Multiplexed bulk and single-cell RNA-seq hybrid enables cost-efficient disease modeling with chimeric organoids.

Disease modeling with isogenic Induced Pluripotent Stem Cell (iPSC)-differentiated organoids serves as a powerful technique for studying disease mechanisms. Multiplexed coculture is crucial to mitigate batch effects when studying the genetic effects of disease-causing variants in differentiated iPSCs or organoids, and demultiplexing at the single-cell level can be conveniently achieved by assessing natural genetic barcodes. Here, to enable cost-efficient time-series experimental designs via multiplexed bulk and single-cell RNA-seq of hybrids, we introduce a computational method in our Vireo Suite, Vireo-bulk, to effectively deconvolve pooled bulk RNA-seq data by genotype reference, and thereby quantify donor abundance over the course of differentiation and identify differentially expressed genes among donors. Furthermore, with multiplexed scRNA-seq and bulk RNA-seq, we demonstrate the usefulness and necessity of a pooled design to reveal donor iPSC line heterogeneity during macrophage cell differentiation and to model rare WT1 mutation-driven kidney disease with chimeric organoids. Our work provides an experimental and analytic pipeline for dissecting disease mechanisms with chimeric organoids.

Receiver in-phase and quadrature skew tolerant baud-rate timing recovery scheme for short-reach coherent optical interconnection.

A baud-rate sampling timing recovery (TR) scheme with receiver IQ skew tolerance is proposed and experimentally demonstrated. The proposed scheme performs independent TR for the in-phase and quadrature (IQ) tributary signals, thereby tracking the sampling phase error while naturally compensating for receiver IQ skew. The robustness of the IQ-independent TR to frequency offset (FO) and phase noise is theoretically analyzed. To address IQ misalignment caused by the IQ-independent TR, the use of pseudo-noise (PN) sequences for IQ frame synchronization is proposed. The proposed scheme achieves accurate timing recovery with hardware-efficient baud-rate sampling in the presence of receiver IQ skew, laying the foundation for stable performance of subsequent baud-rate equalization. The performance of the scheme is validated in a 56 GBaud polarization division multiplexed (PDM) 16QAM coherent experimental system. Experimental results demonstrate that the proposed scheme achieves similar BER performance to the modified Gardner + real-valued multiple-input multiple-output (RVMIMO) (@2 SPS) scheme. Moreover, the proposed scheme exhibits robustness to arbitrary IQ skew compared to the ABSPD + RVMIMO (@1 SPS) scheme.

Multiplication-free and hardware-efficient baud-rate timing error detector for Nyquist and faster than Nyquist optical IM/DD systems.

Clock recovery (CR) algorithms that support higher baud rates and advanced modulation formats are crucial for short-distance optical interconnections, and it is desirable to push CR to operate at baud rate with minimal computing resources and power. In this Letter, we proposed a hardware-efficient and multiplication operation-free baud-rate timing error detector (TED) as a solution to meet these demands. Our approach involves employing both the absolute value of samples and the nonlinear sign operation to emphasize the clock tone, which is deteriorated by severe bandwidth limitation in Nyquist and faster than Nyquist (FTN) systems. Through experimental investigations based on a transceiver system with a 3 dB bandwidth of 30 GHz, the proposed baud-rate TED exhibits excellent performance. The proposed scheme successfully achieves clock synchronization of the received signals with the transmitted signals, including 50 GBaud PAM4/8, 80 GBaud PAM4, and up to 120 GBaud PAM4 FTN signals. To the best of our knowledge, the CR based on the proposed baud-rate TED is the most optimal solution for ultrahigh-speed short-reach IM/DD transmission, comprehensively considering the timing jitter, bit error rate (BER), and implementation complexity.

Effect of Public Fillers on Cement-Stabilized Recycled Mixes of Road Performance: Mechanical Properties, Microstructure, and Durability.

