CycC1;1-WRKY75 complex-mediated transcriptional regulation of SOS1 controls salt stress tolerance in Arabidopsis.

SALT OVERLY SENSITIVE1 (SOS1) is a key component of plant salt tolerance. However, how SOS1 transcription is dynamically regulated in plant response to different salinity conditions remains elusive. Here, we report that C-type Cyclin1;1 (CycC1;1) negatively regulates salt tolerance by interfering with WRKY75-mediated transcriptional activation of SOS1 in Arabidopsis (Arabidopsis thaliana). Disruption of CycC1;1 promotes SOS1 expression and salt tolerance in Arabidopsis because CycC1;1 interferes with RNA polymerase II recruitment by occupying the SOS1 promoter. Enhanced salt tolerance of the cycc1;1 mutant was completely compromised by an SOS1 mutation. Moreover, CycC1;1 physically interacts with the transcription factor WRKY75, which can bind to the SOS1 promoter and activate SOS1 expression. In contrast to the cycc1;1 mutant, the wrky75 mutant has attenuated SOS1 expression and salt tolerance, whereas overexpression of SOS1 rescues the salt sensitivity of wrky75. Intriguingly, CycC1;1 inhibits WRKY75-mediated transcriptional activation of SOS1 via their interaction. Thus, increased SOS1 expression and salt tolerance in cycc1;1 were abolished by WRKY75 mutation. Our findings demonstrate that CycC1;1 forms a complex with WRKY75 to inactivate SOS1 transcription under low salinity conditions. By contrast, under high salinity conditions, SOS1 transcription and plant salt tolerance are activated at least partially by increased WRKY75 expression but decreased CycC1;1 expression.

CK2 promotes jasmonic acid signaling response by phosphorylating MYC2 in Arabidopsis.

Jasmonic acid (JA) signaling plays a pivotal role in plant development and defense. MYC2 is a master transcription factor in JA signaling, and was found to be phosphorylated and negatively regulated by MAP kinase and receptor-like kinase. However, the kinases that positively regulate MYC2 through phosphorylation and promote MYC2-mediated activation of JA response have not been identified. Here, we identified CK2 as a kinase that phosphorylates MYC2 and thus regulates the JA signaling. CK2 holoenzyme can interact with MYC2 using its regulatory subunits and phosphorylate MYC2 at multiple sites with its catalytic subunits. Inhibition of CK2 activity in a dominant-negative plant line, CK2mut, repressed JA response. On the other hand, increasing CK2 activity by overexpression of CKB4, a regulatory subunit gene of CK2, enhanced JA response in a MYC2-dependent manner. Substitution of the Ser and Thr residues at phosphorylation sites of MYC2 by CK2 with Ala impaired MYC2 function in activating JA response. Further investigations evidenced that CK2 facilitated the JA-induced increase of MYC2 binding to the promoters of JA-responsive genes in vivo. Our study demonstrated that CK2 plays a positive role in JA signaling, and reveals a previously undiscovered mechanism that regulates MYC2 function.

PHR1 involved in the regulation of low phosphate-induced leaf senescence by modulating phosphorus homeostasis in Arabidopsis.

Phosphorus (P) is a crucial macronutrient for plant growth, development, and reproduction. The effects of low P (LP) stress on leaf senescence and the role of PHR1 in LP-induced leaf senescence are still unknown. Here, we report that PHR1 plays a crucial role in LP-induced leaf senescence, showing delayed leaf senescence in phr1 mutant and accelerated leaf senescence in 35S:PHR1 transgenic Arabidopsis under LP stress. The transcriptional profiles indicate that 763 differentially expressed SAGs (DE-SAGs) were upregulated and 134 DE-SAGs were downregulated by LP stress. Of the 405 DE-SAGs regulated by PHR1, 27 DE-SAGs were involved in P metabolism and transport. PHR1 could bind to the promoters of six DE-SAGs (RNS1, PAP17, SAG113, NPC5, PLDζ2, and Pht1;5), and modulate them in LP-induced senescing leaves. The analysis of RNA content, phospholipase activity, acid phosphatase activity, total P and phosphate content also revealed that PHR1 promotes P liberation from senescing leaves and transport to young tissues under LP stress. Our results indicated that PHR1 is one of the crucial modulators for P recycling and redistribution under LP stress, and the drastic decline of P level is at least one of the causes of early senescence in P-deficient leaves.

Polymer-based cascaded waveguide Bragg grating for blood glucose sensing.

