Chlorinated Oligomers with Regulate Planarity Achieving Superior Photovoltaic Performance.

Chlorine substitution, as an effective and low-cost modification strategy, has been applied in the design of donor and acceptor structures in organic solar cells. We synthesized a series of chlorinated dimerized acceptors to investigate the effect of chlorine numbers and locations on the photovoltaic properties. The results show that the planarity and morphology of DYV-γ-2Cl are greatly improved due to the appropriate numbers and positions of the substituted chlorine atoms. Therefore, the device based on PM6:DYV-γ-2Cl achieves a superior power conversion efficiency (PCE) of 15.54% among the three oligomeric acceptors with optimized molecular planarity and film morphology. This work demonstrated the positive effect of suitable numbers and the substitution positions of chlorines on the molecular arrangement and photovoltaic properties of the corresponding dimerized acceptors.

Turning Non-Emissive Schiff Bases Into Aggregate Emitters.

Schiff bases are a crucial component in various functional materials but often exhibit non-emissive behavior which significantly limits their potential applications as luminescent materials. However, traditional approaches to convert them into aggregate emitters often require intricate molecular design, tedious synthesis, and significant time and resource consumption. Herein, we present a cocrystallization-induced emission strategy that can transform non-emissive (hetero)aryl-substituted Schiff bases into green-yellow to yellow aggregate emitters via even simple grinding of a mixture of Schiff bases and 1,2,4,5-tetracyanobenzene (TCB) mixtures. The combined experimental and theoretical analysis revealed that the cocrystallization inhibits the C=N isomerization and promotes face-to-face π-π interaction, which restricts access to both the dark state and canonical intersection to ultimately induce emission. Furthermore, the induced emission enables the observation of solid-state molecular diffusion through fluorescence signals, advancing white light emission diodes, and notably, solution-processed organic light-emitting diodes based on cocrystal for the first time. This study not only highlights the potential of developing new C=N structural motifs for AIEgens but also could boost advancements in related structure motifs like C=C and N=N.

Mammalian enabled protein enhances tamoxifen sensitivity of the hormone receptor-positive breast cancer patients by suppressing the AKT signaling pathway.

BACKGROUND: Mammalian enabled (MENA) protein is a member of the enabled/vasodilator stimulated phosphoprotein (Ena/VASP) protein family, which regulates cytoplasmic actin network assembly. It plays a significant role in breast cancer invasion, migration, and resistance against targeted therapy and chemotherapy. However, its role in the efficacy of endocrine therapy for the hormone receptor-positive (HR+) breast cancer patients is not known. This study investigated the role of MENA in the resistance against tamoxifen therapy in patients with HR+ breast cancer and the underlying mechanisms. METHODS: MENA expression levels in the clinical HR+ breast cancer samples (n = 119) were estimated using immunohistochemistry (IHC) to determine its association with the clinicopathological features, tamoxifen resistance, and survival outcomes. Western blotting (WB) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis was performed to estimate the MENA protein and mRNA levels in the tamoxifen-sensitive and -resistant HR+ breast cancer cell lines. Furthermore, CCK8, colony formation, and the transwell invasion and migration assays were used to analyze the effects of MENA knockdown on the biological behavior and tamoxifen sensitivity of the HR+ breast cancer cell lines. Xenograft tumor experiments were performed in the nude mice to determine the tumor growth rates and tamoxifen sensitivity of the control and MENA knockdown HR+ breast cancer cells in the presence and absence of tamoxifen treatment. Furthermore, we estimated the growth rates of organoids derived from the HR+ breast cancer patients (n = 10) with high and low MENA expression levels when treated with tamoxifen. RESULTS: HR+ breast cancer patients with low MENA expression demonstrated tamoxifen resistance and poorer prognosis compared to those with high MENA expression. Univariate and multivariate Cox regression analysis demonstrated that MENA expression was an independent predictor of tamoxifen resistance in patients with HR+ breast cancer. MENA knockdown HR+ breast cancer cells showed significantly reduced tamoxifen sensitivity in the in vitro experiments and the in vivo xenograft tumor mouse model compared with the corresponding controls. Furthermore, MENA knockdown increased the in vitro invasion and migration of the HR+ breast cancer cells. HR+ breast cancer organoids with low MENA expression demonstrated reduced tamoxifen sensitivity than those with higher MENA expression. Mechanistically, P-AKT levels were significantly upregulated in the MENA-knockdown HR + breast cancer cells treated with or without 4-OHT compared with the corresponding controls. CONCLUSIONS: This study demonstrated that downregulation of MENA promoted tamoxifen resistance in the HR+ breast cancer tissues and cells by enhancing the AKT signaling pathway. Therefore, MENA is a promising prediction biomarker for determining tamoxifen sensitivity in patients with HR+ breast cancer.

