Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation.

Testicular nuclear receptor 4 (TR4) modulates the transcriptional activation of genes and plays important roles in many diseases. The regulation of TR4 on target genes involves direct interactions with DNA molecules via the DNA-binding domain (DBD) and recruitment of coregulators by the ligand-binding domain (LBD). However, their regulatory mechanisms are unclear. Here, we report high-resolution crystal structures of TR4DBD, TR4DBD-DNA complexes and the TR4LBD-JAZF1 complex. For DNA recognition, multiple factors come into play, and a specific mutual selectivity between TR4 and target genes is found. The coactivators SRC-1 and CREBBP can bind at the interface of TR4 originally occupied by the TR4 activation function region 2 (AF-2); however, JAZF1 suppresses the binding through a novel mechanism. JAZF1 binds to an unidentified surface of TR4 and stabilizes an α13 helix never reported in the nuclear receptor family. Moreover, the cancer-associated mutations affect the interactions and the transcriptional activation of TR4 in vitro and in vivo, respectively. Overall, our results highlight the crucial role of DNA recognition and a novel mechanism of how JAZF1 reinforces the autorepressed conformation and influences the transcriptional activation of TR4, laying out important structural bases for drug design for a variety of diseases, including diabetes and cancers.

Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation.

The central region of MDM2 is critical for p53 activation and tumor suppression. Upon ribosomal stress, this region is bound by ribosomal proteins, particularly ribosomal protein L11 (RPL11), leading to MDM2 inactivation and subsequent p53 activation. Here, we solved the complex structure of human MDM2-RPL11 at 2.4 Å. MDM2 extensively interacts with RPL11 through an acidic domain and two zinc fingers. Formation of the MDM2-RPL11 complex induces substantial conformational changes in both proteins. RPL11, unable to bind MDM2 mutants, fails to induce the activation of p53 in cells. MDM2 mimics 28S rRNA binding to RPL11. The C4 zinc finger determines RPL11 binding to MDM2 but not its homolog, MDMX. Our results highlight the essential role of the RPL11-MDM2 interaction in p53 activation and tumor suppression and provide a structural basis for potential new anti-tumor drug development.

Establishment and verification of formulas of target tracking based on dual liquid crystal polarization gratings.

In this paper, the relationship between miss distance, target position, and rotation angle of dual liquid crystal polarization gratings (LCPGs) is proposed for the first time, a target tracking system based on the rotating dual LCPGs is established, and a closed-loop target tracking process based on the formula is described. We establish the optical structure of the dual LCPGs, and the simulation compares the difference between the altitude and azimuth angles of the target position from the formula and the ZEMAX simulation. In the simulation validation, we also compare and analyze the proposed formula with the formula for vertical incidence to illustrate the necessity to introduce miss distance. We assemble a target coarse tracking device and perform the tracking experiment using the proposed formula to test the coarse tracking accuracy of the system. The coarse tracking accuracy and the angle information we obtained from simulation and experiment meet our proposed technical specification of no more than 0.45mrad, showing that the proposed formula provides a good basis for stable target coarse tracking and is instructive for engineering applications.

Thermodynamics of ideal illumination: a novel figure of merit for characterizing illumination efficiency.

The advancement of modern lighting technologies has led to many revolutions in lighting efficiency and presentation. The progression from filament bulbs, to CFL, and now LED technologies have produced a bounty of energy-efficient lighting options for design engineers and consumers. As the light-producing elements of a lighting fixture improve, the limiting factor in efficient illumination is no longer the light source, but the optical system itself. There are many characterization methods and standards for defining light for illumination in terms of color and human response. With concerns of how things like light pollution and energy requirements impact our society and the world around us, it is critical to understand how well a lighting fixture can illuminate a desired area while minimizing light lost to the environment and maximizing the total radiative intensity (radiance) of a space. This work presents two figures of merit, one for over-illumination and another for under-illumination, to characterize the optics of a lighting system based on a ray tracing methodology. Five common simplified optical design, with four varying beam angles, were simulated to present these new figures of merit. Results showed that common imaging optical systems such as parabolic and ellipse reflectors struggled to produce a well-lit area without over illumination, while nonimaging alternatives like the compound parabolic and compound elliptical reflectors were able to reach the thermodynamic ideal of a fully illuminated area without light lost to the environment. This work hopes to inform illumination engineers and lighting designers to help improve their optical design to maximize performance and minimize waste.

