Set3 HDAC mediates effects of overlapping noncoding transcription on gene induction kinetics.

The Set3 histone deacetylase complex (Set3C) binds histone H3 dimethylated at lysine 4 (H3K4me2) to mediate deacetylation of histones in 5'-transcribed regions. To discern how Set3C affects gene expression, genome-wide transcription was analyzed in yeast undergoing a series of carbon source shifts. Deleting SET3 primarily caused changes during transition periods, as genes were induced or repressed. Surprisingly, a majority of Set3-affected genes are overlapped by noncoding RNA (ncRNA) transcription. Many Set3-repressed genes have H3K4me2 instead of me3 over promoter regions, due to either reduced H3K4me3 or ncRNA transcription from distal or antisense promoters. Set3C also represses internal cryptic promoters, but in different regions of genes than the Set2/Rpd3S pathway. Finally, Set3C stimulates some genes by repressing an overlapping antagonistic antisense transcript. These results show that overlapping noncoding transcription can fine-tune gene expression, not via the ncRNA but by depositing H3K4me2 to recruit the Set3C deacetylase.

Single-Atom Verification of the Optimal Trade-Off between Speed and Cost in Shortcuts to Adiabaticity.

The approach of shortcuts to adiabaticity enables the effective execution of adiabatic dynamics in quantum information processing with enhanced speed. Owing to the inherent trade-off between dynamical speed and the cost associated with the transitionless driving field, executing arbitrarily fast operations becomes impractical. To understand the accurate interplay between speed and energetic cost in this process, we propose theoretically and verify experimentally a new trade-off, which is characterized by a tightly optimized bound within s-parametrized phase spaces. Our experiment is carried out in a single ultracold ^{40}Ca^{+} ion trapped in a harmonic potential. By exactly operating the quantum states of the ion, we execute the Landau-Zener model as an example, where the quantum speed limit as well as the cost are governed by the spectral gap. We witness that our proposed trade-off is indeed tight in scenarios involving both initially eigenstates and initially thermal equilibrium states. Our work helps understanding the fundamental constraints in shortcuts to adiabaticity and illuminates the potential of underutilized phase spaces that have been traditionally overlooked.

A Two-Step Regional Ionospheric Modeling Approach for PPP-RTK.

In the precise point positioning/real-time kinematic (PPP-RTK) technique, high-precision ionospheric delay correction information is an important prerequisite for rapid PPP convergence. The commonly used ionospheric modeling approaches in the PPP-RTKs only take the trend term of the ionospheric total electron content (TEC) variations into account. As a result, the residual ionospheric delay still affects the positioning solutions. In this study, we propose a two-step regional ionospheric modeling approach that involves combining a polynomial fitting model (PFM) and a Kriging interpolation (KI) model. In the first step, a polynomial fitting method is used to model the trend term of the ionospheric TEC variations. In the second step, a KI method is used to compensate for the residual term of the ionospheric TEC variations. Datasets collected from continuously operating reference stations (CORSs) in Hunan Province, China, are used to validate the PFM/KI method by comparing with a single PFM method and a combined PFM and inverse distance weighting interpolation (IDWI) method. The experimental results show that the two-step PFM/KI modeled ionospheric delay achieves an average root mean square (RMS) error of 1.8 cm, which is improved by about 48% and 23% when compared with the PFM and PFM/IDWI methods, respectively. Regarding the positioning performance, the PPP-RTK with the PFM/KI method takes an average of 1.8 min or 4.0 min to converge to a positioning accuracy of 1.3 cm or 2.5 cm in the horizontal and vertical directions, respectively. The convergence times are decreased by about 18% and 14% in the horizontal direction and 9% and 5% in the vertical direction over the PFM and the PFM/IDWI methods, respectively.

Single-Cell Transcriptomic Analysis Reveals Myocardial Fibrosis Mechanism of Doxorubicin-Induced Cardiotoxicity.

