CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling.

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/ß1 and αV/ß5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.

Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors.

Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/ß5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin's function in exercise and human health.

FAF1 blocks ferroptosis by inhibiting peroxidation of polyunsaturated fatty acids.

Iron-dependent peroxidation of polyunsaturated fatty acids (PUFAs) leads to ferroptosis. While detoxification reactions removing lipid peroxides in phospholipids such as that catalyzed by glutathione peroxidase 4 (GPX4) protect cells from ferroptosis, the mechanism through which cells prevent PUFA peroxidation was not completely understood. We previously identified Fas-associated factor 1 (FAF1) as a protein directly interacting with free PUFAs through its UAS domain. Here we report that this interaction is crucial to protect cells from ferroptosis. In the absence of FAF1, cultured cells became sensitive to ferroptosis upon exposure to physiological levels of PUFAs, and mice developed hepatic injury upon consuming a diet enriched in PUFA. Mechanistically, we demonstrate that FAF1 assembles a globular structure that sequesters free PUFAs into a hydrophobic core, a reaction that prevents PUFA peroxidation by limiting its access to iron. Our study suggests that peroxidation of free PUFAs contributes to ferroptosis, and FAF1 acts upstream of GPX4 to prevents initiation of ferroptosis by limiting peroxidation of free PUFAs.

Amelioration of pathologic α-synuclein-induced Parkinson's disease by irisin.

Physical activity provides clinical benefit in Parkinson's disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood-brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the α-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test. Recombinant sustained irisin treatment of primary cortical neurons attenuated α-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of α-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic α-syn by enhancing endolysosomal degradation of pathologic α-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.

Laser-Printed Photoanode: Femtosecond Laser-Induced Crystalline Phase Transformation of WO3 Nanorods for Space-Efficient and Flexible Thin-Film Solar Water-Splitting Cells.

Despite its potential for clean hydrogen harvesting, photoelectrochemical (PEC) water-splitting cells face challenges in commercialization, particularly related its harvesting performance and productivity at an industrial scale. Herein, a facile fabrication method of flexible thin-film photoanode for PEC water-splitting to overcome these limitations, based on laser processing technologies, is proposed. Laser-induced graphene, a carbon structure produced through direct laser writing carbonization (DLWC), plays a dual role: a flexible and stable current collector and a substrate for the hydrothermal synthesis of tungsten trioxide (WO3) nanorods (NRs). To facilitate water-splitting, a femtosecond-pulsed laser (fs laser) is focused on the WO3 NRs, converting their crystalline phase from pristine orthorhombic to monoclinic structure without thermal damage. With NiFe layered double hydroxide (LDH) catalyst, the flexible thin-film photoanode exhibits good PEC performance (1.46 mA cm-2 at 1.23 VRHE) and retains ≈90% of its performance after 3000 bending cycles. With its excellent mechanical properties, the flexible photoanode can be operated in various shapes with different curvatures, enabling space-efficient PEC water-splitting by loading larger photoanode within a given space. This study is expected to contribute to the advancement of large-scale solar water-splitting cells, introducing a new approach to enhance H2/O2 production and expand its application range.

Manipulation of resonance orders and absorbing materials for structural colors in transmission with improved color purity.

We present an improved color purity of additive transmissive structural color filters by controlling a resonance order and by inserting a highly absorbing material. The proposed structure consists of a single metal sandwiched by two transparent dielectric media serving as a cavity to minimize the ohmic loss in the metal mirrors, which is distinctly different from a conventional Fabry-Perot (FP) cavity that is in general designed to have two metal mirrors. Low reflections at an air-dielectric interface cause a quality-factor of a resonance to be reduced, causing a degraded color purity, which can be improved by employing a 1st order resonance that exhibits a narrower bandwidth than a fundamental FP resonant mode (0th order). For a red color with the improved purity, introducing an ultrathin absorbing layer in the middle of a top cavity enables the 1st resonance to be trivially influenced while selectively suppressing a 2nd order resonance appearing at the shorter wavelength region. Moreover, angle-insensitive performances up to 60° are attained by utilizing a cavity material with high index of refraction. Besides, the fabrication of the structural coloring devices involves a few deposition steps, thus rendering the approach suitable for applications over the large area. The described concept could be applied to diverse applications, such as colored solar panels, sensors, imaging devices, and decorations.

