Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 µM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

Dual vector millimeter-wave signal generation based on optical carrier suppression modulation and direct detection with one photodetector.

We propose a novel, to the best of our knowledge, scheme for dual vector millimeter-wave (mm-wave) signal generation and transmission, based on optical carrier suppression (OCS) modulation, precoding, and direct detection by a single-ended photodiode (PD). At the transmitter side, two independent vector radio frequency (RF) signals with precoding, generated via digital signal processing (DSP), are used to drive an in-phase/quadrature (I/Q) modulator operating at the optical OCS modulation mode to simultaneously generate two independent frequency-doubling optical vector mm-wave signals, which can reduce the bandwidth requirement of transmitter's components and enhance spectral efficiency. With the aid of the single-ended PD and subsequent DSP at the receiver side, two independent frequency-doubling vector mm-wave signals can be separated and demodulated without data error. Based on our proposed scheme, we experimentally demonstrate the generation, transmission, and detection of 2-Gbaud 30-GHz quadrature-phase-shift-keying (QPSK) and 2-Gbaud 46-GHz QPSK signals over 10-km single-mode fiber-28 (SMF-28) and 1-m wireless transmission. The results indicate that the bit-error ratio (BER) of the dual vector mm-wave signals can each reach the hard-decision forward-error-correction (HD-FEC) threshold of 3.8 × 10-3.

OAM mode-division multiplexing IM/DD transmission at 4.32†Tbit/s with a low-complexity adaptive-network-based fuzzy inference system nonlinear equalizer.

Stochastic nonlinear impairment is the primary factor that limits the transmission performance of high-speed orbital angular momentum (OAM) mode-division multiplexing (MDM) optical fiber communication systems. This Letter presents a low-complexity adaptive-network-based fuzzy inference system (LANFIS) nonlinear equalizer for OAM-MDM intensity-modulation direct-detection (IM/DD) transmission with three OAM modes and 15 wavelength division multiplex (WDM) channels. The LANFIS equalizer could adjust the probability distribution functions (PDFs) of the distorted pulse amplitude modulation (PAM) symbols to fit the statistical characteristics of the WDM-OAM-MDM transmission channel. Therefore, although the transmission symbols in the WDM-OAM-MDM system are subjected to a stochastic nonlinear impairment, the proposed LANFIS equalizer can effectively compensate the distorted signals. The proposed equalizer outperforms the Volterra equalizer with improvements in receiver sensitivity of 2, 1.5, and 1.3 dB for three OAM modes at a wavelength of 1550.12 nm, respectively. It also outperforms a CNN equalizer, with improvements in receiver sensitivity of 1, 0.5, and 0.3 dB, respectively. Moreover, complexity reductions of 67%, 74%, and 99.9% are achieved for the LANFIS equalizer compared with the Volterra, CNN, and ANFIS equalizers, respectively. The proposed equalizer has high performance and low complexity, making it a promising candidate for a high-speed WDM-OAM-MDM system.

Advanced TiO2/Al2O3 Bilayer ALD Coatings for Improved Lithium-Rich Layered Oxide Electrodes.

Surface modification is a highly effective strategy for addressing issues in lithium-rich layered oxide (LLO) cathodes, including phase transformation, particle cracking, oxygen gas release, and transition-metal ion dissolution. Existing single-/double-layer coating strategies face drawbacks such as poor component contact and complexity. Herein, we present the results of a low-temperature atomic layer deposition (ALD) process for creating a TiO2/Al2O3 bilayer on composite cathodes made of AS200 (Li1.08Ni0.34Co0.08Mn0.5O2). Electrochemical analysis demonstrates that TiO2/Al2O3-coated LLO electrodes exhibit improved discharge capacities and enhanced capacity retention compared with uncoated samples. The TAA-5/AS200 bilayer-coated electrode, in particular, demonstrates exceptional capacity retention (∼90.4%) and a specific discharge capacity of 146 mAh g-1 after 100 cycles at 1C within the voltage range of 2.2 to 4.6 V. The coated electrodes also show reduced voltage decay, lower surface film resistance, and improved interfacial charge transfer resistances, contributing to enhanced stability. The ALD-deposited TiO2/Al2O3 bilayer coatings exhibit promising potential for advancing the electrochemical performance of lithium-rich layered oxide cathodes in lithium-ion batteries.