In order to address the challenges of resource utilization posed by construction waste, the substitution of natural aggregate (NA) with public fill (PF) contents was investigated for load reclamation and road grassroots applications. A comprehensive assessment of road performance for the recycled mixture was conducted, focusing on parameters such as unconfined compressive strength, splitting strength, compressive resilience modulus, dry shrinkage, and frost resistance. Additionally, the impact of incorporating PF at various types and replacement ratios on the microstructure of cement-stabilized aggregate (CSA) was analyzed. The results indicated that the unconfined compressive strength of cement-stabilized recycled mixture with varying PF contents meets the base strength requirements for heavy, medium, and light traffic pavement on secondary and sub-secondary roads in China. Notably, the unconfined compressive strength and resilience modulus follow a similar pattern, reaching their peak at a 25% PF content. Microscopic examination reveals that an appropriate PF content leads to the predominant formation of C(N)-A-S-H, hydrotalcite, Ca(OH)2, and CaCO3 as paste reaction products. As the replacement of public fill increases from 0% to 25%, there is a gradual stacking of gel products, which enhances the compactness of the microstructure by cementing together unreacted particles. Consequently, this process reduces dry shrinkage strain and effectively mitigates the formation of reflection cracks. Applying large quantities of public fill to road construction can effectively deal with various waste accumulation problems and produce a novel road material with significant social, economic, and environmental benefits.

Human Leukocyte Antigens and Sulfamethoxazole/Cotrimoxazole-Induced Severe Cutaneous Adverse Reactions: A Systematic Review and Meta-Analysis.

Importance: Sulfamethoxazole (SMX) and cotrimoxazole (CTX), a fixed-dose combination of SMX and trimethoprim in a 5:1 ratio, are antibacterial sulfonamides commonly used for treating various diseases. A substantial prevalence of severe cutaneous adverse reactions (SCARs) following the administration of these drugs has been reported. However, the association between human leukocyte antigen (HLA) genotypes and SMX/CTX-induced SCARs has remained unclear. Objective: To investigate the association between HLA genotypes and SMX/CTX-induced SCARs. Data sources: A comprehensive search was conducted in CENTRAL (Cochrane Library), MEDLINE, and Embase from inception to January 17, 2023. Study Selection: Case-control studies that recruited patients who had experienced SCARs following SMX or CTX were included, and HLA alleles were analyzed. Data Extraction and Synthesis: Two independent authors extracted data on study characteristics and outcome data. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. The Newcastle-Ottawa Scale for case-control studies was used to assess study quality. Odds ratios (ORs) were calculated using a random-effects model for meta-analysis. Main Outcomes and Measures: The prespecified outcome was the OR comparing SMX/CTX-induced SCARs with healthy or SMX/CTX-tolerant controls based on different HLA alleles. Results: Six studies involving 322 patients with SCAR were included, including 236 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis, 86 with drug reaction with eosinophilia and systemic symptoms, 8448 healthy controls, and 229 tolerant controls. Significant associations were found in HLA-A*11:01 (OR, 2.10; 95% CI, 1.11-4.00), HLA-B*13:01 (OR, 5.96; 95% CI, 1.58-22.56), HLA-B*15:02 (OR, 2.23; 95% CI, 1.20-4.14), HLA-B*38:02 (OR, 3.47; 95% CI, 1.42-8.48), and HLA-C*08:01 (OR, 2.63; 95% CI, 1.07-6.44) compared with tolerant controls. In the Stevens-Johnson syndrome/toxic epidermal necrolysis subgroup, significant associations were found in HLA-B*15:02 (OR, 3.01; 95% CI, 1.56-5.80) and HLA-B*38:02 (OR, 5.13; 95% CI, 1.96-13.47). In the drug reaction with eosinophilia and systemic symptoms subgroup, significant associations were found in HLA-A*68:01 (OR, 12.86; 95% CI, 1.09-151.34), HLA-B*13:01 (OR, 23.09; 95% CI, 3.31-161.00), HLA-B*39:01 (OR, 4.56; 95% CI, 1.31-15.82). Conclusions and Relevance: The results of this systematic review and meta-analysis suggest that multiple HLA alleles (HLA-A*11:01, HLA-B*13:01, HLA-B*15:02, HLA-B*38:02, and HLA-C*0801) are associated with SMX/CTX-induced SCARs.

The role of histone H3 leucine 126 in fine-tuning the copper reductase activity of nucleosomes.