Tumor invasion in the hyponychium is associated with distant metastasis and poor prognosis in subungual melanoma: A histologic landscape of 44 cases.

BACKGROUND: Subungual melanoma (SUM) has a poor prognosis because of delayed diagnosis. Its progression, consensus on surgical treatment, and correlation with clinical outcomes remain unclear. OBJECTIVE: We aimed to identify the pattern of dermal invasion in different locations of the nail apparatus and its relationship with prognosis. METHODS: In this retrospective review of surgically treated SUM patients between January 2011 and April 2019, the nail apparatus was divided into 5 anatomic subunits: the dorsal roof of proximal nail fold, ventral floor of proximal nail fold, germinal matrix, nail bed, and hyponychium. Invasions in the subunits were categorized using 3 criteria: no tumor, in situ tumor, or invasion. RESULTS: Among 44 cases of SUM, dermal invasion occurred mostly in the distal areas, with 11, 30, 18, 7, and 4 in the hyponychium, nail bed, germinal matrix, ventral floor of proximal nail fold, and dorsal roof of proximal nail fold, respectively. The patients with hyponychial invasion showed a significantly greater Breslow depth (P = .009), a higher rate of lymph node metastasis (P = .019), distant metastasis (P = .036), and shorter disease-free survival (P = .001). CONCLUSION: Hyponychial invasion is an important prognostic predictor of SUM, given its strong association with invasion depth, metastatic progression, and disease-free survival. Patients with invasion in the hyponychium should undergo more strict workup, treatment, and surveillance.

Light absorption enhancement in ultrathin perovskite solar cells using light scattering of high-index dielectric nanospheres.

Arrays of high-index dielectric nanoparticles supporting both electrical and magnetic resonances have gained increasing attention for their excellent light-trapping (LT) effects, thus greatly improving the performance of ultrathin solar cells. This work explores front-located, high-index dielectric subwavelength nanosphere arrays as an efficient and broadband LT structure patterned on top of an ultrathin perovskite solar cell (PSC) for a greatly enhanced absorption. Combined strong light scattering and anti-reflection properties achieved by optimized geometrical parameters of the LT structure lead to a broadband absorption enhancement in the ultrathin thickness of a photoactive layer (100 nm) yielding the short-circuit current density (Jsc) of 18.7 mA/cm2, which is 31.7% higher than that of a planar counterpart. Moreover, effects of the LT structure on far-field radiation patterns, scattering cross-sections, multipoles' contributions, and asymmetry parameters along with the incidence angle and polarization dependence are investigated. The present strategy could be applied to diverse applications, such as other ultrathin or semitransparent solar cells, absorbers and photodetectors.

A smartphone-based teleconsultation system for the management of chronic pressure injuries.

We investigated the accuracy of pressure injury evaluation using tele-devices and examined the concordance between automatically generated recommendations and primary manual recommendations. Caregivers took photos and videos of pressure injuries using smartphones with built-in cameras and uploaded the media to the application. The wound team evaluated the wound using a specially modified version of the Pressure Sore Status Tool. This was compared with the Pressure Sore Status Tool score assessed during the actual examination of the patient. We developed an automatic algorithm for dressing based on the Pressure Sore Status Tool score, checking for consistency between this and the primary manual recommendation. A total of 60 patients diagnosed with pressure injuries were included. The κ coefficients indicated substantial agreement for wound size and total score, and excellent for all other items. We found that the overall concordance rates were statistically significant for all items (p < 0.001). For the primary dressing, the κ coefficient for the concordance rate of automatic algorithm and manual recommendation was 0.771, while that of teleconsultation system and manual recommendation was 0.971. For the secondary dressing, the figures were 0.798 and 0.989, respectively. All values were statistically significant (p < 0.001). We presented strong evidence documenting the utilization of a smartphone, patient-driven system, and demonstrated that the measurements obtained were comparable to the ones obtained by a trained, on-site, wound team. Furthermore, we confirmed agreement between automatically generated recommendations and primary manual recommendations.

