveals the key role of the PPP in TMφs and underscores the importance of metabolic adaptation in supporting Mφ efferocytosis.

Reduction in postpartum weight with laser acupuncture: A randomized control trial.

BACKGROUND: Gestational weight gain and weight retention at 1 year after delivery are associated with long-term obesity. We aimed to investigate the effect of laser acupuncture therapy on postpartum weight control. METHODS: We randomly assigned 66 subjects with postpartum weight retention to a laser acupuncture group and control group. The subjects were treated at acupoints including the stomach and hunger points of the ear, ST25, ST28, ST40, SP15, CV9, and SP6 by using verum or sham laser acupuncture over 5 sessions per week. After 12 treatment sessions, the differences in the body mass index (BMI), body fat percentage (BFP), and waist-to-buttocks ratio (WBR) of the patients were analyzed and compared between the laser acupuncture and control groups via analysis of variance, chi-square tests, and stepwise regression tests. RESULTS: The characteristics of the patients did not significantly differ between the laser acupuncture and control groups. Analysis of repeated measures data between the laser acupuncture and control groups indicated the presence of significant differences in postpartum BMI (P < 0.001) and BFP (P < 0.001); however, no significant difference was observed for WBR (P = 0.09). CONCLUSION: Laser acupuncture reduces postpartum weight retention by improving BMI and BFP, but does not impact the WBR following short-term treatment.

Demographic and Prescribing Patterns of Chinese Herbal Products for Individualized Therapy for Ischemic Heart Disease in Taiwan: Population-Based Study.

OBJECTIVE: Combinations of Chinese herbal products (CHPs) are widely used for ischemic heart disease (IHD) in Taiwan. We analyzed the usage and frequency of CHPs prescribed for patients with IHD. METHODS: A nationwide population-based cross-sectional study was conducted, 53531 patients from a random sample of one million in the National Health Insurance Research Database (NHIRD) from 2000 to 2010 were enrolled. Descriptive statistics, the multiple logistic regression method and Poisson regression analysis were employed to estimate the adjusted odds ratios (aORs) and adjusted risk ratios (aRRs) for utilization of CHPs. RESULTS: The mean age of traditional Chinese medicine (TCM) nonusers was significantly higher than that of TCM users. Zhi-Gan-Cao-Tang (24.85%) was the most commonly prescribed formula CHPs, followed by Xue-Fu-Zhu-Yu-Tang (16.53%) and Sheng-Mai-San (16.00%). The most commonly prescribed single CHPs were Dan Shen (29.30%), Yu Jin (7.44%), and Ge Gen (6.03%). After multivariate adjustment, patients with IHD younger than 29 years had 2.62 times higher odds to use TCM than those 60 years or older. Residents living in Central Taiwan, having hyperlipidemia or cardiac dysrhythmias also have higher odds to use TCM. On the contrary, those who were males, who had diabetes mellitus (DM), hypertension, stroke, myocardial infarction (MI) were less likely to use TCM. CONCLUSIONS: Zhi-Gan-Cao-Tang and Dan Shen are the most commonly prescribed CHPs for IHD in Taiwan. Our results should be taken into account by physicians when devising individualized therapy for IHD. Further large-scale, randomized clinical trials are warranted in order to determine the effectiveness and safety of these herbal medicines.

Pilot-scale study on the acid-catalyzed steam explosion of rice straw using a continuous pretreatment system.

A continuous acid-catalyzed steam explosion pretreatment process and system to produce cellulosic ethanol was developed at the pilot-scale. The effects of the following parameters on the pretreatment efficiency of rice straw feedstocks were investigated: the acid concentration, the reaction temperature, the residence time, the feedstock size, the explosion pressure and the screw speed. The optimal presteaming horizontal reactor conditions for the pretreatment process are as follows: 1.7 rpm and 100-110 °C with an acid concentration of 1.3% (w/w). An acid-catalyzed steam explosion is then performed in the vertical reactor at 185 °C for 2 min. Approximately 73% of the total saccharification yield was obtained after the rice straw was pretreated under optimal conditions and subsequent enzymatic hydrolysis at a combined severity factor of 0.4-0.7. Moreover, good long-term stability and durability of the pretreatment system under continuous operation was observed.