The copper reductase activity of histone H3 suggests undiscovered characteristics within the protein. Here, we investigated the function of leucine 126 (H3L126), which occupies an axial position relative to copper binding. Typically found as a methionine or leucine in copper binding proteins, the axial ligand influences the reduction potential of the bound ion, modulating its tendency to accept or yield electrons. We found that mutation of H3L126 to methionine (H3L126M) enhanced the enzymatic activity of native yeast nucleosomes in vitro and increased intracellular levels of Cu1+, leading to improved copper-dependent activities including mitochondrial respiration and growth in oxidative media with low copper. Conversely, H3L126 to histidine (H3L126H) mutation decreased nucleosome's enzymatic activity and adversely affected copper-dependent activities in vivo. Our findings demonstrate that H3L126 fine-tunes the copper reductase activity of nucleosomes and highlight the utility of nucleosome enzymatic activity as a novel paradigm to uncover previously unnoticed features of histones.

Glutamate rescues heat stress-induced apoptosis of Sertoli cells by enhancing the activity of antioxidant enzymes and activating the Trx1-Akt pathway in vitro.

Heat stress reduces the number of Sertoli cells, which is closely related to an imbalanced redox status. Glutamate functions to maintain the equilibrium of redox homeostasis. However, the role of glutamate in heat treated Sertoli cells remains unclear. Herein, Sertoli cells from 3-week-old piglets were treated at 44 °C for 30 min (heat stress). Glutamate levels increased significantly following heat stress treatment, followed by a gradual decrease during recovery, while glutathione (GSH) showed a gradual increase. The addition of exogenous glutamate (700 µM) to Sertoli cells before heat stress significantly reduced the heat stress-induced apoptosis rate, mediated by enhanced levels of antioxidant substances (superoxide dismutase (SOD), total antioxidant capacity (TAC), and GSH) and reduced levels of oxidative substances (reactive oxygen species (ROS) and malondialdehyde (MDA)). Glutamate addition to Sertoli cells before heat stress upregulated the levels of glutamate-cysteine ligase, modifier subunit (Gclm), glutathione synthetase (Gss), thioredoxin (Trx1) and B-cell leukemia/lymphoma 2 (Bcl-2), and the ratio of phosphorylated Akt (protein kinase B)/total Akt. However, it decreased the levels of Bcl2-associated X protein (Bax) and cleaved-caspase 3. Addition of the inhibitor of glutaminase (Gls1), Bptes (Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide, 30 µM)to Sertoli cells before heat stress reversed these effects. These results inferred that glutamate rescued heat stress-induced apoptosis in Sertoli cells by enhancing activity of antioxidant enzymes and activating the Trx1-Akt pathway. Thus, glutamate supplementation might represent a novel strategy to alleviate the negative effect of heat stress.

Comprehensive assessment of copper's effect on marine organisms under ocean acidification and warming in the 21st century.

Copper (Cu) has sparked widespread global concern as one of the most hazardous metals to aquatic animals. Ocean acidification (OA) and warming (OW) are expected to alter copper's bioavailability based on pH and temperature-sensitive effects; research on their effects on copper on marine organisms is still in its infancy. Therefore, under representative concentration pathways (RCP) 2.6, 4.5, and 8.5, we used the multiple linear regression-water quality criteria (MLR-WQC) method to assess the effects of OA and OW on the ecological risk posed by copper in the Ocean of East China (OEC), which includes the Bohai Sea, Yellow Sea, and East China Sea. The results showed that there was a positive correlation between temperature and copper toxicity, while there was a negative correlation between pH and copper toxicity. The short-term water quality criteria (WQC) values were 1.53, 1.41, 1.30 and 1.13 µg·L-1, while the long-term WQC values were 0.58, 0.48, 0.40 and 0.29 µg·L-1 for 2020, 2099-RCP2.6, 2099-RCP4.5 and 2099-RCP8.5, respectively. Cu in the OEC poses a moderate ecological risk. Under the current copper exposure situation, strict intervention (RCP2.6) only increases the ecological risk of copper exposure by 20 %, and no intervention (RCP8.5) will increase the ecological risk of copper exposure by nearly double. The results indicate that intervention on carbon emissions can slow down the rate at which OA and OW worsen the damage copper poses to marine creatures. This study can provide valuable information for a comprehensive understanding of the combined impacts of climate change and copper on marine organisms.