Switchable Power Generation in Triboelectric Nanogenerator Toward Chip-Less Wearable Power Module Applications.

A conceptual shift toward next-generation wearable electronics is driving research into self-powered electronics technologies that can be independently operated without plugging into the grid for external power feeding. Triboelectric nanogenerators (TENGs) are emerging as a key component of self-powered electronics, but a power type mismatch between supply and demand limits their direct implementation into wearable self-powered electronics. Here, a TENG with switchable power mode capability is reported where the charge flow direction is modulated over the course of slow and random mechanical stimuli, with exceptional rectification capabilities as high as ≈133, stable outputs over the cycles, and design flexibility in different platforms. Importantly, the remarkable switchable power generation with fabric counter materials illuminates a new path for the smooth integration of flexible TENGs into wearable self-powered electronics.

Dynamic Transition between Monomer and Excimer Phosphorescence in Organic Near-Infrared Phosphorescent Crystals.

Achieving efficient near-infrared room-temperature phosphorescence of purely organic phosphors remains scarce and challenging due to strong nonradiative decay. Additionally, the investigation of triplet excimer phosphorescence is rarely reported, despite the fact that excimer, a special emitter commonly formed in crystals with strong π-π interactions, can efficiently change the fluorescent properties of compounds. Herein, a series of dithienopyrrole derivatives with low triplet energy levels and stable triplet states, exhibiting persistent near-infrared room-temperature phosphorescence, is developed. Via the modification of halogen atoms, the crystals display tunable emissions of monomers from 645 to 702 nm, with a maximum lifetime of 3.68 ms under ambient conditions. Notably, excimer phosphorescence can be switched on at low temperatures, enabled by noncovalent interactions rigidifying the matrix and stabilizing triplet excimer. Unprecedentedly, the dynamic transition process is captured between the monomer and excimer phosphorescence with temperature variations, revealing that the unstable triplet excimers in crystals with a tendency to dissociate can result in the effective quench of room-temperature phosphorescence. Excited state transitions across varying environments are elucidated, interpreting the structural dynamics of the triplet excimer and demonstrating strategies for devising novel near-infrared phosphors.

The predictive value of peripheral blood CD4 cells ATP concentration for immune-related adverse events in advanced non-small cell lung cancer patients.

OBJECTIVE: Lung cancer with the highest incidence and mortality in the world. Immune checkpoint inhibitors (ICIs), can bring long-term survival benefits to patients, but also can bring immune-related adverse events (irAEs) in some patients during therapy. Therefore, the aim of this study was to investigate the predictive effect of peripheral blood WBC, NLR, sATPCD4 and nATPCD4 on irAEs in advanced non-small cell lung cancer (NSCLC). METHODS: Clinical data of 112 patients with advanced NSCLC who were treated with PD -1/PD -L1 inhibitor in the Fifth Affiliated Hospital of Guangzhou Medical University from December 15, 2019 to April 30, 2023 were retrospectively analyzed. These patients were divided into the irAEs group (n = 27) and non-irAEs group (n = 85). The clinical data of the two groups were compared. Receiver operating characteristic (ROC) curves were drawn to determine the threshold value of baseline peripheral blood parameters to predict the occurrence of irAEs. Multivariate logistic regression analysis was used to explore the relationship between peripheral blood markers and the incidence of irAEs. RESULTS: The patient characteristics have no significant difference between irAEs and non-irAEs group. But the baseline peripheral blood WBC, sATPCD4 and nATPCD4 of patients in the irAEs group were higher than those in the non-irAEs group (p < 0.05), and the NLR in irAEs group was similar to in the non-irAEs group (p = 0.639).Univariate analysis showed that high WBC, sATPCD4 and nATPCD4 may the risk factors for the occurrence of irAEs (p < 0.05). Multivariate logistic regression analysis showed that high sATPCD4 and nATPCD4 were independent risk factors for the occurrence of irAEs (p < 0.05). The best critical values of WBC, sATPCD4 and nATPCD4 before treatment for predicting the occurrence of irAEs were 8.165 × 109cells/L (AUC = 0.705) ,484.5 ng/mL (AUC = 0.777), and 156 ng/mL (AUC = 0.840), respectively. CONCLUSIONS: sATPCD4 and nATPCD4 were independent risk factors for the occurrence of irAEs in advanced NSCLC patients. This discovery provides a new method to predict the occurrence of irAEs in patients. Based on the prediction results, corresponding treatment measures can be taken to reduce the incidence of adverse events.