Myocardial fibrosis is a pathological feature of doxorubicin-induced chronic cardiotoxicity that severely affects the prognosis of oncology patients. However, the specific cellular and molecular mediators driving doxorubicin-induced cardiac fibrosis, and the relative impact of different cell populations on cardiac fibrosis, remain unclear.This study aimed to explore the mechanism of doxorubicin-induced cardiotoxicity and myocardial fibrosis and to find potential therapeutic targets. Single-cell RNA sequencing was used to analyze the transcriptome of non-cardiomyocytes from normal and doxorubicin-induced chronic cardiotoxicity in mouse model heart tissue.We established a mouse model of doxorubicin-induced cardiotoxicity with a well-defined fibrotic phenotype. Analysis of single-cell sequencing results showed that fibroblasts were the major origin of extracellular matrix in doxorubicin-induced myocardial fibrosis. Further resolution of fibroblast subclusters showed that resting fibroblasts were converted to matrifibrocytes and then to myofibroblasts to participate in the myocardial remodeling process in response to doxorubicin treatment. Ctsb expression was significantly upregulated in fibroblasts after doxorubicin-induced.This study provides a comprehensive map of the non-cardiomyocyte landscape at high resolution, reveals multiple cell populations contributing to pathological remodeling of the cardiac extracellular matrix, and identifies major cellular sources of myofibroblasts and dynamic gene-expression changes in fibroblast activation. Finally, we used this strategy to detect potential therapeutic targets and identified Ctsb as a specific target for fibroblasts in doxorubicin-induced myocardial fibrosis.

Ruxolitinib attenuates acute rejection and can serve as an immune induction therapy in heart transplantation.

The benefits of IL2RA antagonists in heart transplant patients are controversial. We aimed to elucidate the effects of IL2RA antagonists and identify targets that could be better than IL2RA antagonists. By using single-cell RNA sequencing of immune cells at different time points in patients receiving IL2RA antagonists, we identified nineteen types of cells. We revealed higher IL2RA expression in regulatory T cells (Tregs), suggesting that IL2RA antagonists attenuated IL-2-induced Treg activation. CD4_C04_IFNGR1 and CD8_C05_IFITM2 which had more cytotoxic effects, remained elevated at later time points. IFNGR1 was upregulated in these two subtypes, but was not expressed in Treg. Ruxolitinib targeted the pathways of IFNGR1 (JAK1/2) while not affecting the pathway of IL-2-induced Tregs activation (JAK3). Ruxolitinib showed prolonged survival compared to IL2RA mAb-treated mice. Our study provided dynamic changes of immune cells after IL2RA antagonists treatment at single-cell resolution. Ruxolitinib has potential as a new immunoinduction therapy without affecting Treg.

PYCR2 promotes growth and aerobic glycolysis in human liver cancer by regulating the AKT signaling pathway.

Hepatocellular carcinoma (HCC) is the world's third most fatal cancer. Because metabolic rewiring is a hallmark of HCC, studies into the causes of aberrant glycolysis could provide insight into novel HCC therapeutic strategies. Pyrroline-5-carboxylate reductase 2 (PYCR2), a key enzyme of proline synthesis, has previously been found to play vital roles in various malignancies regarding amino acid metabolism and oxidative stress response. Our study investigated the mechanistic function of PYCR2 in HCC. We used Gene Expression Profiling Interactive Analysis to perform bioinformatics analysis of PYCR2 expression and survival in human HCC patients based on the Cancer Genome Atlas database. The function of PYCR2 in cell viability and glycolysis was assessed using CCK-8 and ECAR assays. Transducing shRNA or overexpression vectors into the HCC cell line altered the expression status of PYCR2. PYCR2 expression was validated using quantitative real-time PCR and Western blot. In mouse xenograft models, the role of PYCR2 in HCC tumor formation was confirmed. PYCR2 was overexpressed in human HCC tumor tissue and was associated with a poor prognosis. The functional assay revealed that silencing PYCR2 inhibited cell viability, glycolysis, and AKT activation. Furthermore, the xenograft experiment demonstrated that silencing PYCR2 significantly inhibited tumor growth and Ki67 expression. On the other hand, PYCR2 overexpression significantly promoted cell viability and glycolysis, which could be inhibited by either a glycolysis inhibitor or an AKT inhibitor, indicating that PYCR2 may function via glycolysis and the AKT pathway. Moreover, despite the overexpression of PYCR2 in vivo, treatment with a glycolysis inhibitor may considerably suppress tumor growth. Our findings suggest that PYCR2 may play an oncogenic role in HCC growth by promoting glycolysis and activating AKT, emphasizing PYCR2's clinical relevance in HCC management as a novel potential therapeutic target.