Waveguide Bragg grating (WBG) blood glucose sensing, as a biological sensing technology with broad application prospects, plays an important role in the fields of health management and medical treatment. In this work, a polymer-based cascaded WBG is applied to glucose detection. We investigated photonic devices with two different grating structures cascaded-a crossed grating and a bilateral grating-and analyzed the effects of the crossed grating period, bilateral grating period, and number of grating periods on the sensing performance of the glucose sensor. Finally, the spectral reflectance characteristics, response time, and sensing specificity of the cascaded WBG were evaluated. The experimental results showed that the glucose sensor has a sensitivity of 175 nm/RIU in a glucose concentration range of 0-2 mg/ml and has the advantages of high integration, a narrow bandwidth, and low cost.

PandaOmics: An AI-Driven Platform for Therapeutic Target and Biomarker Discovery.

PandaOmics is a cloud-based software platform that applies artificial intelligence and bioinformatics techniques to multimodal omics and biomedical text data for therapeutic target and biomarker discovery. PandaOmics generates novel and repurposed therapeutic target and biomarker hypotheses with the desired properties and is available through licensing or collaboration. Targets and biomarkers generated by the platform were previously validated in both in vitro and in vivo studies. PandaOmics is a core component of Insilico Medicine's Pharma.ai drug discovery suite, which also includes Chemistry42 for the de novo generation of novel small molecules, and inClinico─a data-driven multimodal platform that forecasts a clinical trial's probability of successful transition from phase 2 to phase 3. In this paper, we demonstrate how the PandaOmics platform can efficiently identify novel molecular targets and biomarkers for various diseases.

Discovery of 3-hydroxymethyl-azetidine derivatives as potent polymerase theta inhibitors.

Inhibition of the low fidelity DNA polymerase Theta (Polθ) is emerging as an attractive, synthetic-lethal antitumor strategy in BRCA-deficient tumors. Here we report the AI-enabled development of 3-hydroxymethyl-azetidine derivatives as a novel class of Polθ inhibitors featuring central scaffolding rings. Structure-based drug design first identified A7 as a lead compound, which was further optimized to the more potent derivative B3 and the metabolically stable deuterated compound C1. C1 exhibited significant antiproliferative properties in DNA repair-compromised cells and demonstrated favorable pharmacokinetics, showcasing that 3-hydroxymethyl-azetidine is an effective bio-isostere of pyrrolidin-3-ol and emphasizing the potential of AI in medicinal chemistry for precise molecular modifications.

Discovery of novel MAT2A inhibitors by an allosteric site-compatible fragment growing approach.

The methionine adenosyltransferase MAT2A catalyzes the synthesis ofthe methyl donor S-adenosylmethionine (SAM) and thereby regulates critical aspects of metabolism and transcription. Aberrant MAT2A function can lead to metabolic and transcriptional reprogramming of cancer cells, and MAT2A has been shown to promote survival of MTAP-deficient tumors, a genetic alteration that occurs in âˆ¼ 13 % of all tumors. Thus, MAT2A holds great promise as a novel anticancer target. Here, we report a novel series of MAT2A inhibitors generated by a fragment growing approach from AZ-28, a low-molecular weight MAT2A inhibitor with promising pre-clinical properties. X-ray co-crystal structure revealed that compound 7 fully occupies the allosteric pocket of MAT2A as a single molecule mimicking MAT2B. By introducing additional backbone interactions and rigidifying the requisite linker extensions, we generated compound 8, which exhibited single digit nanomolar enzymatic and sub-micromolar cellular inhibitory potency for MAT2A.

Discovery of macrocyclic CDK2/4/6 inhibitors with improved potency and DMPK properties through a highly efficient macrocyclic drug design platform.

Cyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that enabled the highly efficient discovery of a novel, macrocyclic CDK2/4/6 inhibitor from an acyclic precursor (NUV422). Using dihedral angle scan and structure-based, computer-aided drug design to select an optimal ring-closing site and linker length for the macrocycle, we identified compound 8 as a potent new CDK2/4/6 inhibitor with optimized cellular potency and safety profile compared to NUV422. Our platform leverages both experimentally-solved as well as generative chemistry-derived macrocyclic structures and can be deployed to streamline the design of macrocyclic new drugs from acyclic starting compounds, yielding macrocyclic compounds with enhanced potency and improved drug-like properties.

Jujuboside B alleviates acetaminophen-induced hepatotoxicity in mice by regulating Nrf2-STING signaling pathway.