Analysis of scintillation effects along a 7 km urban space laser communication path.

In this study, the scintillation effects along a 7 km space laser communication path in an urban area were examined, including the relationship between the scintillation and bit error rate and the variation of the scintillation index with changes in the transmitting and receiving apertures. It was concluded that multi-aperture transmitting technology can effectively reduce the scintillation caused by atmospheric turbulence. For the investigated urban link, the scintillation index could meet the communication requirements for adjusting the receiving aperture. These results will facilitate space laser communication improvement and turbulence suppression along horizontal urban paths.

Design of a superresolution large-aperture telescopic optical system with a wide field of view.

A pupil modulator is a useful tool to improve the resolution of an optical imaging system beyond the classical diffraction limit. However, when this technology is used in a large-aperture telescopic imaging system, the field of view (FOV) with good superresolution (SR) imaging quality is significantly smaller than the designed FOV of the baseline optical system. In this paper, we investigate the influence of various aberrations on the SR properties of a telescopic system using a low sidelobe five-ring pure phase pupil modulator. On this basis, we propose an optimal design method for a wide FOV and a large-aperture telescopic baseline optical system with uniform image quality and a particular residue of symmetric aberration. The design results show that when the optimized 4 m aperture baseline optical system and the modulator are combined as the imaging system, the imaging system has a round and very similar point spread function in the FOV range of 0.28°; the SR gain ratio is 1.234-1.254; and the highest sidelobe intensity is less than 0.1; thus, the system maintains a high resolution ratio and a low sidelobe energy throughout the entire FOV. Finally, a reasonable tolerance model of the baseline optical system is established. The central symmetry tolerances are observed to be loose in this model, thereby reducing the cost and manufacturing difficulty of the system.

Structural Basis of Reversible Phosphorylation by Maize Pyruvate Orthophosphate Dikinase Regulatory Protein.

Pyruvate orthophosphate dikinase (PPDK) is one of the most important enzymes in C4 photosynthesis. PPDK regulatory protein (PDRP) regulates the inorganic phosphate-dependent activation and ADP-dependent inactivation of PPDK by reversible phosphorylation. PDRP shares no significant sequence similarity with other protein kinases or phosphatases. To investigate the molecular mechanism by which PDRP carries out its dual and competing activities, we determined the crystal structure of PDRP from maize (Zea mays). PDRP forms a compact homo-dimer in which each protomer contains two separate N-terminal (NTD) and C-terminal (CTD) domains. The CTD includes several key elements for performing both phosphorylation and dephosphorylation activities: the phosphate binding loop (P-loop) for binding the ADP and inorganic phosphate substrates, residues Lys-274 and Lys-299 for neutralizing the negative charge, and residue Asp-277 for protonating and deprotonating the target Thr residue of PPDK to promote nucleophilic attack. Surprisingly, the NTD shares the same protein fold as the CTD and also includes a putative P-loop with AMP bound but lacking enzymatic activities. Structural analysis indicated that this loop may participate in the interaction with and regulation of PPDK. The NTD has conserved intramolecular and intermolecular disulfide bonds for PDRP dimerization. Moreover, PDRP is the first structure of the domain of unknown function 299 enzyme family reported. This study provides a structural basis for understanding the catalytic mechanism of PDRP and offers a foundation for the development of selective activators or inhibitors that may regulate photosynthesis.

Polarization control strategy of a laser communication terminal with a periscopic scanner using dual rotating waveplates.