Self-Adaptive Droplet Bouncing on a Dual Gradient Surface.

Rapid detachment of impacting droplets from underlying substrate is highly preferred for mass, momentum, and energy exchange in many practical applications. Driven by this, the past several years have witnessed a surge in engineering macrotexture to reduce solid-liquid contact time. Despite these advances, these strategies in reducing contact time necessitate the elegant control of either the spatial location for droplet contact or the range of impacting velocity. Here, this work circumvents these limitations by designing a dual gradient surface consisting of a vertical spacing gradient made of tapered pillar arrays and a lateral curvature gradient characterized as macroscopic convex. This design enables the impacting droplets to self-adapt to asymmetric or pancake bouncing mode accordingly, which renders significant contact time reduction (up to ≈70%) for a broad range of impacting velocities (≈0.4-1.4 m s-1 ) irrespective of the spatial impacting location. This new design provides a new insight for designing liquid-repellent surfaces, and offers opportunities for applications including dropwise condensation, energy conversion, and anti-icing.

Benefits of applying molecular barcoding systems are not uniform across different genomic applications.

BACKGROUND: Despite the wide variety of Next Generation Sequencing (NGS)-based methods, it remains challenging to detect mutations present at very low frequencies. This problem is particularly relevant in oncology, where the limiting amount of input material, and its low quality, often limit the performance of the assays. Unique Molecular Identifiers (UMIs) are a molecular barcoding system often coupled with computational methods of noise suppression to improve the reliability of detection of rare variants. Although widely adopted, UMI inclusion imposes additional technical complexity and sequencing cost. Currently, there are no guidelines on UMI usage nor a comprehensive evaluation of their advantage across different applications. METHODS: We used DNA sequencing data generated by molecular barcoding and hybridization-based enrichment, from various types and quantities of input material (fresh frozen, formaldehyde-treated and cell-free DNA), to evaluate the performance of variant calling in different clinically relevant contexts. RESULTS: Noise suppression achieved by read grouping based on fragment mapping positions ensures reliable variant calling for many experimental designs even without exogenous UMIs. Exogenous barcodes significantly improve performance only when mapping position collisions occur, which is common in cell-free DNA. CONCLUSIONS: We demonstrate that UMI usage is not universally beneficial across experimental designs and that it is worthwhile to critically consider the comparative advantage of UMI usage for a given NGS application prior to experimental design.

Synchronized triple-wavelength fiber lasers at 1, 1.55, and 1.9†µm.

Synchronized lasers working at different wavelengths are of great significance for numerous applications, such as high-energy femtosecond pulse emission, Raman microscopy, and precise timing distribution. Here, we report synchronized triple-wavelength fiber lasers working at 1, 1.55, and 1.9 µm, respectively, by combining the coupling and injection configurations. The laser system consists of three fiber resonators gained by ytterbium-doped fiber, erbium-doped fiber, and thulium-doped fiber, respectively. Ultrafast optical pulses formed in these resonators are obtained by passive mode-locking with the use of a carbon-nanotube saturable absorber. A maximum cavity mismatch of ∼1.4 mm is reached by the synchronized triple-wavelength fiber lasers in the synchronization regime by finely tuning the variable optical delay lines incorporated in the fiber cavities. In addition, we investigate the synchronization characteristics of a non-polarization-maintaining fiber laser in an injection configuration. Our results provide a new, to the best of our knowledge, perspective on multi-color synchronized ultrafast lasers with broad spectral coverage, high compactness, and a tunable repetition rate.

The association of SOD and HsCRP with the efficacy of sulforaphane in schizophrenia patients with residual negative symptoms.