Tuneable Efficient White Emission of Sb3+/Mn2+ Co-Doped Lead-Free Perovskites for Single-Component White Light-Emitting Diodes.

Inorganic lead-free perovskite nanocrystals (NCs) with broadband self-trapped exciton (STEs) emission and low toxicity have shown enormous application prospects in the field of display and lighting. However, white light-emitting diodes (WLEDs) based on a single-component material with high photoluminescence quantum yield (PLQY) remain challenging. Here, we demonstrate a novel codoping strategy by introducing Sb3+/Mn2+ ions to achieve the tuneable dual emission in lead-free perovskite Cs3InCl6 NCs. The PLQY increases to 59.64% after doping with Sb3+. The codoped Cs3InCl6 NCs exhibit efficient white light emission due to the energy transfer channel from STEs to Mn2+ ions with PLQY of 51.38%. Density functional theory (DFT) calculations have been used to verify deeply the effects of Sb3+/Mn2+ doping. WLEDs based on Sb3+/Mn2+-codoped Cs3InCl6 NCs are explored with color rendering index of 85.5 and color coordinate of (0.398, 0.445), which have been successfully applied as photodetector lighting sources. This work provides a new perspective for designing novel lead-free perovskites to achieve single-component WLEDs.

[Characteristics of Microorganisms and Antibiotic Resistance Genes of the Riparian Soil in the Lanzhou Section of the Yellow River].

Riparian soil is a critical area of watersheds. The characteristics of biological contaminants in riparian soil affect the pollution control of the watershed water environment. Thus, the microbial community structure, antibiotic resistance genes (ARGs), and mobile genetic elements (MGEs) in the riparian soil of the Lanzhou section of the Yellow River were investigated by analyzing the characteristics of soil samples collected from farmland, mountains, and industrial land. The results showed that the Proteobacteria, Bacteroidetes, and Actinobacteria were the dominant phyla in the riparian soil of Lanzhou section of the Yellow River. The microbial structure in the riparian soil was significantly correlated with the land use type (P < 0.05). The α diversity index of bacterial communities in land types was in the order of farmland > mountain > industry. Sulfonamide-typed ARGs were the most dominant genes in the soil of the Lanzhou section of the Yellow River Basin, among which the sul1 gene had the highest abundance, 20-36 000 times that of other detected ARGs. Moreover, the total absolute abundance of ARGs in industrial soil was the highest. Principal coordinate analysis (PCoA) displayed that the ARGs characteristics had a significant correlation with land types (P < 0.05), and intl1 and tnpA-04 drove the diffuseness of sulfonamide and tetracycline ARGs, respectively. Redundancy analysis (RDA) demonstrated that the content of inorganic salt ions and total phosphorus in the soil of the riparian zone of the Yellow River Lanzhou section were the main environmental factors, modifying the distribution of the microbial structure. Halobacterota and Acidobacteriota were the main microflora that drove the structural change in ARGs.

Ice shelf basal channel shape determines channelized ice-ocean interactions.

Growing evidence has confirmed the critical role played by basal channels beneath Antarctic ice shelves in both ice shelf stability and freshwater input to the surrounding ocean. Here we show, using a 3D ice shelf-ocean boundary current model, that deeper basal channels can lead to a significant amplification in channelized basal melting, meltwater channeling, and warming and salinization of the channel flow. All of these channelized quantities are also modulated by channel width, with the level of modulation determined by channel height. The explicit quantification of channelized basal melting and the meltwater transport in terms of channel cross-sectional shape is potentially beneficial for the evaluation of ice shelf mass balance and meltwater contribution to the nearshore oceanography. Complicated topographically controlled circulations are revealed to be responsible for the unique thermohaline structure inside deep channels. Our study emphasizes the need for improvement in observations of evolving basal channels and the hydrography inside them, as well as adjacent to the ice front where channelized meltwater emerges.