HSP90 C-terminal domain inhibition promotes VDAC1 oligomerization via decreasing K274 mono-ubiquitination in Hepatocellular Carcinoma.

Voltage-dependent anion-selective channel protein 1 (VDAC1) is the most abundant protein in the mitochondrial outer membrane and plays a crucial role in the control of hepatocellular carcinoma (HCC) progress. Our previous research found that cytosolic molecular chaperone heat shock protein 90 (Hsp90) interacted with VDAC1, but the effect of the C-terminal and N-terminal domains of Hsp90 on the formation of VDAC1 oligomers is unclear. In this study, we focused on the effect of the C-terminal domain of Hsp90 on VDAC1 oligomerization, ubiquitination, and VDAC1 channel activity. We found that Hsp90 C-terminal domain inhibitor Novobiocin promoted VDAC1 oligomerization, release of cytochrome c, and activated mitochondrial apoptosis pathway. Atomic coarse particle modeling simulation revealed C-terminal domain of Hsp90α stabilized VDAC1 monomers. The purified VDAC1 was reconstituted into a planar lipid bilayer, and electrophysiology experiments of patch clamp showed that the Hsp90 C-terminal inhibitor Novobiocin increased VDAC1 channel conductance via promoting VDAC1 oligomerization. The mitochondrial ubiquitination proteomics results showed that VDAC1 K274 mono-ubiquitination was significantly decreased upon Novobiocin treatment. Site-directed mutation of VDAC1 (K274R) weakened Hsp90α-VDAC1 interaction and increased VDAC1 oligomerization. Taken together, our results reveal that Hsp90 C-terminal domain inhibition promotes VDAC1 oligomerization and VDAC1 channel conductance by decreasing VDAC1 K274 mono- ubiquitination, which provides a new perspective for mitochondria-targeted therapy of HCC.

Contrast-enhanced, single-shot LED array microscopy based on Fourier ptychographic algorithm and deep learning.

LED array microscopes have the advantages of miniaturisation and low cost. It has been demonstrated that LED array microscopes outperform Köhler illumination microscopes in some applications. A LED array allows for a large numerical aperture of illumination. The larger numerical aperture of illumination brings the higher spatial resolution, but the lower image contrast as well. Therefore, there is a tradeoff between resolution and contrast for LED array microscopes. The Fourier ptychographic algorithm can overcome this tradeoff by increasing image contrast without sacrificing spatial resolution. However, the Fourier ptychographic algorithm requires acquisition of multiple images, which is time-consuming and results in live sample imaging challenging. To solve this problem, we develop contrast-enhanced, single-shot LED array microscopy based on the Fourier ptychographic algorithm and deep learning. The sample to be imaged is under illumination by all LEDs of the array simultaneously. The image captured is fed to several trained convolutional neural networks to generate the same number of images that are required by the Fourier ptychographic algorithm. We experimentally present that the image contrast of the final reconstruction is remarkably improved in comparison with the image captured. The proposed method can also produce chromatic-aberration-free results, even when an objective without aberration correction is used. We believe the method might provide live sample imaging with a low-cost approach.

Knowledge transfer between physicians from different geographical regions in China's online health communities.

