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A MEMS grating modulator with a tunable sinusoidal grating for large-scale extendable apertures
Microelectromechanical system (MEMS) grating modulators enable versatile beam steering functions through the electrostatic actuation of movable ribbons. These modulators operate at ultrahigh frequencies in the hundred kHz range, and their micromirror-free configuration simplifies the fabrication process and reduces costs compared to micromirror-based modulators. However, these modulators are limited in their optical efficiency and aperture. Here, we present a MEMS grating modulator with a notably extendable aperture and a high optical efficiency that benefits from the adoption of a tunable sinusoidal grating. Instead of end-constrained movable ribbons, we constrain the MEMS grating modulator through broadside-constrained continuous ribbons. The end-free grating enables improved scalability along the ribbons, and the continuous sinusoidal surface of the grating allows an increased fill factor. As an example, we experimentally demonstrate a MEMS grating modulator with a large-scale aperture of 30 × 30 mm and an optical efficiency of up to 90%. The modulation depth enables intensity modulation across a broad wavelength range from 635 to 1700 nm. The experimental results demonstrate that the reported modulator has a mechanical settling time of 1.1 μs and an extinction ratio of over 20 dB. Furthermore, it offers a dynamic modulation contrast of over 95% within a 250 kHz operating frequency and achieves full modulation within a field of view (FOV) of ±30°. The reported MEMS grating modulator holds promise for application in high-speed light attenuation and modulating retroreflector free-space optical (MRR-FSO) communication systems. Our device also paves new ways for future high-speed, energy-efficient, and cost-effective communication networks.
The EstroGene2.0 database for endocrine therapy response and resistance in breast cancer
Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities (https://estrogeneii.web.app/). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed transcriptomic landscape and substantial diversity in response to different classes of ER modulators. Endocrine-resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signalings, which is recapitulated clinically. Dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of cell model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer’s response to endocrine therapies and explore resistance mechanisms.
Isovitexin targets SIRT3 to prevent steroid-induced osteonecrosis of the femoral head by modulating mitophagy-mediated ferroptosis
The death of osteoblasts induced by glucocorticoid (GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head (SIONFH). Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH. Isovitexin has demonstrated antioxidant properties, but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored. In this study, we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches. We found an imbalance in mitochondrial homeostasis and ferroptosis-induced impairment of osteogenic capacity in SIONFH. Subsequently, we investigated the cause-and-effect relationship between mitochondria and ferroptosis, as well as the regulatory role of mitophagy in maintaining mitochondrial homeostasis and controlling ferroptosis. We then identified the critical involvement of SIRT3 in modulating mitochondrial homeostasis and ferroptosis. Furthermore, molecular docking and co-immunoprecipitation confirmed the strong interaction between SIRT3 and BNIP3. Strikingly, restoring SIRT3 expression significantly inhibited pathological mitophagy mediated by the BNIP3/NIX pathway. Additionally, we discovered that Isovitexin, by promoting SIRT3 expression, effectively regulated mitophagy, preserved mitochondrial homeostasis in osteoblasts, suppressed ferroptosis, and restored osteogenic capacity, leading to remarkable improvements in SIONFH. These findings reveal the effects and molecular mechanisms of Isovitexin on SIONFH and highlight the potential of targeting SIRT3 as a promising strategy to suppress mitophagy-mediated ferroptosis in osteoblasts and against SIONFH.
Chemogenomics for steroid hormone receptors (NR3)
The nine human NR3 nuclear receptors translate steroid hormone signals in transcriptomic responses and operate multiple highly important processes ranging from development over reproductive tissue function to inflammatory and metabolic homeostasis. Although several NR3 ligands such as glucocorticoids are invaluable drugs, this family is only partially explored, for example, in autoimmune diseases and neurodegeneration, but may hold therapeutic potential in new areas. Here we report a chemogenomics (CG) library to reveal elusive effects of NR3 receptor modulation in phenotypic settings. 34 highly annotated and chemically diverse ligands covering all NR3 receptors were selected considering complementary modes of action and activity, selectivity and lack of toxicity. Endoplasmic reticulum stress resolving effects of N3 CG subsets in proof-of-concept application validate suitability of the set to connect phenotypic outcomes with targets and to explore NR3 receptors from a translational perspective.
Diurnal timing of physical activity in relation to obesity and diabetes in the German National Cohort (NAKO)
Physical activity supports weight regulation and metabolic health, but its timing in relation to obesity and diabetes remains unclear. We aimed to assess the diurnal timing of physical activity and its association with obesity and diabetes.
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