We assessed the problem of low mixing efficiency caused by unstable signal polarization because of a moving reflector in a laser communication terminal with a periscopic scanner. A real-time polarization compensation method based on rotating waveplates is presented, which keeps the receiving signal light polarization at 45° linear polarized and improves system mixing efficiency. A geometric model of the laser communication terminal was first established, its polarization transmission characteristics were analyzed by three-dimensional polarization tracks, and a system polarization transmission matrix was calculated. The relationship between scan angle and polarization of the output signal was simulated. The connections between a polarization-compensating λ/4 waveplate and the λ/2 waveplate rotation angle and scan angle were established. These findings will pave the way for real-time polarization control technology for coherent free-space laser communications.

Discovery of mitochondrion-targeting copper(II)-plumbagin and -bipyridine complexes as chemodynamic therapy agents with enhanced antitumor activity.

Four copper(II)-plumbagin and -bipyridine complexes (Cu1-Cu4) were synthesized as chemodynamic therapy agents with enhanced antitumor activity. As lipophilic and positively charged compounds, Cu1-Cu4 were preferentially accumulated in mitochondria and activated the mitochondrial apoptosis pathway. Mechanistic studies showed that Cu1-Cu4 reacted with GSH to reduce Cu2+ ions to Cu+ ions, catalyzed the formation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H2O2) through a Fenton-like reaction, induced mitochondrial dysfunction, and activated caspase-9/3, which eventually led to apoptosis. Cu1-Cu4 arrested HeLa cells in the S phase and eventually killed cancer cells. Cu2 showed a favorable pharmacokinetic profile in mice. Moreover, Cu2 effectively inhibited the growth of HeLa xenografts in nude mice and showed low toxicity in vivo.

Efficacy and safety of intercostal nerve anastomosis in immediate subpectoral prosthetic breast reconstruction after nipple-areola-sparing mastectomy: a randomized, controlled, open-label clinical study.

Purpose: This aims to investigate the efficacy and safety of intercostal nerve anastomosis among breast cancer patients who undergo immediate subpectoral prosthetic breast reconstruction after nipple-areola-sparing mastectomy. Methods: From 2022 to 2023, female patients between the ages of 20 and 60 diagnosed with stage I-IIIA breast cancer, who required and were willing to undergo immediate subpectoral prosthetic breast reconstruction after nipple-areola-sparing mastectomy, were screened and assigned to take the operation with (treatment group) or without (control group) intercostal nerve anastomosis (the nerves with appropriate length and thickness were selected from the 2nd-4th intercostal nerves, which were then dissociated and anastomosed to the posterior areola tissue). A radial incision at the surface projection of the tumor location was used. The patients' breast local sensation was assessed using Semmes-Weinstein monofilaments before the operation as well as at 10 days, 3 months, and 6 months postoperatively. Furthermore, the patients' quality of life was evaluated 6 months postoperatively using the EORTC QLQ-C30 questionnaire. Adverse events, operation duration, drainage volume, and the duration of drainage tube carrying time were also monitored and recorded. Results: Compared to the pre-operative period, a significant decrease in local sensation was observed 10 days after surgery in both groups. However, the control group showed a significant reduction in sensation at 3 and 6 months postoperatively, while the treatment group showed noticeable recovery. A statistically significant difference (P < 0.001) in local sensation between the pre-operative and post-operative periods was observed at the final follow-up in the two groups. By the time of 3 and 6 months postoperatively, a significant difference was seen in the local sensation between the two groups. Intercostal nerve anastomosis was found to significantly improve the patients' quality of life, including emotional (P = 0.01), physical (P = 0.04), and social functioning (P = 0.02) and pain (P = 0.04). There were no significant differences in general characteristics (such as age, BMI, and subtypes). Although intercostal nerve anastomosis increased the duration of operation by around 20 min (P < 0.001), it did not affect the volume or duration of postoperative drainage tube usage between the two groups. Conclusion: This study indicated that intercostal nerve anastomosis improved the local sensation and quality of life of patients who underwent immediate subpectoral prosthetic breast reconstruction after nipple-areola-sparing mastectomy. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=42487, identifier ChiCTR1900026340.

Primary choriocarcinoma of the colon: a case report and review of the literature.