Online Health Communities (OHCs) are a type of self-organizing platform that provide users with access to social support, information, and knowledge transfer opportunities. The medical expertise of registered physicians in OHCs plays a crucial role in maintaining the quality of online medical services. However, few studies have examined the effectiveness of OHCs in transferring knowledge between physicians and most do not distinguish between the explicit and tacit knowledge transferred between physicians. This study aims to demonstrate the cross-regional transfer characteristics of medical knowledge, especially tacit and explicit knowledge. Based on data collected from 4716 registered physicians on Lilac Garden (DXY.cn), a leading Chinese OHC, Exponential Random Graph Models are used to (1) examine the overall network and two subnets of tacit and explicit knowledge (i.e., clinical skills and medical information), and (2) identify patterns in the knowledge transferred between physicians, based on regional variations. Analysis of the network shows that physicians located in economically developed regions or regions with sufficient workforces are more likely to transfer medical knowledge to those from poorer regions. Analysis of the subnets demonstrate that only Gross Domestic Product (GDP) flows are supported in the clinical skill network since discussions around tacit knowledge are a direct manifestation of physicians' professional abilities. These findings extend current understanding about social value creation in OHCs by examining the medical knowledge flows generated by physicians between regions with different health resources. Moreover, this study demonstrates the cross-regional transfer characteristics of explicit and tacit knowledge to complement the literature on the effectiveness of OHCs to transfer different types of knowledge.

Integrative analysis reveals marker genes for intestinal mucosa barrier repairing in clinical patients.

This study aims to identify biomarkers of intestinal repair and provide potential therapeutic clues for improving functional recovery and prognostic performance after intestinal inflammation or injury. Here, we conducted a large-scale screening of multiple transcriptomic and scRNA-seq datasets of patients with inflammatory bowel disease (IBD), and identified 10 marker genes that potentially contribute to intestinal barrier repairing: AQP8, SULT1A1, HSD17B2, PADI2, SLC26A2, SELENBP1, FAM162A, TNNC2, ACADS, and TST. Analysis of a published scRNA-seq dataset revealed that expression of these healing markers were specific to absorptive cell types in intestinal epithelium. Furthermore, we conducted a clinical study where 11 patients underwent ileum resection demonstrating that upregulation of post-operative AQP8 and SULT1A1 expression were associated with improved recovery of bowel functions after surgery-induced intestinal injury, making them confident biomarkers of intestinal healing as well as potential prognostic markers and therapeutic targets for patients with impaired intestinal barrier functions.

Saikosaponin A and D attenuate skeletal muscle atrophy in chronic kidney disease by reducing oxidative stress through activation of PI3K/AKT/Nrf2 pathway.

BACKGROUND: Skeletal muscle atrophy in chronic kidney disease (CKD) leads to a decline in quality of life and increased risk of morbidity and mortality. We have obtained evidence that oxidative stress is essential in the progression of CKD-related muscle atrophy. Whether Saikosaponin A and D, two emerging antioxidants extracted from Bupleurum chinense DC, alleviate muscle atrophy remains to be further studied. The purpose of this study was to investigate the effects and mechanisms of these two components on CKD complicated with muscle atrophy. METHODS: In this research, muscle dystrophy model was established using 5/6 nephrectomized mice in vivo and in vitro with Dexamethasone (Dex)-managed C2C12 myotubes. RESULTS: The results of RNA-sequencing showed that exposure to Dex affected the antioxidant activity, catalytic activity and enzyme regulator activity of C2C12 cells. According to KEGG analysis, the largest numbers of differentially expressed genes detected were enriched in the PI3K/AKT pathway. In vivo, Saikosaponin A and D remain renal function, cross-section size, fiber-type composition and anti-inflammatory ability. These two components suppressed the expression of MuRF-1 and enhanced the expression of MyoD and Dystrophin. In addition, Saikosaponin A and D maintained redox balance by increasing the activities of antioxidant enzymes while inhibiting the excessive accumulation of reactive oxygen species. Furthermore, Saikosaponin A and D stimulated PI3K/AKT and its downstream Nrf2 pathway in CKD mice. The effects of Saikosaponin A and D on increasing the inner diameter of C2C12 myotube, reducing oxidative stress and enhancing expression of p-AKT, p-mTOR, p70S6K, Nrf2 and HO-1 proteins were observed in vitro. Importantly, we verified that these protective effects could be significantly reversed by inhibiting PI3K and knocking out Nrf2. CONCLUSIONS: In summary, Saikosaponin A and D improve CKD-induced muscle atrophy by reducing oxidative stress through the PI3K/AKT/Nrf2 pathway.

Fault Diagnosis Method for Imbalanced Data Based on Multi-Signal Fusion and Improved Deep Convolution Generative Adversarial Network.