Systematic review and meta-analysis of the interventional effects of resveratrol in a rat model of myocardial ischemia-reperfusion injury.

Objective: To evaluate the intervention effect of resveratrol on rat model of myocardial ischemia-reperfusion injury. Methods: The relevant studies on the intervention of resveratrol on rat models of myocardial ischemia reperfusion injury were searched in PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang and China Science and Technology Journal Database from the start of database establishment to January 2023. Data were extracted from studies that met the inclusion criteria. The results included electrocardiogram (ECG) and myocardial injury markers: ST changes, cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), creatine kinase (CK), creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH); hemodynamic indicators: heart rate (HR), left ventricular diastolic pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP), maximum rate of increase of left ventricular pressure (+dp/dtmax), maximum rate of decrease of left ventricular pressure (-dp/dtmax); oxidative damage indicators: nitric oxide (NO), reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA); inflammatory factors: tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6); apoptosis index: B-cell lymphoma-2 (Bcl-2), BCL2-Associated X (Bax), cardiomyocyte apoptosis index (AI); heart tissue structure: myocardial infarction size. Finally, a meta-analysis of these results was conducted. The methodological quality of the studies was assessed using the SYRCLE Bias Risk tool. Results: A total of 43 studies were included in the meta-analysis, and the quality of the included studies was assessed. It was found that the evidence quality of these 43 studies was low, and no study was judged to have low risk bias in all risk assessments. The results showed that resveratrol could reduce ST segment, cTn-I, cTn-T, CK, CK-MB, LDH, LVEDP, ROS, MDA, TNF-α, IL-6, AI levels and myocardial infarction size. HR, LVDP, LVSP, +dp/dtmax, NO, Bcl-2, and SOD levels were increased. However, resveratrol had no significant effect on -dp/dtmax and Bax outcome measures. Conclusion: Resveratrol can reduce ST segment in rat model of myocardial ischemia-reperfusion injury, alleviate myocardial injury, improve ventricular systolic and diastolic ability in hemodynamics, reduce inflammatory response and oxidative damage, and reduce myocardial necrosis and apoptosis. Due to the low quality of the methodologies included in the studies, additional research is required.

Madecassoside alleviates acute kidney injury by regulating JNK-mediated oxidative stress and programmed cell death.

BACKGROUND: Acute kidney injury (AKI) has high morbidity and mortality, which is manifested by inflammation and apoptosis. Effective treatment methods for AKI are currently lacking. OBJECTIVE: This study demonstrated the protecting effects of Madecassoside (MA) in the cisplatin- and hypoxia-reoxygenation-induced renal tubular epithelial cells in vitro and AKI mice in vivo. METHODS: In vivo AKI mouse models were established by inducing them with cisplatin and renal ischemia-reperfusion. In vitro injury models of mouse renal tubular epithelial cells were established by inducing them with cisplatin and hypoxia and reoxygenation, respectively. The mechanism of MA effects was further explored using molecular docking and RNA-sequencing. RESULTS: MA could significantly reduce kidney injury in the cisplatin-and renal ischemia-reperfusion (IRI)-induced AKI. Further validation in the two cellular models also showed that MA had protect effects. MA can alleviate AKI in vitro and in vivo by inhibiting inflammation, cell apoptosis, and oxidative stress. MA exhibited high permeability across the Caco-2 cell, can enter cells directly. Through RNA-seq and molecular docking analysis, this study further demonstrated that MA inhibits its activity by directly binding to JNK kinase, thereby inhibiting c-JUN mediated cell apoptosis and improving AKI. In addition, MA has better renal protective effects compared to curcumin and JNK inhibitor SP600125. CONCLUSION: The results demonstrate that MA might be a potential drug for the treatment of AKI and act through the JNK/c-JUN signaling pathway.

Stevioside attenuates bleomycin-induced pulmonary fibrosis by activating the Nrf2 pathway and inhibiting the NF-κB and TGF-ß1/Smad2/3 pathways.