Choriocarcinoma usually arises in the uterus and gonads. Primary choriocarcinoma (PCC) in an extragenital organ is rare. When it occurs in the gastrointestinal tract, the stomach is the most common site. Only 12 cases of PCC of the colon have been reported in the world literature. Most cases were associated with adenocarcinoma. We report the case of a 36-year-old man with PCC of the colon and review the clinical characteristics of previously documented cases.

[Preliminary study of breast cancer magnetic resonance targeting diagnosis basing on magnetic nanoparticles in vitro].

OBJECTIVE: To develop a magnetic nanoparticles based magnetic resonance (MR) probe targeting CD40 mutant in the imaging of breast cancer cells in vitro. METHODS: For preparing an immunologically competent probe, monoclonal antibody was conjugated with ultrasmall superparamagnetic iron oxide (USPIO) particles basing on chemical cross-linking method.Its bioactivity was analyzed with flow cytometry, confocal microscopy and Prussian blue staining. The probe's cell MR imaging in vitro was conducted on breast cancer cells (M231) high expressing CD40 mutant. The signal data from different groups were collected and analyzed with one-way variance and least significant difference-t test. RESULTS: The molecular probe carrying nanoparticles and CD40 mutant antibody was constructed and separated successfully. The probe had similar magnetic property compared with original USPIO particles.It could recognize CD40 mutant on breast cancer cells (M231) with high specificity. MR cell imaging in vitro shows that T2 and T2(*) obviously shortened after probe binding with M231 cells and T2 weighted imaging become darker than control groups, the time of T2 is 5H6-USPIO (51.66 ± 5.31) , 5C11-USPIO (92.89 ± 4.72), USPIO (64.56 ± 3.85) ms. The T2 and T2(*) relaxation time of experiment group was shorter than control groups with statistical significance (P < 0.01) . CONCLUSION: MR molecular probe targeting CD40 mutant may bind with breast cancer cells (M231) to provide further in vivo animal MR imaging. And CD40 mutant is expected to provide a new target for MR molecular imaging of breast cancer.

Impact of sentinel lymph node biopsy through the axillary cribriform fascia approach on intraoperative indicators and postoperative complications.

The aim of this study was to compare intraoperative indicators and postoperative complications of sentinel lymph node biopsy (SLNB) via the axillary cribriform membrane and traditional axillary fold with blue dye to make a priority choice. This single-center, retrospective cohort study enrolled 330 eligible breast cancer patients with stage of cTis ~ 2N0M0 in our hospital from August 2018 to July 2021. Multiple linear and binary logistic regression were used to evaluate the effects of different surgical approaches on intraoperative indicators (drainage volume, tube time, intraoperative bleeding, operative time and the number of sentinel lymph nodes (SLNs)) and postoperative complications (upper limb edema and dysfunction). All statistical tests were two sided. Multiple linear and logistic regression results after adjusting the covariate showed that the axillary cribriform fascia approach could render more greater intraoperative indictors and reduce the risk of upper limb dysfunction (P = 0.038, OR 0.32, 95%CI 0.11-0.94). High BMI could increase the drainage volume, tube time and operative time. There was no significant difference in the number of SLNs between the two approaches and it also had no relationship with intraoperative indicators and postoperative complications. Overall, 6 (1.8%) experienced upper limb edema and 18 (5.5%) experienced upper limb dysfunction. Univariate logistic regression analysis showed that radiotherapy increased the risk of upper limb edema (P = 0.032, OR = 12.76, 95%CI 1.25-130.06). SLNB through the axillary cribriform fascia approach produces more satisfied intraoperative indictors, a lower risk of upper limb dysfunction.

Platinum-Based Mcl-1 Inhibitor Targeting Mitochondria Achieves Enhanced Antitumor Activity as a Single Agent or in Combination with ABT-199.