Dysregulation of mitophagy in carcinogenesis and tumor progression.

The mitochondrial role in carcinogenesis and cancer progression is an area of active research, with many unresolved questions. Various aspects of altered mitochondrial function have been implicated in tumorigenesis and tumor progression, including mitochondrial dysfunction, a metabolic switch to aerobic glycolysis, and dysregulation of mitophagy. Mitophagy is a highly specific quality control process which eliminates dysfunctional mitochondria and promotes mitochondrial turnover, and is involved in the adaptation to nutrient stress by controlling mitochondrial mass. The dysregulation of mitochondrial turnover has both a positive and negative role in cancer. This review will begin with a basic overview of the molecular mechanisms of mitophagy, and highlight recent trends in mitophagy from cancer studies. We will conclude this review by discussing areas of research in normal mitophagy that have yet to be explored in the context of cancer such as mitochondrial proteases, the mitochondrial unfolded protein response, and mitokine action. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

Implications of oncocytic change in papillary thyroid cancer.

OBJECTIVE: Although the presence of oncocytic change in less than 75% of a tumour is not considered to indicate oncocytic variants of papillary thyroid carcinoma (PTC), we frequently observe partial oncocytic change, especially in obese PTC patients. Thus, we sought to investigate the relationship between the presence of oncocytic change of PTC and its prognosis. DESIGN, SETTING AND PARTICIPANTS: We retrospectively studied 142 patients with PTC who had undergone surgery between 2000 and 2005, and re-evaluated their PTC slides to record the proportion of oncocytic change in 10% increments from 0% to 100%. MAJOR OUTCOME MEASURE: We analysed the relationship between the proportion of oncocytic change and clinicopathological prognostic factors. RESULTS: Oncocytic change was found in 45·8% (65/142) of PTC patients. The proportion of patients with oncocytic change was higher in obese patients than in lean patients and showed a significant correlation with the BMI (r = 0·195, P = 0·020). The PTC patients with oncocytic change showed a higher recurrence rate than PTC patients without oncocytic change (30·8% vs 11·7%, respectively; P = 0·005). The presence of oncocytic change in PTC patients was associated with a shorter disease-free survival in a Kaplan-Meier analysis after a mean follow-up of 8·9 years. CONCLUSION: The patients with PTC with oncocytic change presented with a higher recurrence rate and were more likely to be obese. These findings suggest that presence of oncocytic change is a poor prognostic factor in PTC patients, even if the oncocytic change involves less than 75% of a tumour.

Cellular responses to excess fatty acids: focus on ubiquitin regulatory X domain-containing protein 8.

PURPOSE OF REVIEW: Although fatty acids are crucial for cell survival, their overaccumulation triggers lipotoxicity that leads to metabolic syndrome. Thus, cells maintain their homeostasis by multiple feedback regulatory systems. This review focuses on how cells regulate the level of fatty acids by these systems. RECENT FINDINGS: Ubiquitin regulatory X domain-containing protein 8 has been identified as a specific sensor for unsaturated fatty acids that regulates lipogenic activity. SUMMARY: Together with the previously identified peroxisome proliferator-activated receptors and liver X receptor, these proteins sense the presence of unsaturated fatty acids and initiate reactions preventing their overaccumulation. Understanding the mechanism of the signal transduction pathways mediated by these proteins may offer new strategies to treat metabolic syndrome.

Recent advances in label-free imaging and quantification techniques for the study of lipid droplets in cells.

Lipid droplets (LDs), once considered mere storage depots for lipids, have gained recognition for their intricate roles in cellular processes, including metabolism, membrane trafficking, and disease states like obesity and cancer. This review explores label-free imaging techniques' applications in LD research. We discuss holotomography and vibrational spectroscopic microscopy, emphasizing their potential for studying LDs without molecular labels, and we highlight the growing integration of artificial intelligence. Clinical applications in disease diagnosis and therapy are also considered.

Deletion of FNDC5/Irisin modifies murine osteocyte function in a sex-specific manner.

Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (KO), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine.

Resonant-mode engineering for additive reflective structural colors with high brightness and high color purity.