Objective: This study aimed to investigate the effects of stevioside (STE) on pulmonary fibrosis (PF) and the potential mechanisms. Methods: In this study, a mouse model of PF was established by a single intratracheal injection of bleomycin (BLM, 3 mg/kg). The experiment consisted of four groups: control group, BLM group, and STE treatment groups (STE 50 and 100 mg/kg). ELISA and biochemical tests were conducted to determine the levels of TNF-α, IL-1ß, IL-6, NO, hydroxyproline (HYP), SOD, GSH, and MDA. Histopathological changes and collagen deposition in lung tissues were observed by HE and Masson staining. Immunohistochemistry was performed to determine the levels of collagen I-, collagen III-, TGF-ß1- and p-Smad2/3-positive cells. Western blot analysis was used to measure the expression of epithelial-mesenchymal transition (EMT) markers, including α-SMA, vimentin, E-cadherin, and ZO-1, as well as proteins related to the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, nuclear transcription factor-κB (NF-κB) pathway, and TGF-ß1/Smad2/3 pathway in lung tissues. Results: STE significantly alleviated BLM-induced body weight loss and lung injury in mice, decreased HYP levels, and reduced the levels of collagen I- and collagen III-positive cells, thereby decreasing extracellular matrix (ECM) deposition. Moreover, STE markedly improved oxidative stress (MDA levels were decreased, while SOD and GSH activity were enhanced), the inflammatory response (the levels of TNF-α, IL-1ß, IL-6, and NO were reduced), and EMT (the expression of α-SMA and vimentin was downregulated, and the expression of E-cadherin and ZO-1 was upregulated). Further mechanistic analysis revealed that STE could activate the Nrf2 pathway and inhibit the NF-κB and TGF-ß1/Smad2/3 pathways. Conclusion: STE may alleviate oxidative stress by activating the Nrf2 pathway, suppress the inflammatory response by downregulating the NF-κB pathway, and inhibit EMT progression by blocking the TGF-ß1/Smad2/3 pathway, thereby improving BLM-induced PF.

Chemical Inhibitors Targeting the Oncogenic m6A Modifying Proteins.

Epigenetics is brought to RNA, introducing a new dimension to gene expression regulation. Among numerous RNA modifications, N6-methyladenosine (m6A) is an abundant internal modification on eukaryote mRNA first identified in the 1970s. However, the significance of m6A modification in mRNA had been long neglected until the fat mass and obesity-associated (FTO) enzyme was identified as the first m6A demethylase almost 40 years later. The m6A modification influences nearly every step of RNA metabolism and thus broadly affects gene expression at multiple levels, playing a critical role in many biological processes, including cancer progression, metastasis, and immune evasion. The m6A level is dynamically regulated by RNA epigenetic machinery comprising methyltransferases such as methyltransferase-like protein 3 (METTL3), demethylases FTO and AlkB human homologue 5 (ALKBH5), and multiple reader proteins. The understanding of the biology of RNA epigenetics and its translational drug discovery is still in its infancy. It is essential to further develop chemical probes and lead compounds for an in-depth investigation into m6A biology and the translational discovery of anticancer drugs targeting m6A modifying oncogenic proteins.In this Account, we present our work on the development of chemical inhibitors to regulate m6A in mRNA by targeting the FTO demethylase, and the elucidation of their mode of action. We reported rhein to be the first substrate competitive FTO inhibitor. Due to rhein's poor selectivity, we identified meclofenamic acid (MA) that selectively inhibits FTO compared with ALKBH5. Based on the structural complex of MA bound with FTO, we designed MA analogs FB23-2 and Dac51, which exhibit significantly improved activities compared with MA. For example, FB23-2 is specific to FTO inhibition in vitro among over 400 other oncogenic proteins, including kinases, proteases, and DNA and histone epigenetic proteins. Mimicking FTO depletion, FB23-2 promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cells and inhibits the progression of primary cells in xenotransplanted mice. Dac51 treatment impairs the glycolytic activity of tumor cells and restores the function of CD8+ T cells, thereby inhibiting the growth of solid tumors in vivo. These FTO inhibitors were and will continue to be used as probes to promote biological studies of m6A modification and as lead compounds to target FTO in anticancer drug discovery.Toward the end, we also include a brief review of ALKBH5 demethylase inhibitors and METTL3 methyltransferase modulators. Collectively, these small-molecule modulators that selectively target RNA epigenetic proteins will promote in-depth studies on the regulation of gene expression and potentially accelerate anticancer target discovery.

Protein acetylation and related potential therapeutic strategies in kidney disease.