BACKGROUND: Jujuboside B (JuB) is the main bioactive saponin component of Chinese anti-insomnia herbal medicine Ziziphi Spinosae Semen, which has been reported to possess varied pharmacological functions. Even though it has been traditionally used to treat inflammation- and toxicity-related diseases, the effects of JuB on acetaminophen (APAP) overdose-induced hepatotoxicity have not been determined yet. METHODS: C57BL/6 J mice were pre-treated with JuB (20 or 40 mg/kg) for seven days before APAP (400 mg/kg) injection. After 24 h of APAP treatment, serum, and liver tissues were collected to evaluate the therapeutic effects. To investigate whether the Nrf2-STING signaling pathway is involved in the protective effects of JuB against APAP-induced hepatotoxicity, the mice received the DMXAA (the specific STING agonist) or ML385 (the specific Nrf2 inhibitor) during the administration of JuB, and Hematoxylin-eosin staining, Real-time PCR, immunohistochemical, and western blot were performed. RESULTS: JuB pretreatment reversed APAP-induced CYP2E1 accumulations and alleviated APAP-induced acute liver injury. Furthermore, JuB treatment significantly inhibited oxidative stress and the pro-inflammatory cytokines, as well as alleviated hepatocyte apoptosis induced by APAP. Besides, our result also demonstrated that JuB treatment upregulated the levels of total Nrf2, facilitated its nuclear translocation, upregulated the expression of HO-1 and NQO-1, and inhibited the APAP-induced STING pathway activation. Finally, we verified that the beneficial effects of JuB were weakened by DMXAA and ML385. CONCLUSION: Our study suggested that JuB could ameliorate APAP-induced hepatic damage and verified a previously unrecognized mechanism by which JuB prevented APAP-induced hepatotoxicity through adjusting the Nrf2-STING pathway.

Tailoring Near-Infrared-IIb Fluorescence of Thulium(III) by Nanocrystal Structure Engineering.

Currently, mainstream lanthanide probes with fluorescence located in the second near-infrared subwindow of 1500-1700 nm (NIR-IIb) are predominantly Er(III)-based nanoparticles (NPs). Here we report a newly developed NIR-IIb fluorescent nanoprobe, α-Tm NP (cubic-phase NaYF4@NaYF4:Tm@NaYF4), with an emission at 1630 nm. We activate the 1630 nm emission of Tm(III) in α-Tm NP through the large spread of the Stark split sublevels induced by the crystal-field effect of the α-NaYF4 host. Further, we systematically investigated the effect of crystalline structure of the host NaYF4 NP (cubic phase (α) or hexagonal phase (ß)), the type and concentrations of dopants (Yb(III), Tm(III), and Ca(II) ions) in the α-phase host, and the thicknesses of the interlayer and inert shell on the NIR-IIb fluorescence of Tm(III). The ultimate nanostructure presents a significant enhancement factor of the NIR-IIb photoluminescence intensity of Tm(III) up to ∼315. With this bright NIR-IIb fluorescent nanoprobe, we demonstrate high-spatial-resolution time-coursing imaging of breast cancer bone metastasis.

Effect of probiotics and synbiotics on complications of wound infection after colorectal surgery: A meta-analysis.

Wound infection is a serious complication that impacts the prognosis of patients after colorectal surgery (CS). Probiotics and synbiotics (Pro and Syn) are live bacteria that produce bacteriostatic agents in the intestinal system and have a positive effect on postoperative wound infections. The purpose of this study was to evaluate the effect of Pro and Syn on complications of wound infection after CS. In November 2023, we searched relevant clinical trial reports from Pubmed, Cochrane Library, and Embase databases and screened the retrieved reports, extracted data, and finally analysed the data by using RevMan 5.3. A total of 12 studies with 1567 patients were included in the study. Pro and Syn significantly reduced total infection (OR, 0.44; 95% CI, 0.35, 0.56; p < 0.00001), surgical incision site infection (SSI) (OR, 0.61; 95% CI, 0.45, 0.81; p = 0.002), pneumonia (OR, 0.43; 95% CI, 0.25, 0.72; p = 0.001), urinary tract infection (OR, 0.28; 95% CI, 0.14, 0.56; p = 0.0003), and Pro and Syn did not reduce anastomotic leakage after colorectal surgery (OR, 0.84; 95% CI, 0.50, 1.41; p = 0.51). Pro and Syn can reduce postoperative wound infections in patients with colorectal cancer, which benefits patients' postoperative recovery.

Sorting Nexin1 negatively modulates phosphate uptake by facilitating Phosphate Transporter1;1 degradation in Arabidopsis.