Searching for Two-Neutrino and Neutrinoless Double Beta Decay of

^{134}Xe is a candidate isotope for neutrinoless double beta decay (0νßß) search. In addition, the two-neutrino case (2νßß) allowed by the standard model of particle physics has not yet been observed. With the 656-kg natural xenon in the fiducial volume of the PandaX-4T detector, which contains 10.4% of ^{134}Xe, and its initial 94.9-day exposure, we have established the most stringent constraints on 2νßß and 0νßß of ^{134}Xe half-lives, with limits of 2.8×10^{22} yr and 3.0×10^{23} yr at 90% confidence level, respectively. The 2νßß (0νßß) limit surpasses the previously reported best result by a factor of 32 (2.7), highlighting the potential of large monolithic natural xenon detectors for double beta decay searches.

FMLens: Towards Better Scaffolding the Process of Fund Manager Selection in Fund Investments.

The fund investment industry heavily relies on the expertise of fund managers, who bear the responsibility of managing portfolios on behalf of clients. With their investment knowledge and professional skills, fund managers gain a competitive advantage over the average investor in the market. Consequently, investors prefer entrusting their investments to fund managers rather than directly investing in funds. For these investors, the primary concern is selecting a suitable fund manager. While previous studies have employed quantitative or qualitative methods to analyze various aspects of fund managers, such as performance metrics, personal characteristics, and performance persistence, they often face challenges when dealing with a large candidate space. Moreover, distinguishing whether a fund manager's performance stems from skill or luck poses a challenge, making it difficult to align with investors' preferences in the selection process. To address these challenges, this study characterizes the requirements of investors in selecting suitable fund managers and proposes an interactive visual analytics system called FMLens. This system streamlines the fund manager selection process, allowing investors to efficiently assess and deconstruct fund managers' investment styles and abilities across multiple dimensions. Additionally, the system empowers investors to scrutinize and compare fund managers' performances. The effectiveness of the approach is demonstrated through two case studies and a qualitative user study. Feedback from domain experts indicates that the system excels in analyzing fund managers from diverse perspectives, enhancing the efficiency of fund manager evaluation and selection.

ZIF-67-Derived Flexible Sulfur Cathode with Improved Redox Kinetics for High-Performance Li-S Batteries.

Lithium-sulfur (Li-S) batteries have received much attention due to their high energy density and low price. In recent years, alleviating the volume expansion and suppressing the shuttle effect during the charge and discharge processes of Li-S batteries have been widely addressed. However, the slow conversion kinetics from polysulfide (LiPSs) to Li2S2/Li2S still limits the application of Li-S batteries. Therefore, we designed a ZIF-67 grown on cellulose (named ZIF-67@CL) as an electrocatalyst to improve the interconversion kinetics from LiPSs to Li2S2/Li2S for Li-S batteries. Based on the results of adsorption experiments of LiPSs, ZIF-67@CL and CL hosts were immersed in Li2S4 solution to adsorb LiPSs, and the UV-Vis test was conducted on the supernatant after adsorption. The results showed that the ZIF-67@CL had a stronger adsorption for LiPSs compared with the cellulose (CL). Furthermore, in the Li2S nucleation tests, the fabricated cells were galvanostatically discharged to 2.06 V at 0.112 mA and then potentiostatically discharged at 2.05 V. Based on the results of Li2S nucleation tests, the catalytic effect of ZIF-67 was further verified. As a result, the sulfur cathode used a ZIF-67 catalyst (named S/ZIF-67@CL) and delivered an initial capacity of 1346 mAh g-1 at a current density of 0.2 C. Even at a high current density of 2 C, it exhibited a high-capacity performance of 1087 mAh g-1 on the first cycle and maintained a capacity output of 462 mAh g-1 after 150 cycles, with a Coulombic efficiency of over 99.82%.

Cost-effectiveness of immune checkpoint inhibitors in treating metastatic urothelial cancer.