Kidney disease can be caused by various internal and external factors that have led to a continual increase in global deaths. Current treatment methods can alleviate but do not markedly prevent disease development. Further research on kidney disease has revealed the crucial function of epigenetics, especially acetylation, in the pathology and physiology of the kidney. Histone acetyltransferases (HATs), histone deacetylases (HDACs), and acetyllysine readers jointly regulate acetylation, thus affecting kidney physiological homoeostasis. Recent studies have shown that acetylation improves mechanisms and pathways involved in various types of nephropathy. The discovery and application of novel inhibitors and activators have further confirmed the important role of acetylation. In this review, we provide insights into the physiological process of acetylation and summarise its specific mechanisms and potential therapeutic effects on renal pathology.

Hidden conditional random field-based equalizer for the 3D-CAP-64 transmission of OAM mode-division multiplexed ring-core fiber communication.

As a key technique for achieving ultra-high capacity optical fiber communications, orbital angular momentum (OAM) mode-division multiplexing (MDM) is affected by severe nonlinear impairments, including modulation related nonlinearities, square-law nonlinearity and mode-coupling-induced nonlinearity. In this paper, an equalizer based on a hidden conditional random field (HCRF) is proposed for the nonlinear mitigation of OAM-MDM optical fiber communication systems with 20 GBaud three-dimensional carrierless amplitude and phase modulation-64 (3D-CAP-64) signals. The HCRF equalizer extracts the stochastic nonlinear feature of the OAM-MDM 3D-CAP-64 signals by estimating the conditional probabilities of the hidden variables, thereby enabling the signals to be classified into subclasses of constellation points. The nonlinear impairment can then be mitigated based on the statistical probability distribution of the hidden variables of the OAM-MDM transmission channel in the HCRF equalizer. Our experimental results show that compared with a convolutional neural network (CNN)-based equalizer, the proposed HCRF equalizer improves the receiver sensitivity by 2 dB and 1 dB for the two OAM modes used here, with l = + 2 and l = + 3, respectively, at the 7% forward error correction (FEC) threshold. When compared with a Volterra nonlinear equalizer (VNE) and CNN-based equalizer, the computational complexity of the proposed HCRF equalizer was found to be reduced by 30% and 41%, respectively. The bit error ratio (BER) performance and reduction in computational complexity indicate that the proposed HCRF equalizer has great potential to mitigate nonlinear distortions in high-speed OAM-MDM fiber communication systems.

400 Gbit/s 4 mode transmission for IM/DD OAM mode division multiplexing optical fiber communication with a few-shot learning-based AffinityNet nonlinear equalizer.

Nonlinear impairment in a high-speed orbital angular momentum (OAM) mode-division multiplexing (MDM) optical fiber communication system presents high complexity and strong stochasticity due to the massive optoelectronic devices. In this paper, we propose an Affinity Network (AffinityNet) nonlinear equalizer for an OAM-MDM intensity-modulation direct-detection (IM/DD) transmission with four OAM modes. The labeled training and testing signals from the OAM-MDM system can be regarded as "small sample" and "large target", respectively. AffinityNet can be used to build an accurate nonlinear model using "small sample" based on few-shot learning and can predict the stochastic characteristic nonlinearity of OAM-MDM with a high level of generalization. As a result, the AffinityNet nonlinear equalizer can effectively compensate the stochastic nonlinearity in the OAM-MDM system, despite the large difference between the training and testing signals due to the stochastic nonlinear impairment. An experiment was conducted on a 400 Gbit/s transmission with four OAM modes using a pulse amplitude modulation-8 (PAM-8) signal over a 2 km ring-core fiber (RCF). Our experimental results show that the proposed nonlinear equalizer outperformed the conventional Volterra equalizer with improvements in receiver sensitivity of 1.7, 1.8, 3, and 3.3 dB for the four OAM modes at the 15% forward error correction (FEC) threshold, respectively. In addition, the proposed equalizer outperformed a convolutional neural network (CNN) equalizer with improvements in receiver sensitivity of 0.8, 0.5, 0.9, and 1.4 dB for the four OAM modes at the 15% FEC threshold. In the experiment, a complexity reduction of 37% and 83% of the AffinityNet equalizer is taken compared to the conventional Volterra equalizer and CNN equalizer, respectively. The proposed equalizer is a promising candidate for a high-speed OAM-MDM optical fiber communication system.