OBJECTIVES: Emerging evidence indicates a connection between oxidative stress, immune-inflammatory processes, and the negative symptoms of schizophrenia. In addition to possessing potent antioxidant and anti-inflammatory properties, sulforaphane (SFN) has shown promise in enhancing cognitive function among individuals with schizophrenia. This study aims to investigate the efficacy of combined treatment with SFN in patients with schizophrenia who experience negative symptoms and its effect on the levels of superoxide dismutase (SOD) and the inflammatory marker, high-sensitivity C-reactive protein (HsCRP). DESIGN: Forty-five patients with schizophrenia were recruited, who mainly experienced negative symptoms during a stable period. In addition to the original treatments, the patients received SFN tablets at a daily dose of 90 mg for 24 weeks. At baseline, 12 weeks, and 24 weeks, the participants were interviewed and evaluated. The reduction rate of the Positive and Negative Syndrome Scale (PANSS) was used to assess each participant. The side effects scale of Treatment Emergent Symptom Scale (TESS) was applied to assess the adverse reactions. Additionally, the levels of the SOD, HsCRP, and other indicators were examined. RESULTS: The study findings revealed a significant decrease in PANSS negative subscale scores (P < 0.001). Furthermore, there was a significant increase in SOD activity and HsCRP levels (P < 0.001 and P < 0.05). Notably, the group of participants who exhibited a reduction in PANSS negative subscale scores demonstrated a significant improvement in HsCRP levels (P < 0.05). CONCLUSIONS: Our study suggests that SFN may potentially serve as a safe adjunctive intervention to improve the negative symptoms of schizophrenia. The potential mechanism by which SFN improves negative symptoms in schizophrenia patients may involve its anti-inflammatory properties, specifically its ability to reduce HsCRP levels. Trial registration ClinicalTrial.gov (ID: NCT03451734).

Identification of Turtle-Shell Growth Year Using Hyperspectral Imaging Combined with an Enhanced Spatial-Spectral Attention 3DCNN and a Transformer.

Turtle shell (Chinemys reecesii) is a prized traditional Chinese dietary therapy, and the growth year of turtle shell has a significant impact on its quality attributes. In this study, a hyperspectral imaging (HSI) technique combined with a proposed deep learning (DL) network algorithm was investigated for the objective determination of the growth year of turtle shells. The acquisition of hyperspectral images was carried out in the near-infrared range (948.72-2512.97 nm) from samples spanning five different growth years. To fully exploit the spatial and spectral information while reducing redundancy in hyperspectral data simultaneously, three modules were developed. First, the spectral-spatial attention (SSA) module was developed to better protect the spectral correlation among spectral bands and capture fine-grained spatial information of hyperspectral images. Second, the 3D convolutional neural network (CNN), more suitable for the extracted 3D feature map, was employed to facilitate the joint spatial-spectral feature representation. Thirdly, to overcome the constraints of convolution kernels as well as better capture long-range correlation between spectral bands, the transformer encoder (TE) module was further designed. These modules were harmoniously orchestrated, driven by the need to effectively leverage both spatial and spectral information within hyperspectral data. They collectively enhance the model's capacity to extract joint spatial and spectral features to discern growth years accurately. Experimental studies demonstrated that the proposed model (named SSA-3DTE) achieved superior classification accuracy, with 98.94% on average for five-category classification, outperforming traditional machine learning methods using only spectral information and representative deep learning methods. Also, ablation experiments confirmed the effectiveness of each module to improve performance. The encouraging results of this study revealed the potentiality of HSI combined with the DL algorithm as an efficient and non-destructive method for the quality control of turtle shells.

[Application of 1470 nm semiconductor laser in the treatment of benign prostatic hyperplasia in ultra-aged patients].

OBJECTIVE: To investigate the clinical effect and safety of transurethral 1470 nm semiconductor laser vaporization and cutting in the treatment of super high age and high risk benign prostatic hyperplasia. METHODS: The clinical data of 38 patients with super-high-risk prostate who underwent transurethral surgery in our hospital from April 2016 to December 2017 were retrospectively analyzed. All patients had obvious progressive dysuria. The diagnosis of benign prostatic hyperplasia was confirmed by urinary color Doppler ultrasound, anal finger examination, PSA, prostate biopsy, etc., and prostate cancer was excluded. Each patient was aged ≥85 years old and combined with one or more types. Senile basic diseases such as diabetes, hypertension, coronary heart disease, emphysema, sequelae of cerebral infarction, etc. The patients were randomly divided into two groups. The observation group was treated with transurethral 1470 nm semiconductor laser vaporization and the control group was treated with transurethral plasma electrotomy. To observe the changes of vital signs, bleeding, duration of surgery, postoperative bladder irrigation time, urinary catheter retention time, and changes of hemoglobin before and after surgery. Surgical safety. The international prostate symptom score (IPSS), quality of life score (QoL), maximum urinary flow rate (Qmax), and post-void residual urine volume (PVR) were evaluated 2 months after surgery and compared with preoperative evaluation to evaluate the surgical outcome. RESULTS: All 38 operations were successfully completed.The vital signs of the patients were stable during the operation. The average operation time of the observation group and the control group was (79.6±24.7 vs 69.5±19.8) min, P>0.05. The hemoglobin decreased by (6.9±3.0) g/L vs (13.2±4.0) g/L， after operation.P<0.05; postoperative bladder irrigation time (14.7±2.8 vs 23.5±5.3)h, P<0.05; average postoperative urinary catheter retention time (3.8±0.4 vs 5.7±0.9)d, P<0.05; average postoperative hospital stay (5.3±1.1 vs 7.2±1.9)d, P<0.05; all patients were followed up for 2 months, IPSS, QoL, Qmax, PVR and other indicators were significantly improved compared with preoperative, no major bleeding, urinary incontinence, cardiopulmonary failure and Significant urinary tract irritation symptoms occur. CONCLUSION: Compared with plasma electric resection, transurethral 1470 nm semiconductor laser treatment of benign prostatic hyperplasia has the advantages of high safety and remarkable effect, especially suitable for patients with high age and high risk.