Discovery of small molecule inhibitors targeting Mcl-1 (Myeloid cell leukemia 1) confronts many challenges. Based on the fact that Mcl-1 is mainly localized in mitochondria, we propose a new strategy of targeting mitochondria to improve the binding efficiency of Mcl-1 inhibitors. We report the discovery of complex 9, the first mitochondrial targeting platinum-based inhibitor of Mcl-1, which selectively binds to Mcl-1 with high binding affinity. Complex 9 was mainly concentrated in the mitochondria of tumor cells which led to an enhanced antitumor efficacy. Complex 9 induced Bax/Bak-dependent apoptosis in LP-1 cells and synergized with ABT-199 to kill ABT-199 resistant cells in multiple cancer models. Complex 9 was effective and tolerable as a single agent or in combination with ABT-199 in mouse models. This research work demonstrated that developing mitochondria-targeting Mcl-1 inhibitors is a new potentially efficient strategy for tumor therapy.

Characterization, spectroscopic and crystallographic analyses of ß-lactoglobulin and docosahexaenoic acid nanocomplexes.

In this work, we investigated the interaction of docosahexaenoic acid (DHA) with ß-lactoglobulin (ß-Lg) using spectroscopic and crystallographic methods. The fluorescence results showed that DHA formed complexes with ß-Lg with a binding constant of 4.13 × 104 M-1. The secondary structure of ß-Lg was not significantly (p > 0.05) changed after binding with DHA. Dynamic light scattering showed the particle size of ß-Lg-DHA complexes was about 5 nm, the same as that of ß-Lg alone. The turbidity of DHA in aqueous solution decreased after binding with ß-Lg. The crystallographic results showed that DHA was bound at one site in the calyx of ß-Lg and that the aliphatic chain was hidden inside the hydrophobic ß-barrel while the carboxyl group was located at the calyx entrance. These findings indicate that ß-Lg can act as an effective nanocarrier for DHA.

Design and Functional Characterization of a Novel Abscisic Acid Analog.

The phytohormone abscisic acid (ABA) plays a crucial role in mediating plant growth and development by recruiting genetically redundant ABA receptors. To overcome its oxidation inactivation, we developed a novel ABA analog named 2',3'-benzo-iso-ABA (iso-PhABA) and studied its function and structural characterization with A. thaliana ABA receptors. The (+)-iso-PhABA form showed much higher ABA-like activities than (+)-ABA including inhibitory effects on the seed germination of lettuce and A. thaliana, wheat embryo germination and rice seedling elongation. The PP2C (protein phosphatases 2C) activity assay showed that (+)-iso-PhABA acted as a potent and selective ABA receptor agonist, which is preferred to PYL10. In some cases, (-)-iso-PhABA showed moderate to high activity for the PYL protein inhibiting PP2C activity, suggesting different mechanisms of action of iso-PhABA and ABA. The complex crystal structure of iso-PhABA with PYL10 was determined and elucidated successfully, revealing that (+)-iso-PhABA was better coordinated in the same binding pocket compared to (+)-ABA. Moreover, the detailed interaction network of iso-PhABA/PYL10 was disclosed and involves hydrogen bonds and multiple hydrophobic interactions that provide a robust framework for the design of novel ABA receptor agonists/antagonists.

Electrochemical detection of glutathione by using thymine-rich DNA-gated switch functionalized mesoporous silica nanoparticles.

A novel electrochemical sensor for highly sensitive and selective detection of glutathione (GSH) was developed coupled thymine-Hg2+-thymine (T-Hg2+-T) coordination with mesoporous silica nanoparticles (MSN). Hg2+ ions could specifically interact with thymine bases to form strong and stable T-Hg2+-T complexes. And the electroactive molecules-methylene blue (MB) was sealed in the inner pores of MSN with a unique sequential thymine (T)-rich DNA in the presence of Hg2+. After the target was added, the formed duplex DNA T-Hg2+-T complex could deform into single-stranded DNA by a competitive displacement reaction, leading to the release of MB entrapped in the MSN. Thus the target-dependent amount of released MB could be conveniently monitored with an n-dodecanethiol modified screen-printed gold electrode. Using GSH as a model target, the proposed assay showed a wide detection ranging from 1.0nM to 1.0µM with a detection limit of 0.6nM. This strategy was simple and universal for various analytes with different competitive displacement ligands, possessing a great potential for convenient biotools testing and commercial application.