Novel insights into STAT3 in renal diseases.

Signal transducer and activator of transcription 3 (STAT3) is a cell-signal transcription factor that has attracted considerable attention in recent years. The stimulation of cytokines and growth factors can result in the transcription of a wide range of genes that are crucial for several cellular biological processes involved in pro- and anti-inflammatory responses. STAT3 has attracted considerable interest as a result of a recent upsurge in study because of their role in directing the innate immune response and sustaining inflammatory pathways, which is a key feature in the pathogenesis of many diseases, including renal disorders. Several pathological conditions which may involve STAT3 include diabetic nephropathy, acute kidney injury, lupus nephritis, polycystic kidney disease, and renal cell carcinoma. STAT3 is expressed in various renal tissues under these pathological conditions. To better understand the role of STAT3 in the kidney and provide a theoretical foundation for STAT3-targeted therapy for renal disorders, this review covers the current work on the activities of STAT3 and its mechanisms in the pathophysiological processes of various types of renal diseases.

Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties.

The fat mass and obesity-associated protein (FTO) is an RNA N6-methyladenosine (m6A) demethylase highly expressed in diverse cancers including acute myeloid leukemia (AML). To improve antileukemia drug-like properties, we have designed 44/ZLD115, a flexible alkaline side-chain-substituted benzoic acid FTO inhibitor derived from FB23. A combination of structure-activity relationship analysis and lipophilic efficiency-guided optimization demonstrates that 44/ZLD115 exhibits better drug-likeness than the previously reported FTO inhibitors, FB23 and 13a/Dac85. Then, 44/ZLD115 shows significant antiproliferative activity in leukemic NB4 and MOLM13 cell lines. Moreover, 44/ZLD115 treatment noticeably increases m6A abundance on the AML cell RNA, upregulates RARA gene expression, and downregulates MYC gene expression in MOLM13 cells, which are consistent with FTO gene knockdown. Lastly, 44/ZLD115 exhibits antileukemic activity in xenograft mice without substantial side effects. This FTO inhibitor demonstrates promising properties that can be further developed for antileukemia applications.

[Determination of four aflatoxins in feeds by high throughput automated immunoaffinity magnetic beads purification-ultra performance liquid chromatography].

Aflatoxin (AFT) is an extremely toxic and highly toxic carcinogenic substance. This is particularly problematic due to the risk of aflatoxin contamination in raw feed materials and products during production, transportation, and storage. In this study, immunoaffinity magnetic beads (IMBs) were prepared for the purification of four aflatoxins (aflatoxin B1 (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1) and aflatoxin G2 (AFG2)). The aflatoxin contents were then determined rapidly and accurately using ultra performance liquid chromatography (UPLC). More specifically, the coupling ratio of magnetic beads (MBs) to the aflatoxin monoclonal antibody was initially optimized, wherein an MB volume of 1 mL and an antibody content of 2.0 mg was found to meet the purification requirements of this method. The magnetic properties of the MBs and the IMBs were then investigated using a vibrating sample magnetometer (VSM) at room temperature. As a result, the maximum saturation super magnetizations of the MBs and the IMBs were determined to be 28.61 and 23.22 emu/g, respectively, indicating that the saturation magnetization intensity of the IMBs was reduced by coupling with a non-magnetic antibody. However, the saturation magnetization intensity remained sufficiently high to permit magnetic separation from the solution. In addition, the appearance of the IMBs was examined using a biomicroscope, and it was clear that the magnetic cores were wrapped in agarose gel. Furthermore, the reaction time between the IMBs and the aflatoxins was investigated, and the optimal reaction time for meeting the purification requirements was determined to be 2 min. The stability of the IMBs was then evaluated under refrigerated storage conditions at 4 ℃. It was found that the prepared IMBs maintained a high aflatoxin enrichment capacity for at least eight months. Through the examination of three different extraction solutions, a mixture of acetonitrile and water (70∶30, v/v) was found to be optimal for the extraction of aflatoxins from the feed samples. Moreover, five sample dilutions and purification effects were also examined, and phosphate-buffered saline (containing 0.5% Tween-20) was selected as the preferred sample dilutant. With the optimized conditions, the effectiveness of using IMB for the purification of different feed samples was investigated. The resulting UPLC chromatogram showed no spurious peaks close to the target peaks, demonstrating a good purification performance. Following matrix spiking (5, 20, and 40 µg/kg, calculated based on AFB1) of the four feed samples (i. e., soybean meal, distillers dried grains with solubles, pig feed, and chicken feed), the spiked recoveries of the four aflatoxins ranged from 91.1% to 119.4% with a relative standard deviation (RSD) of <6.9%. In addition, the inter-day precision was 4.5% to 7.5%, and the method exhibited a good reproducibility. Subsequently, the developed method was used to detect AFB1 using reference materials. The test value was 18.6 µg/kg with an accuracy of 110.3%, thereby constituting satisfactory results. Upon testing 21 randomly purchased feed samples using this method, four of these samples contained AFB1, and the test results obtained using the developed method and stable isotope dilution LC-MS/MS were comparable. It was therefore apparent that the IMB purification method combined with UPLC analysis exhibited a good accuracy for aflatoxin determination. Thus, an automatic purification system was established to facilitate the operation and use of IMBs. This system was able to purify 24 samples simultaneously in 30 min. An IMB purification kit for was also designed and produced for aflatoxin detection in feed samples. The kit contained the sample dilutant, IMBs, the washing solution, and the eluent. After extraction of the feed sample, the extraction solution was added to the sample wells provided in the kit, and the purification system automatically completed the steps of aflatoxin enrichment, impurity washing, and elution of the target toxin. It should be noted that the purification process does not require the operator to manually add the solution, thereby simplifying operation. Overall, the purification method established in this study achieved the high-throughput and automatic purification of the four aflatoxins in feed samples.