Exploiting the Synergistic Electronic Interaction between Pt-Skin Wrapped Intermetallic PtCo Nanoparticles and Co-N-C Support for Efficient ORR/EOR Electrocatalysis in a Direct Ethanol Fuel Cell.

The development of low-Pt catalysts with high activity and durability is critical for fuel cells. Here, Pt-skin wrapped sub-5 nm PtCo intermetallic nanoparticles are successfully mounted on single atom Co-N-C support by exploiting the barrier effect of Co-anchor. According to a collaborative experimental and computational investigation, the increased oxygen reduction reaction activity of PtCo/Co-N-C arises from the direct electron transfer from PtCo to Co-N-C, and the resulting optimal d-band center of Pt. Owing to such unique electronic structure interaction and synergistic effect, the specific and mass activities of PtCo/Co-N-C are up to 4.20 mA cm-2 and 2.71 A mgPt-1 , respectively, with barely degraded stability after 40 000 CV cycles. The PtCo/Co-N-C also exhibits outstanding activity as an ethanol electrocatalyst. This work shows a new and effective route to boost the overall efficiency of direct ethanol fuel cells in acidic media by integrating intermetallic low-Pt alloys and single atom carbon support.

Contribution of prgH gene for Salmonella Pullorum to virulence and the expression of NLRP3, Caspase-1 and IL-1ß in chickens.

Type III secretion system 1 (T3SS1) encoded by Salmonella pathogenicity island 1 (SPI1) is associated with invasion of host cells by Salmonella, PrgH encoded by prgH gene is an important component of T3SS1. This study aimed to explore the contribution of prgH gene for Salmonella Pullorum to virulence and the expression of NLRP3, Caspase-1 and IL-1ß in chickens. A prgH gene deletion mutant (C79-13ΔprgH) was firstly generated, and the result of LD50 showed that deletion of prgH significantly decreased the virulence of Salmonella Pullorum in one-day-old HY-line white chickens, and the colonization also decreased in chickens after loss of prgH. Next, the expressions of NLRP3, Caspase-1, and IL-1ß were detected in acute infection model of chickens by qRT-PCR and/or ELISA, respectively, and the results showed that the mutant strain C79-13ΔprgH reduced the expression levels of NLRP3, Caspase-1, and IL-1ß in chickens compared to the group infected with the wild type strain C79-13. Taken together, all of these findings indicated that prgH promotes the virulence and the expression of NLRP3, Caspase-1, and IL-1ß for Salmonella Pullorum in chickens.

Optical amplification enables a huge sensitivity improvement to laser heterodyne radiometers for high-resolution measurements of atmospheric gases.

A novel, to the best of our knowledge, performance-enhanced laser heterodyne radiometer has been developed by utilizing a semiconductor optical amplifier to amplify the collected weak solar radiation in an optical fiber. High-spectral-resolution measurements of atmospheric carbon dioxide column absorption are used to validate the technique and performance of the developed instrument. The implementation of optical amplification led to a 9-times improvement in sensitivity according to the Allan variance analysis for noise fluctuations, and resulted in a 7.7-times enhancement in measurement precision for atmospheric carbon dioxide. The promising results showed the great potential of employing this type of compact fiber-optics-based spectral radiometer for applications such as atmospheric greenhouse gas sensing.