The Adhesion of Lactobacillus salivarius REN to a Human Intestinal Epithelial Cell Line Requires S-layer Proteins.

Lactobacillus salivarius REN, a novel probiotic isolated from Chinese centenarians, can adhere to intestinal epithelial cells and subsequently colonize the host. We show here that the surface-layer protein choline-binding protein A (CbpA) of L. salivarius REN was involved in adherence to the human colorectal adenocarcinoma cell line HT-29. Adhesion of a cbpA deletion mutant was significantly reduced compared with that of wild-type, suggesting that CbpA acts as an adhesin that mediates the interaction between the bacterium and its host. To identify the molecular mechanism of adhesion, we determined the crystal structure of a truncated form of CbpA that is likely involved in binding to its cell-surface receptor. The crystal structure identified CbpA as a peptidase of the M23 family whose members harbor a zinc-dependent catalytic site. Therefore, we propose that CbpA acts as a multifunctional surface protein that cleaves the host extracellular matrix and participates in adherence. Moreover, we identified enolase as the CbpA receptor on the surface of HT-29 cells. The present study reveals a new class of surface-layer proteins as well as the molecular mechanism that may contribute to the ability of L. salivarius REN to colonize the human gut.

Electrochemical sensor for glutathione detection based on mercury ion triggered hybridization chain reaction signal amplification.

In this work, we design a new simple and highly sensitive strategy for electrochemical detection of glutathione (GSH) via mercury ion (Hg(2+)) triggered hybridization chain reaction (HCR) signal amplification. It is observed that in the absence of GSH, a specific thymine-Hg(2+)-thymine (T-Hg(2+)-T) coordination can fold into hairpin structures. While in the presence of GSH, it thus can be chelated with Hg(2+), resulting in Hg(2+) released from the T-Hg(2+)-T hairpin complex which then forms into ssDNA structure to further hybridize with the surface-immobilized capture DNA probe on the gold electrode with a sticky tail left. The presence of two hairpin helper probes through HCR leads to the formation of extended dsDNA superstructure on the electrode surface, which therefore causes the intercalation of numerous electroactive species ([Ru(NH3)6](3+)) into the dsDNA grooves, followed by a significantly amplified signal output whose intensity is related to the concentration of the GSH. Taking advantage of merits of enzyme-free amplification power of the HCR, the inherent high sensitivity of the electrochemical technique, and label-free detection which utilizes an electroactive species as a signaling molecule that binds to the anionic phosphate backbone of DNA strands via electrostatic force, not only does the proposed strategy enable sensitive detection of GSH, but show high selectivity against other amino acid, making our method a simple and sensitive addition to the amplified GSH detection.

Structural basis and functions of abscisic acid receptors PYLs.

Abscisic acid (ABA) plays a key role in many developmental processes and responses to adaptive stresses in plants. Recently, a new family of nucleocytoplasmic PYR/PYL/RCAR (PYLs) has been identified as bona fide ABA receptors. PYLs together with protein phosphatases type-2C (PP2Cs), Snf1 (Sucrose-non-fermentation 1)-related kinases subfamily 2 (SnRK2s) and downstream substrates constitute the core ABA signaling network. Generally, PP2Cs inactivate SnRK2s kinases by physical interaction and direct dephosphorylation. Upon ABA binding, PYLs change their conformations and then contact and inhibit PP2Cs, thus activating SnRK2s. Here, we reviewed the recent progress in research regarding the structures of the core signaling pathways of ABA, including the (+)-ABA, (-)-ABA and ABA analogs pyrabactin as well as 6AS perception by PYLs, SnRK2s mimicking PYLs in binding PP2Cs. PYLs inhibited PP2Cs in both the presence and absence of ABA and activated SnRK2s. The present review elucidates multiple ABA signal perception and transduction by PYLs, which might shed light on how to design small chemical compounds for improving plant performance in the future.