Identification of key mutations responsible for the enhancement of receptor-binding affinity and immune escape of SARS-CoV-2 Omicron variant.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised concerns worldwide due to its enhanced transmissibility and immune escapability. The first dominant Omicron BA.1 subvariant harbors more than 30 mutations in the spike protein from the prototype virus, of which 15 mutations are located at the receptor binding domain (RBD). These mutations in the RBD region attracted significant attention, which potentially enhance the binding of the receptor human angiotensin-converting enzyme 2 (hACE2) and decrease the potency of neutralizing antibodies/nanobodies. This study applied the molecular dynamics simulations combined with the molecular mechanics-generalized Born surface area (MMGBSA) method, to investigate the molecular mechanism behind the impact of the mutations acquired by Omicron on the binding affinity between RBD and hACE2. Our results indicate that five key mutations, i.e., N440K, T478K, E484A, Q493R, and G496S, contributed significantly to the enhancement of the binding affinity by increasing the electrostatic interactions of the RBD-hACE2 complex. Moreover, fourteen neutralizing antibodies/nanobodies complexed with RBD were used to explore the effects of the mutations in Omicron RBD on their binding affinities. The calculation results indicate that the key mutations E484A and Y505H reduce the binding affinities to RBD for most of the studied neutralizing antibodies/nanobodies, mainly attributed to the elimination of the original favorable gas-phase electrostatic and hydrophobic interactions between them, respectively. Our results provide valuable information for developing effective vaccines and antibody/nanobody drugs.

Design, synthesis, and biological evaluation of novel spirocyclic compounds as potential anti-glioblastoma agents.

Glioblastoma (GBM) is an aggressive brain tumor with extremely limited clinical treatment options. Because of the blood-brain barrier (BBB), it is difficult for anti-GBM drug candidates to enter the brain to exert their therapeutic effects. The spirocyclic skeleton structure exhibits good lipophilicity and permeability, enabling small-molecule compounds to cross the BBB. Herein, we designed and synthesized novel 3-oxetanone-derived spirocyclic compounds containing a spiro[3.4]octane ring and determined their structure-activity relationship for antiproliferation in GBM cells. Among these, the chalcone-spirocycle hybrid 10m/ZS44 exhibited high antiproliferative activity in U251 cells and permeability in vitro. Furthermore, 10m/ZS44 activated the SIRT1/p53-mediated apoptosis pathway to inhibit proliferation in U251 cells, whereas it minimally impaired other cell-death pathways, such as pyroptosis or necroptosis. In a mouse xenograft model, 10m/ZS44 exhibited a substantial inhibitory effect on GBM tumor growth without showing obvious toxicity. Overall, 10m/ZS44 represents a promising spirocyclic compound for the treatment of GBM.

Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition.

EZH2 has been regarded as an efficient target for diffuse large B-cell lymphoma (DLBCL), but the clinical benefits of EZH2 inhibitors (EZH2i) are limited. To date, only EPZ-6438 has been approved by FDA for the treatment of follicular lymphoma and epithelioid sarcoma. We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. In this study we explored the molecular mechanism underlying the primary resistance to EZH2 inhibitors and sought for combination therapy strategy to overcome it. By analyzing EPZ-6438 and HH2853 response profiling, we found that EZH2 inhibition increased intracellular iron through upregulation of transferrin receptor 1 (TfR-1), ultimately triggered resistance to EZH2i in DLBCL cells. We demonstrated that H3K27ac gain by EZH2i enhanced c-Myc transcription, which contributed to TfR-1 overexpression in insensitive U-2932 and WILL-2 cells. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy.

The fecal shield is a double-edged sword for larvae of a leaf beetle.

Larvae of some leaf beetles carry masses of feces covering parts or all of the body, which is called a "fecal shield". In general, the shield is thought to be a defense structure against natural enemies. However, some studies have suggested that defense effectiveness varies depending on the natural enemy. In this study, we used a fecal retention leaf beetle Ophrida xanthospilota (Coleoptera: Chrysomelidae), and 2 local generalist predators (an ant, Camponotus japonicus (Hymenoptera: Formicidae) and a stinkbug, Arma custos [Hemiptera: Pentatomidae]) as a system to test the hypothesis that the fecal shield of O. xanthospilota plays different roles in predation behavior of different predators and can provide multiple chemical communication signals in predator-prey interactions. Prey bioassays showed that the fecal shield of O. xanthospilota larvae repelled the ant C. japonicus while attracting the stinkbug A. custos. The results also strongly demonstrated that hexane extracts of the fecal shield significantly repelled C. japonicus, while dichloromethane (DCM) extracts did not inhibit ant predation. Interestingly, DCM extracts attracted A. custos, but hexane extracts did not. Therefore, we suggest that the fecal shield is a double-edged sword for the larvae of O. xanthospilota. Our results also indicated that the risk-benefit tradeoff of an insect should be estimated at a community level involving multiple enemies (predators and parasites) and herbivores, rather than in a single prey-predator pair.

Photonic-aided W-band dual-vector RF signal generation and detection enabled by bandpass delta-sigma modulation and heterodyne detection.

We propose a photonic-aided dual-vector radio-frequency (RF) signal generation and detection scheme enabled by bandpass delta-sigma modulation and heterodyne detection. With the aid of the bandpass delta-sigma modulation, our proposed scheme is transparent to the modulation format of the dual-vector RF signals and can support the generation, wireless transmission, and detection of both single-carrier (SC) and orthogonal-frequency-division-multiplexing (OFDM) vector RF signals with high-level quadrature-amplitude-modulation (QAM) modulation. With the aid of the heterodyne detection, our proposed scheme can support up to W-band (75-110 GHz) dual-vector RF signal generation and detection. For the validation of our proposed scheme, we experimentally demonstrate the simultaneous generation of a SC-64QAM signal at 94.5 GHz and a SC-128QAM signal at 93.5 GHz and their error-free high-fidelity transmission over a 20-km single-mode fiber 28 (SMF-28) and a 1-m single-input single-output (SISO) wireless link at the W-band. To the best of our knowledge, this is the first time that delta-sigma modulation has been introduced into a W-band photonic-aided fiber-wireless integration system to achieve flexible and high-fidelity dual-vector RF signal generation and detection.

Sciatic hernia led to strangulated ileum and ipsilateral ovary: A case report and review of literature.

Sciatic hernia is one of the rarely pelvic floor hernias. We report a 45-year-old woman who presented with acute crampy pain of hypogastrium which radiated down the back of the left thigh and found a mass in her left buttock area which is about fist size with local pain, so she had to force to bow position when walking. She was also associated with definite gastro-intestinal symptoms. Computed tomography (CT) of the pelvis and abdomen demonstrated the herniation of an ileal loop through the sciatic foramen on the left side. The diagnosis and management of this case are herein described and previous publications on sciatic hernias are reviewed.