The realization of accurate fault diagnosis is crucial to ensure the normal operation of machines. At present, an intelligent fault diagnosis method based on deep learning has been widely applied in mechanical areas due to its strong ability of feature extraction and accurate identification. However, it often depends on enough training samples. Generally, the model performance depends on sufficient training samples. However, the fault data are always insufficient in practical engineering as the mechanical equipment often works under normal conditions, resulting in imbalanced data. Deep learning-based models trained directly with the imbalanced data will greatly reduce the diagnosis accuracy. In this paper, a diagnosis method is proposed to address the imbalanced data problem and enhance the diagnosis accuracy. Firstly, signals from multiple sensors are processed by the wavelet transform to enhance data features, which are then squeezed and fused through pooling and splicing operations. Subsequently, improved adversarial networks are constructed to generate new samples for data augmentation. Finally, an improved residual network is constructed by introducing the convolutional block attention module for enhancing the diagnosis performance. The experiments containing two different types of bearing datasets are adopted to validate the effectiveness and superiority of the proposed method in single-class and multi-class data imbalance cases. The results show that the proposed method can generate high-quality synthetic samples and improve the diagnosis accuracy presenting great potential in imbalanced fault diagnosis.

Dysregulation of Grainyhead-like 3 expression causes widespread developmental defects.

BACKGROUND: The gene encoding the transcription factor, Grainyhead-like 3 (Grhl3), plays critical roles in mammalian development and homeostasis. Grhl3-null embryos exhibit thoraco-lumbo-sacral spina bifida and soft-tissue syndactyly. Additional studies reveal that these embryos also exhibit an epidermal proliferation/differentiation imbalance. This manifests as skin barrier defects resulting in peri-natal lethality and defective wound repair. Despite these extensive analyses of Grhl3 loss-of-function models, the consequences of gain-of-function of this gene have been difficult to achieve. RESULTS: In this study, we generated a novel mouse model that expresses Grhl3 from a transgene integrated in the Rosa26 locus on an endogenous Grhl3-null background. Expression of the transgene rescues both the neurulation and skin barrier defects of the knockout mice, allowing survival into adulthood. Despite this, the mice are not normal, exhibiting a range of phenotypes attributable to dysregulated Grhl3 expression. In mice homozygous for the transgene, we observe a severe Shaker-Waltzer phenotype associated with hearing impairment. Micro-CT scanning of the inner ear revealed profound structural alterations underlying these phenotypes. In addition, these mice exhibit other developmental anomalies including hair loss, digit defects, and epidermal dysmorphogenesis. CONCLUSION: Taken together, these findings indicate that diverse developmental processes display low tolerance to dysregulation of Grhl3.

Inhibition of retinoic acid signaling impairs cranial and spinal neural tube closure in mice lacking the Grainyhead-like 3 transcription factor.

Neural tube closure is a dynamic morphogenic event in early embryonic development. Perturbations of this process through either environmental or genetic factors induce the severe congenital malformations known collectively as neural tube defects (NTDs). Deficiencies in maternal folate intake have long been associated with NTDs, as have mutations in critical neurulation genes that include the Grainyhead-like 3 (Grhl3) gene. Mice lacking this gene exhibit fully penetrant thoraco-lumbo-sacral spina bifida and a low incidence of exencephaly. Previous studies have shown that exposure of pregnant mice carrying hypomorphic Grhl3 alleles to exogenous retinoic acid (RA) increases the incidence and severity of NTDs in their offspring. Here, we demonstrate that inhibition of RA signaling using a high affinity pan-RA receptor antagonist administered to pregnant mice at E7.5 induces fully penetrant exencephaly and more severe spina bifida in Grhl3-null mice. Later administration, although prior to neural tube closure has no effect. Similarly, blockade of RA in the context of reduced expression of Grhl2, a related gene known to induce NTDs, has no effect. Taken together, these findings provide new insights into the complexities of the interplay between RA signaling and Grhl3-induced neurulation.

Nanophotonic control of thermal emission under extreme temperatures in air.

