25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages.

Macrophages are critical to turn noninflamed "cold tumors" into inflamed "hot tumors". Emerging evidence indicates abnormal cholesterol metabolites in the tumor microenvironment (TME) with unclear function. Here, we uncovered the inducible expression of cholesterol-25-hydroxylase (Ch25h) by interleukin-4 (IL-4) and interleukin-13 (IL-13) via the transcription factor STAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmed that CH25Hhi subsets were enriched in immunosuppressive macrophage subsets and correlated to lower survival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressive function to enhance infiltrating T cell numbers and activation, which synergized with anti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HC competed with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leading to AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564 to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as an immunometabolic checkpoint, which manipulates macrophage fate to reshape CD8+ T cell surveillance and anti-tumor response.

Study on the UV FEL single-shot damage threshold of an Au thin film.

The damage threshold of an Au-coated flat mirror, one of the reflective optics installed on the FEL-2 beamline of the Dalian Coherent Light Source, China, upon far-UV free-electron laser irradiation is evaluated. The surface of the coating is characterized by profilometer and optical microscope. A theoretical approach of the phenomenon is also presented, by application of conventional single-pulse damage threshold calculations, a one-dimensional thermal diffusion model, as well as finite-element analysis with ANSYS.

Bile Acid Injection Regulated Blood Glucose in T2DM Rats Via the TGR5/GLP-1 Rather than FXR/FGF15 Pathway.

Background and Aims: Type 2 Diabetes mellitus (T2DM) has reached an epidemic status worldwide. Targeting bile acid signaling has therapeutic potential for treating T2DM. However, the effect of bile acid on T2DM and related mechanisms remains unclear. Here, we explored the role of bile acid in T2DM and elucidated the mechanisms involved. Methods: We established an STZ-induced rat model of T2DM and divided it into an bile acid-treated group and saline control group according to the random number table method. We incubated the bile acid-treated group with human bile acid via middle small intestine intubation and the saline control group was incubated with the same amount of normal saline. We compared the fasting body mass, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2h-PG), fasting plasma insulin (FINS), fasting plasma triglyceride (TG), cholesterol, and total bile acid levels between the two groups one week before surgery and one to four weeks after surgery. Mechanically, Western blot, IHC, and ELISA assays were employed to detect the effect of bile acid on the TGR5/GLP-1 and FXR/FGF15 pathways. Results: Bile acid injection could increase the FINS level and decrease the 2h-PBG level of T2DM rats. In addition, bile acid injection did not affect FBG, fasting body mass, TG, CH, and total bile acid. At the same time, bile acid injection could activate the TGR5/GLP-1 pathway but could not influence the FXR/FGF15 pathway. Conclusion: Bile acids treatment promotes glucose homeostasis in the STZ-induced T2MD rat model via the following mechanism by activating the TGR5/GLP-1 signaling pathway rather than FXR/FGF15 pathway to improve glucose tolerance and thus achieve glucose homeostasis. The bile acid/TGR5/GLP-1 signaling pathway may be a crucial mechanism of controlling the blood glucose of T2DM rats, and TGR5/GLP-1 pathway may constitute novel targets for treating T2DM.

Multi-functional gas cell in the vacuum ultraviolet free-electron laser beamline.

A long gas cell, filled with noble gas, is typically positioned between the undulator and the first mirror in the free-electron laser (FEL) beamline to attenuate the laser power as required by the end-stations. In addition to attenuation, the gas cell also serves important functions in various applications, such as spectrometer calibration, resolving power evaluation during beamline commissioning, and filtering of third harmonic in FEL operations. These functions of the gas cell have been successfully tested and implemented at the Dalian Coherent Light Source, a vacuum ultraviolet FEL facility located in Dalian, China. The resolving power of higher than 5000 has been obtained, and accurate calibration has been completed using the gas cell. During operation, the third harmonic of the FEL was attenuated by approximately one order of magnitude with almost the same power of the fundamental. This greatly improved the signal-to-noise ratio at the end-stations.

Relative Energy Deficiency in Sport (REDs) and knee injuries: current concepts for female athletes.

In athletes, a mismatch between caloric intake and energy expended in exercise can eventually lead to Relative Energy Deficiency in Sport (REDs), where the athlete suffers from physiological derangements and decreased sport performance. The prevalence of REDs is higher in females than males. Females are already at a higher risk of knee injuries, which has been attributed to a multitude of factors such as hormonal influences, differences in musculoskeletal anatomy and neuromuscular control compared to males. The literature demonstrates an even higher risk of knee injuries in female athletes with symptoms of REDs. We propose the various factors that influence this risk. A reduction in anabolic hormones can affect muscle development and tendon repair. A relationship between poor neuromuscular control and knee injury has been established, and this can be further worsened in patients with menstrual dysfunction. Chronic deficiency in nutrients such as collagen and vitamin D can result in poorer recovery from microtrauma in tendons and ligaments. All these factors may contribute to increasing the risk of knee injuries, which may include anterior cruciate ligament tears, patella tendinopathy and patellofemoral pain syndrome. This review aims to educate sports clinicians to have a high index of suspicion when treating knee injuries in females; to screen and then manage for REDs if present, for holistic patient care.