Objectives: Immune checkpoint inhibitor (ICI) is an important treatment option for metastatic urothelial carcinoma (mUC) patients. A lot of clinical evidence proved the survival benefits of ICI, but cost-effectiveness of the treatment remains unclear. This study evaluates the cost-effectiveness of the ICIs treatment in different sequences among mUC patients. Methods: We retrospectively analyzed mUC patients who had been treated at our hospital between January 2016 and December 2020. These patients received chemotherapy with or without ICI treatment (Pembrolizumab, Atezolizumab, Nivolumab, Durvalumab, or Avelumab). The patients were divided into three different groups: receiving chemotherapy alone, receiving a combination of first-line ICI and chemotherapy (ICI combination therapy), and receiving chemotherapy as the first-line treatment followed by second-line ICI therapy (Subsequent ICI therapy). The primary endpoint was cost per life day, while lifetime medical costs and overall survival were also evaluated. Results: The 74 enrolled patients had a median age of 67.0 years, with 62.2% being male. Of these patients, 23 had received chemotherapy only, while the remaining patients had received combined therapy with ICI in either first-line or as subsequent agents (37 patients had ever received atezolizumab, 18 pembrolizumab, 1 Durvalumab, 1 Nivolumab, and 1 Avelumab separately.). Fifty-five patients (74.3%, 55/74) received cisplatin amongst all the patients who underwent chemotherapy. Median overall survival was 27.5 months (95% CI, 5.2-49.9) in the first-line ICI combination therapy group, and 8.9 months (95% CI, 7.1-10.8) in the chemotherapy only. Median overall survival for the subsequent ICI therapy group was not reached. The median lifetime cost after metastatic UC diagnosis was USD 31,221. The subsequent ICI therapy group had significantly higher costs when compared with the ICI combination therapy group (155.8 USD per day, [IQR 99.0 to 220.5] v 97.8 USD per day, [IQR 60.8 to 159.19], p = 0.026). Higher insurance reimbursement expenses for the subsequent ICI therapy group were observed when compared with the ICI combination therapy group. Conclusion: Our real-world data suggests that first line use of ICI combined with chemotherapy demonstrates better cost-effectiveness and similar survival outcomes for mUC patients, when compared with subsequent ICI therapy after chemotherapy.

Nanocellulose-Enhanced, Easily Processable Cellulose-Based Flexible Pressure Sensor for Wearable Epidermal Sensing.

Flexible pressure sensors (FPSs) based on biomass materials have gained considerable attention for their potential in wearable electronics, human-machine interaction, and environmental protection. Herein, flexible silver nanowire-dual-cellulose paper (SNdCP) containing common cellulose fibers, cellulose nanofibers (CNFs), and silver nanowires (AgNWs) for FPSs was assembled by a facile papermaking strategy. Compared with bacterial cellulose (BC) and cellulose nanocrystals (CNCs), CNFs possess better dimensions and reinforcement, which enables the composite paper to exhibit better mechanical properties (tensile stress of 164.65 MPa) and electrical conductivity (11600 S·m-1), providing more possibilities for FPSs. Benefiting from these advantages, we construct an easily processable and sensitive human-interactive FPS based on a composite paper with high sensitivity (0.050 kPa-1), fast response/recovery time (158/95 ms), and exceptional stability (>1000 bending cycles), capable of responding to finger motions, voice recognition, and human pulses; through further employment as the array unit and a control circuit, the observed highly adaptive mechano-electric transformability and functions are well maintained. Overall, a facile and versatile strategy with the potential to provide clues for the fabrication of cellulose-based FPSs with outstanding performance was introduced.

The immune landscape and prognostic analysis of CXCL8 immune-related genes in cervical squamous cell carcinoma.

Cervical squamous cell carcinoma (CESC), one of the most common malignancies in women, imposes a significant burden on women's health worldwide. Despite extensive research, the molecular and pathogenic mechanisms of cervical squamous cell carcinoma and CESC remain unclear. This study aimed to explore the immune-related genes, immune microenvironment infiltration, and prognosis of CESC, providing a theoretical basis for guiding clinical treatment. Initially, by mining four gene sets and immune-related gene sets from public databases, 14 immune-related genes associated with CESC were identified. Through univariate and multivariate COX regression analyses, as well as lasso regression analysis, four CESC-independent prognostic genes were identified, and a prognostic model was constructed, dividing them into high and low-risk groups. The correlation between these genes and immune cells and immune functions were explored through ssGSEA enrichment analysis, revealing a close association between the high-risk group and processes such as angiogenesis and epithelial-mesenchymal transition. Furthermore, using public databases and qRT-PCR experiments, significant differences in CXCL8 expression between normal cervical cells and cervical cancer cells were discovered. Subsequently, a CXCL8 knockdown plasmid was constructed, and the efficiency of CXCL8 knockdown was validated in two CESC cell lines, MEG-01 and HCE-1. Through CCK-8, scratch, and Transwell assays, it was confirmed that CXCL8 knockdown could inhibit the proliferation, invasion, and migration abilities of CESC cells. Targeting CXCL8 holds promise for personalized therapy for CESC, providing a strong theoretical basis for achieving clinical translation.