We present quad-layered reflective structural color filters generating vivid additive primary colors by controlling a mode number in a Fabry-Perot (FP) cavity and an anti-reflective (AR) coating layer, thus accomplishing high spectral contrast which is highly demanded in creating sharp colors. The reflection brightness of fabricated structural color filters is over 78% and a color gamut is comparable to the standard color gamut (sRGB). Higher-order resonant modes are exploited yielding a narrow passband with strong suppression of the reflection at shorter and longer wavelength ranges for a green color, while red and blue colors are produced by employing fundamental resonant modes. Besides, the structural color filters maintain both high brightness and high color purity at oblique incidence angles up to 40° due to a small angle of refraction by a cavity medium with high refractive index. Moreover, a large-scale fabrication is enabled owing to the simplicity of a device structure, where thin film deposition is used. The scheme presented in this work may open the door to a number of applications, such as reflective displays, imaging devices, colored photovoltaics, and decorations.

Deletion of FNDC5/irisin modifies murine osteocyte function in a sex-specific manner.

Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (knockout [KO]), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low-calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine.

UAS domain of Ubxd8 and FAF1 polymerizes upon interaction with long-chain unsaturated fatty acids.

Ubxd8, a multidomain protein sensor for long-chain unsaturated fatty acids (FAs), plays a crucial role to maintain cellular homeostasis of FAs. Ubxd8 polymerizes upon interaction with long-chain unsaturated FAs, but the molecular mechanism involved in this polymerization remains unclear. Here we report that the UAS domain of Ubxd8 mediates this polymerization. We show that a positively charged surface area in the domain is required for the reaction. Mutations changing the positively charged residues in this area to glutamates prevented long-chain unsaturated FAs from inducing oligomerization of Ubxd8. Consequently, the mutant protein no longer responded to regulation by long-chain unsaturated FAs in cultured cells. Long-chain unsaturated FAs also induced polymerization of Fas-associated factor 1 (FAF1), the only other mammalian protein that contains a UAS domain homologous to that of Ubxd8. These results provide further insights into protein-FA interactions by identifying the UAS domain as a motif interacting with long-chain unsaturated FAs.

Neuroprotective benzyl benzoate glycosides from Disporum viridescens roots in HT22 hippocampal neuronal cells.

Bioassay-guided fractionation of the EtOAc extract from Disporum viridescens roots led to the isolation of five new benzyl benzoate glycosides, BBGs (1-5). The neuroprotective activities of the BBGs were screened using neuronal HT22 hippocampal cells. BBG-D (4) significantly protected murine hippocampal HT22 cells against glutamate-induced neurotoxicity by maintaining the antioxidative defense systems such as superoxide dismutase, glutathione reductase, glutathione peroxidase, and the glutathione content. BBG-D, in a dose-and time-dependent manner, increased HO-1 expression through the selective activation of pERK signaling among the MAPK pathways. These results suggest that BBG-D could be a promising candidate for the treatment of neurodegenerative diseases related to glutamate-induced oxidative neuronal cytotoxicity.

Identification of Ubxd8 protein as a sensor for unsaturated fatty acids and regulator of triglyceride synthesis.

Fatty acids (FAs) are essential for cell survival, yet their overaccumulation causes lipotoxicity. To prevent lipotoxicity, cells store excess FAs as triglycerides (TGs). In cultured cells TG synthesis is activated by excess unsaturated but not saturated FAs. Here, we identify Ubxd8 as a sensor for unsaturated FAs and regulator of TG synthesis. In cultured cells depleted of FAs, Ubxd8 inhibits TG synthesis by blocking conversion of diacylglycerols (DAGs) to TGs. Excess unsaturated but not saturated FAs relieve this inhibition. As a result, unsaturated FAs are incorporated into TGs, whereas saturated FAs are incorporated into DAGs. In vitro, unsaturated but not saturated FAs alter the structure of purified recombinant Ubxd8 as monitored by changes in its thermal stability, trypsin cleavage pattern, and oligomerization. These results suggest that Ubxd8 acts as a brake that limits TG synthesis, and this brake is released when its structure is altered by exposure to unsaturated FAs.