High-affinity phosphate (Pi) transporters (PHTs) PHT1;1 and PHT1;4 are necessary for plant root Pi uptake especially under Pi-deficient conditions, but how their protein stability is modulated remains elusive. Here, we identified a Ttransfer DNA insertion mutant of Sorting Nexin1 (SNX1), which had more Pi content and less anthocyanin accumulation than the wild type under deficient Pi. By contrast, the snx1-2 mutant displayed higher sensitivity to exogenous arsenate in terms of seed germination and root elongation, revealing higher Pi uptake rates. Further study showed that SNX1 could co-localize and interact with PHT1;1 and PHT1;4 in vesicles and at the plasma membrane. Genetic analysis showed that increased Pi content in the snx1-2 mutant under low Pi conditions could be extensively compromised by mutating PHT1;1 in the double mutant snx1-2 pht1;1, revealing that SNX1 is epistatic to PHT1;1. In addition, SNX1 negatively controls PHT1;1 protein stability; therefore, PHT1;1 protein abundance in the plasma membrane was increased in the snx1-2 mutant compared with the wild type under either sufficient or deficient Pi. Together, our study (i) identifies SNX1 as a key modulator of the plant response to low Pi and (ii) unravels its role in the modulation of PHT1;1 protein stability, PHT1;1 accumulation at the plasma membrane, and root Pi uptake.

Interface-Mediation-Enabled High-Performance Near-Infrared AgAuSe Quantum Dot Light-Emitting Diodes.

Near-infrared (NIR) quantum dot (QD) light-emitting diodes (LEDs) (NIR-QLEDs) for recognition and tracking applications underpin the future of night-vision technology. However, the performance of environmentally benign materials and devices has lagged far behind that of their Pb-containing counterparts. In this study, we demonstrate the superior performance of NIR-QLEDs based on efficient AgAuSe QDs with contact interface mediation. Consequently, we reveal that using cysteamine-treated QD film contact heterointerfaces can effectively eliminate contact defects in devices and preserve their excellent emissive properties. Additionally, the dipole moment orientation of the coordinated additives is inverse of the heterojunction potential difference, simultaneously blocking electrons and enhancing hole injection in operando, optimizing the LED charge injection balance. These devices exhibit a high external quantum efficiency (EQE) and a power conversion efficiency (PCE) of 15.8 and 12.7% at 1046 nm, respectively, a sub-band gap turn-on voltage of 0.9 V, and a low current density (over 10% of the EQE from 0.0017 to 0.31 mA cm-2). These are the highest EQE and PCE values ever reported for environmentally benign NIR-QLEDs. The results of this study can provide a general strategy for the practical application of QDs in electroluminescent devices.

Q-switched vortex waveguide laser generation based on LNOI thin films with implanted Ag nanoparticles.

Lithium-niobate-on-insulator (LNOI) thin films have gained significant attention in integrated photonics due to their exceptional crystal properties and wide range of applications. In this paper, we propose a novel approach to realize a Q-switched vortex waveguide laser by incorporating integrated lithium niobate thin films with embedded silver nanoparticles (Ag:LNOI) as a saturable absorber. The saturable absorption characteristics of Ag:LNOI are investigated using a home-made Z-scan system. Additionally, we integrate Ag:LNOI as a saturable absorber into a Nd:YAG "ear-like" cladding waveguide platform, which is prepared via femtosecond laser direct writing. By combining this setup with helical phase plates for phase modulation in the resonator, we successfully achieve a passive Q-switched vortex laser with a high repetition rate and narrow pulse duration in the near-infrared region. This work demonstrates the potential applications of LNOI thin films towards on-chip integration of vortex waveguide laser sources.

Low half-wave voltage polymeric electro-optic modulator using CLD-1/PMMA for electrocardiogram (ECG) signal acquisition.

Electro-optic (EO) modulators are typically made of inorganic materials such as lithium niobate; the replacement of these modulators with organic EO materials is a promising alternative due to their lower half-wave voltage (Vπ), ease of handling, and relatively low cost. We propose the design and fabrication of a push-pull polymer electro-optic modulator with voltage-length parameters (VπL) of 1.28 V·cm. The device uses a Mach-Zehnder structure and is made of a second-order nonlinear optical host-guest polymer composed of a CLD-1 chromophore and PMMA polymer. The experimental results show that the loss is 1.7 dB, Vπ drops to 1.6 V, and the modulation depth is 0.637 dB at 1550 nm. The results of a preliminary study show that the device is capable of efficiently detecting electrocardiogram (ECG) signals with performance on par with that of commercial ECG devices.

Microring structure for flexible polymer waveguide-based optical pressure sensing.