Nanophotonic materials offer spectral and directional control over thermal emission, but in high-temperature oxidizing environments, their stability remains low. This limits their applications in technologies such as solid-state energy conversion and thermal barrier coatings. Here we show an epitaxial heterostructure of perovskite BaZr0.5Hf0.5O3 (BZHO) and rocksalt MgO that is stable up to 1,100 °C in air. The heterostructure exhibits coherent atomic registry and clearly separated refractive-index-mismatched layers after prolonged exposure to this extreme environment. The immiscibility of the two materials is corroborated by the high formation energy of substitutional defects from density functional theory calculations. The epitaxy of immiscible refractory oxides is, therefore, an effective method to avoid prevalent thermal instabilities in nanophotonic materials, such as grain-growth degradation, interlayer mixing and oxidation. As a functional example, a BZHO/MgO photonic crystal is implemented as a filter to suppress long-wavelength thermal emission from the leading bulk selective emitter and effectively raise its cutoff energy by 20%, which can produce a corresponding gain in the efficiency of mobile thermophotovoltaic systems. Beyond BZHO/MgO, computational screening shows that hundreds of potential cubic oxide pairs fit the design principles of immiscible refractory photonics. Extending the concept to other material systems could enable further breakthroughs in a wide range of photonic and energy conversion applications.

Hsp90 Inhibitor STA9090 induced VPS35 related extracellular vesicle release and metastasis in hepatocellular carcinoma.

Heat shock protein 90 (Hsp90) has been an important therapeutic target for cancer therapy for decades. Unexpectedly, the monotherapy of N-terminal Hsp90 inhibitor STA9090 related clinical trials halted in phase III, and metastases were reported in animal models with the treatment of N-terminal Hsp90 inhibitors. Vacuolar protein sorting-associated protein 35 (VPS35) plays a vital role in endosome-derived EV (extracellular vesicle) traffic in neurodegeneration diseases, but no vps35 related EV were reported in tumors till now. Since tumor derived EVs contributes to metastasis and VPS35 is recently found to be involved in the invasion and metastasis of hepatocellular carcinoma (HCC), whether N-terminal Hsp90 inhibitor STA9090 induced EVs generation and the role of VPS35 in it were explored in this study. We found that N-terminal Hsp90 inhibitor STA9090 upregulated Bclaf1 and VPS35 levels, increased the secretion of EVs, and STA9090-induced-EVs promoted the invasion of HepG2 cells. As the clinical data suggested that the increased Bclaf1 and VPS35 levels correlated with increased metastasis and poorer prognosis in HCC, we focused on the Bclaf1-VPS35-EVs axis to further explore the mechanism of VPS35-related metastasis. The results demonstrated that Bclaf1 facilitated the transcription of VPS35 via bZIP domain, and knockdown of Bclaf1 or VPS35 alleviated pro-metastatic capability of STA9090-induced-EVs. All the results revealed the role of Bclaf1-VPS35-EVs axis on metastasis of HCC, and VPS35 knockdown decreased Hsp90 Inhibitor STA9090 induced extracellular vesicle release and metastasis, which provided a new combination therapeutic strategy to inhibit the metastasis of HCC caused by N-terminal Hsp90 inhibitor induced extracellular vesicles.

Intrathecal Dexmedetomidine Combined With Ropivacaine in Cesarean Section: A Prospective Randomized Double-Blind Controlled Study.

Objective: This study aimed to find the best dose of dexmedetomidine in spinal anesthesia for cesarean section. Methods: 120 American Society of Anesthesiologists (ASA) Class I and II parturients undergoing elective cesarean delivery under spinal anesthesia were randomly allocated into four groups treated with intrathecal ropivacaine (12 mg) alone (Group R) or in combination with dexmedetomidine 5 µg (Group RD1), 7.5 µg (Group RD2) and 10 µg (Group RD3). Characteristics of spinal anesthesia, hemodynamic changes, adverse effects, stress reactions and neonatal outcomes were recorded in the four groups. Results: Patients in Group RD1, RD2, and RD3 had significantly longer sustained sensory and motor block time than patients in Group R. All four groups had comparable onset times of sensory and motor block. The time for the level of sensory block to lower to S1 was longer in Group RD1 (411.07 ± 106.66 min), Group RD2 (397.03 ± 125.39 min) and Group RD3 (468.63 ± 116.43 min) than in Group R (273.60 ± 88.34 min) (p < 0.001). The time to recover from motor block to a Bromage score of IV was longer in Group RD1 (353.60.07 ± 137.28 min), Group RD2 (350.57 ± 118.01 min) and Group RD3 (404.67 ± 112.83 min) than in Group R (232.70 ± 93.29) (p < 0.01). The incidence of chills was significantly lower in the Group RD1, RD2, and RD3 than in the Group R (p < 0.001). There was no significant difference in the incidence of adverse effects such as hypotension, bradycardia, nausea, vomiting, hypoxemia and pruritus in the four groups (p > 0.05). There was no statistically significant visceral traction response or fentanyl use in the four groups (p > 0.05). Phenylephrine dosing was significantly higher in Group RD2 and RD3 than in Group R (p < 0.05), and there was no significant difference in phenylephrine dosing between Group RD1 and Group R (p > 0.05). There were no statistical differences in postnatal Apgar scores (1 min, 5 min after birth) (p > 0.05). The postoperative concentrations of ß-endorphin (ß-EP), cortisol (Cor) and tumor necrosis factor-α (TNF-α) in the Group RD1, RD2, and RD3 were lower than that in Group R (p < 0.05). Conclusion: Intrathecal 5µg of dexmedetomidine as an adjuvant to ropivacaine relieved intraoperative chills, did not increase intraoperative and postoperative adverse effects, did not increase the amount of intraoperative vasoconstrictor used, and reduced intraoperative stress reactions as well as prolonged the duration of maternal sensory and motor block, so this dose is appropriate for cesarean section. Clinical Trial Registration: [www.chictr.org.cn/], identifier [ChiCTR2200056052].