Spectral Filtering Induced by Non-Hermitian Evolution with Balanced Gain and Loss: Enhancing Quantum Chaos.

The dynamical signatures of quantum chaos in an isolated system are captured by the spectral form factor, which exhibits as a function of time a dip, a ramp, and a plateau, with the ramp being governed by the correlations in the level spacing distribution. While decoherence generally suppresses these dynamical signatures, the nonlinear non-Hermitian evolution with balanced gain and loss (BGL) in an energy-dephasing scenario can enhance manifestations of quantum chaos. In the Sachdev-Ye-Kitaev model and random matrix Hamiltonians, BGL increases the span of the ramp, lowering the dip as well as the value of the plateau, providing an experimentally realizable physical mechanism for spectral filtering. The chaos enhancement due to BGL is optimal over a family of filter functions that can be engineered with fluctuating Hamiltonians.

Flexible and adhesive liquid-free ionic conductive elastomers toward human-machine interaction.

Based on the demand for flexible human-machine interaction devices, it is urgent to develop high-performance stretchable ionic conductive materials. However, most gel-based ionic conductive materials are composed of crosslinked polymer networks that contain liquids, and suffer from limitations of solvent volatilization and leakage, and the cross-linking restricts the movement and diffusion of polymer chains, making it difficult for them to achieve adhesion. Here, we introduce flexible and adhesive liquid-free ionic conductive elastomers (ICE) with salt using a non-crosslinked polymer strategy. The ICE show a transparency of 89.5%, Tg of -51.2 °C, negligible weight loss at 200 °C, a tensile fracture strain of 289.5%, and an initial modulus of 45.7 kPa, and is adhesive to various solid surfaces with an interfacial toughness of 11.4 to 41.4 J m-2. Moreover, the ICE exhibit stable electrical conductivity under ambient conditions. Triboelectric nanogenerators (TENGs) were assembled on an electrical shell surface with the adhesive ICE as an electrostatic induction layer and were displayed for use as human-machine interactive keyboards. This approach opens a route to making adhesive and stable polymer ionic conductors for human-machine interaction.

Single-Cell Transcriptomic Atlas of Different Human Cardiac Arteries Identifies Cell Types Associated With Vascular Physiology.

[Figure: see text].

Control of Cdc28 CDK1 by a stress-induced lncRNA.

Genomic analysis has revealed the existence of a large number of long noncoding RNAs (lncRNAs) with different functions in a variety of organisms, including yeast. Cells display dramatic changes of gene expression upon environmental changes. Upon osmostress, hundreds of stress-responsive genes are induced by the stress-activated protein kinase (SAPK) p38/Hog1. Using whole-genome tiling arrays, we found that Hog1 induces a set of lncRNAs upon stress. One of the genes expressing a Hog1-dependent lncRNA in antisense orientation is CDC28, the cyclin-dependent kinase 1 (CDK1) that controls the cell cycle in yeast. Cdc28 lncRNA mediates the establishment of gene looping and the relocalization of Hog1 and RSC from the 3' UTR to the +1 nucleosome to induce CDC28 expression. The increase in the levels of Cdc28 results in cells able to reenter the cell cycle more efficiently after stress. This may represent a general mechanism to prime expression of genes needed after stresses are alleviated.

Design of a compact off-axis freeform three-mirror system in a circular configuration.

A compact off-axis three-mirror system, especially with a wide field of view and small f-number, continues to present challenges in the optical design field. To design a compact off-axis three-mirror system based on a freeform surface, an optimization method with a circular configuration and four parameters is proposed. In the proposed method, the f-number and angles of mirrors are combined to optimize and achieve high-quality imaging, which means the modulation transfer function is close to the diffraction limit. To evaluate the performance of the proposed method, four design examples with different fields of view (4∘×4∘, 6∘×6∘) and f-numbers (2, 1.75) were created. The results showed that the compact off-axis three-mirror system based on a freeform surface can be designed with a wide field of view, small f-number, and high-quality imaging using the proposed method. Unlike other design methods, the surface parameters of mirrors are obtained with only one calculation and are close to the final optimization results, which saves both time and resources for optimization. The findings indicate that the method is accurate and effective for designing compact off-axis three-mirror systems with freeform surfaces.