Cucurbitacin B induces ferroptosis in oral leukoplakia via the SLC7A11/mitochondrial oxidative stress pathway.

BACKGROUND: Oral leukoplakia (OLK), characterized by abnormal epithelial hyperplasia, is the most common precancerous oral mucosa lesion and is closely related to oxidative stress. Cucurbitacin B (CuB), a tetracyclic triterpenoid molecule derived from plants, has shown promising anti-proliferative and antioxidant effects in preclinical studies. However, whether CuB can play an antiproliferative role in OLK by regulating oxidative stress remains elusive. PURPOSE: To investigate the role of CuB in inhibiting the malignant progression of oral leukoplakia and to further explore its underlying mechanisms of action. METHODS: In vitro, the effect of CuB on the proliferation, migration, apoptosis, and cell cycle of OLK cells DOK was detected. The core genes and key pathways of OLK and CuB were analyzed in the transcriptome database, by using immunofluorescence, qRT-PCR, and Western blot to evaluate the expression levels of the ferroptosis markers ROS, GSH, MDA, Fe2+, and marker genes SLC7A11, GPX4, and FTH1. Immunohistochemistry of human tissue was performed to investigate the expression of the SLC7A11. In vivo, the model of OLK was established in C57BL/6 mice and the biosafety of CuB treatment for OLK was further evaluated. RESULTS: CuB substantially suppressed the proliferation of DOK cells. Bioinformatics analysis showed that the core targets of OLK crossing with CuB include SLC7A11 and that the essential pathways involve ROS and ferroptosis. In vitro experiments indicated that CuB might promote ferroptosis by down-regulating the expression of SLC7A11. We observed a gradual increase in SLC7A11 expression levels during the progression from normal oral mucosa to oral leukoplakia with varying degrees of epithelial dysplasia. In vivo experiments demonstrated that CuB inhibited the malignant progression of OLK by promoting ferroptosis in OLK mice and exhibited a certain level of biosafety. CONCLUSION: This study demonstrated for the first time that CuB could effectively inhibit the malignant progression of OLK by inducing ferroptosis via activating the SLC7A11/ mitochondrial oxidative stress pathway. These findings indicate that CuB could serve as the lead compound for the future development of anti-oral leukoplakia drugs.

Polymers from Plant Oils Linked by Siloxane Bonds for Programmed Depolymerization.

The increased production of plastics is leading to the accumulation of plastic waste and depletion of limited fossil fuel resources. In this context, we report a strategy to create polymers that can undergo controlled depolymerization by linking renewable feedstocks with siloxane bonds. α,ω-Diesters and α,ω-diols containing siloxane bonds were synthesized from an alkenoic ester derived from castor oil and then polymerized with varied monomers, including related biobased monomers. In addition, cyclic monomers derived from this alkenoic ester and hydrosiloxanes were prepared and cyclized to form a 26-membered macrolactone containing a siloxane unit. Sequential ring-opening polymerization of this macrolactone and lactide afforded an ABA triblock copolymer. This set of polymers containing siloxanes underwent programmed depolymerization into monomers in protic solvents or with hexamethyldisiloxane and an acid catalyst. Monomers afforded by the depolymerization of polyesters containing siloxane linkages were repolymerized to demonstrate circularity in select polymers. Evaluation of the environmental stability of these polymers toward enzymatic degradation showed that they undergo enzymatic hydrolysis by a fungal cutinase from Fusarium solani. Evaluation of soil microbial metabolism of monomers selectively labeled with 13C revealed differential metabolism of the main chain and side chain organic groups by soil microbes.

Mediator kinase inhibition reverses castration resistance of advanced prostate cancer.

Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling, but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppressed the growth of CRPC xenografts but also induced tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplified and modulated the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affected stromal gene expression, indicating that Mediator kinase activity in CRPC molded the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulated the MYC pathway, and Mediator kinase inhibition suppressed a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors showed efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlated with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediated androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.