Flexible pressure sensors provide a promising platform for artificial smart skins, and photonic devices provide a new technique to fabricate pressure sensors. Here, we present a flexible waveguide-based optical pressure sensor based on a microring structure. The waveguide-based optical pressure sensor is based on a five-cascade microring array structure with a size of 1500 µm × 500 µm and uses the change in output power to linearly characterize the change in pressure acting on the device. The results show that the device has a sensing range of 0-60 kPa with a sensitivity of 23.14 µW/kPa, as well as the ability to detect pulse signals, swallowing, hand gestures, etc. The waveguide-based pressure sensors offer the advantages of good output linearity, high integration density and easy-to-build arrays.

Fabrication and characterization of polymer optical waveguide Bragg grating for pulse signal sensing.

Polymer materials have the advantages of a low Young's modulus and low-cost preparation process. In this paper, a polymer-based optical waveguide pressure sensor based on a Bragg structure is proposed. The change in the Bragg wavelength in the output spectrum of the waveguide Bragg grating (WBG) is used to linearly characterize the change in pressure acting on the device. The polymer-based WBG was developed through a polymer film preparation process, and the experimental results show that the output signal of the device has a sensitivity of 1.275 nm/kPa with a measurement range of 0-12 kPa and an accuracy of 1 kPa. The experimental results indicate that the device already perfectly responds to a pulse signal. It has significant potential application value in medical diagnostics and health testing, such as blood pressure monitoring, sleep quality monitoring, and tactile sensing.

The V protein in oncolytic Newcastle disease virus promotes HepG2 hepatoma cell proliferation at the single-cell level.

BACKGROUND: Newcastle disease virus (NDV) is an oncolytic virus that can inhibit cancer cell proliferation and kill cancer cells. The NDV nonstructural V protein can regulate viral replication; however, whether the V protein contributes to NDV oncolysis is unclear. RESULTS: This study revealed that NDV inhibited tumor cell proliferation and that V protein expression promoted the proliferation of HepG2 cells, as determined at the single-cell level. In addition, to identify the regulatory mechanism of the V protein in HepG2 cells, transcriptome sequencing was performed and indicated that the expression/activation of multiple cell proliferation-related genes/signaling pathways were changed in cells overexpressing the V protein. Hence, the MAPK and WNT signaling pathways were selected for verification, and after blocking these two signaling pathways with inhibitors, the V protein promotion of cell proliferation was found to be attenuated. CONCLUSIONS: The results showed that the V protein regulated the proliferation of cancer cells through multiple signaling pathways, providing valuable references for future studies on the mechanism by which the V protein regulates cancer cell proliferation.

Chemistry42: An AI-Driven Platform for Molecular Design and Optimization.

Chemistry42 is a software platform for de novo small molecule design and optimization that integrates Artificial Intelligence (AI) techniques with computational and medicinal chemistry methodologies. Chemistry42 efficiently generates novel molecular structures with optimized properties validated in both in vitro and in vivo studies and is available through licensing or collaboration. Chemistry42 is the core component of Insilico Medicine's Pharma.ai drug discovery suite. Pharma.ai also includes PandaOmics for target discovery and multiomics data analysis, and inClinico─a data-driven multimodal forecast of a clinical trial's probability of success (PoS). In this paper, we demonstrate how the platform can be used to efficiently find novel molecular structures against DDR1 and CDK20.

Exploring the Advantages of Quantum Generative Adversarial Networks in Generative Chemistry.

De novo drug design with desired biological activities is crucial for developing novel therapeutics for patients. The drug development process is time- and resource-consuming, and it has a low probability of success. Recent advances in machine learning and deep learning technology have reduced the time and cost of the discovery process and therefore, improved pharmaceutical research and development. In this paper, we explore the combination of two rapidly developing fields with lead candidate discovery in the drug development process. First, artificial intelligence has already been demonstrated to successfully accelerate conventional drug design approaches. Second, quantum computing has demonstrated promising potential in different applications, such as quantum chemistry, combinatorial optimizations, and machine learning. This article explores hybrid quantum-classical generative adversarial networks (GAN) for small molecule discovery. We substituted each element of GAN with a variational quantum circuit (VQC) and demonstrated the quantum advantages in the small drug discovery. Utilizing a VQC in the noise generator of a GAN to generate small molecules achieves better physicochemical properties and performance in the goal-directed benchmark than the classical counterpart. Moreover, we demonstrate the potential of a VQC with only tens of learnable parameters in the generator of GAN to generate small molecules. We also demonstrate the quantum advantage of a VQC in the discriminator of GAN. In this hybrid model, the number of learnable parameters is significantly less than the classical ones, and it can still generate valid molecules. The hybrid model with only tens of training parameters in the quantum discriminator outperforms the MLP-based one in terms of both generated molecule properties and the achieved KL divergence. However, the hybrid quantum-classical GANs still face challenges in generating unique and valid molecules compared to their classical counterparts.