An Integrated Transcriptomics and Lipidomics Analysis Reveals That Ergosterol Is Required for Host Defense Against Bacterial Infection in Drosophila.

Animals adjust their lipid metabolism states in response to pathogens infection. However, the underlying molecular mechanisms for how lipid metabolism responds to infection remain to be elusive. In this study, we assessed the temporal changes of lipid metabolism profiles during infection by an integrated transcriptomics and lipidomics analysis. Ergosterol is identified to be required for proper host defense to pathogens. Notably, ergosterol level is increased in the hemolymph upon bacterial infection. We show that the increase of ergosterol level by food supplement or genetic depletion of Acsl, a long-chain fatty acid-CoA synthetase, promotes host survival against bacterial challenges. Together, our results suggest a critical role of lipid metabolism adaption in the process of host defense against invading pathogens.

Cryo-shift: reducing domain shift in cryo-electron subtomograms with unsupervised domain adaptation and randomization.

MOTIVATION: Cryo-Electron Tomography (cryo-ET) is a 3D imaging technology that enables the visualization of subcellular structures in situ at near-atomic resolution. Cellular cryo-ET images help in resolving the structures of macromolecules and determining their spatial relationship in a single cell, which has broad significance in cell and structural biology. Subtomogram classification and recognition constitute a primary step in the systematic recovery of these macromolecular structures. Supervised deep learning methods have been proven to be highly accurate and efficient for subtomogram classification, but suffer from limited applicability due to scarcity of annotated data. While generating simulated data for training supervised models is a potential solution, a sizeable difference in the image intensity distribution in generated data as compared with real experimental data will cause the trained models to perform poorly in predicting classes on real subtomograms. RESULTS: In this work, we present Cryo-Shift, a fully unsupervised domain adaptation and randomization framework for deep learning-based cross-domain subtomogram classification. We use unsupervised multi-adversarial domain adaption to reduce the domain shift between features of simulated and experimental data. We develop a network-driven domain randomization procedure with 'warp' modules to alter the simulated data and help the classifier generalize better on experimental data. We do not use any labeled experimental data to train our model, whereas some of the existing alternative approaches require labeled experimental samples for cross-domain classification. Nevertheless, Cryo-Shift outperforms the existing alternative approaches in cross-domain subtomogram classification in extensive evaluation studies demonstrated herein using both simulated and experimental data. AVAILABILITYAND IMPLEMENTATION: https://github.com/xulabs/aitom. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Hsp90 Inhibitor STA9090 Sensitizes Hepatocellular Carcinoma to Hyperthermia-Induced DNA Damage by Suppressing DNA-PKcs Protein Stability and mRNA Transcription.

As a conserved molecular chaperone, heat shock protein 90 (Hsp90) maintains the stability and homeostasis of oncoproteins and helps cancer cells survive. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a pivotal role in the non-homologous end joining pathway for DNA double-strand breaks (DSB) repair. Tumor cells contain higher levels of DNA-PKcs to survive by the hostile tumor microenvironment and various antitumor therapies. Here, we showed that increased levels of Hsp90α, Hsp90ß, and DNA-PKcs correlated with a poor overall survival in hepatocellular carcinoma (HCC). We revealed that Hsp90 N-terminal domain and C-terminal domain have different effects on DNA-PKcs protein and mRNA levels. The stability of DNA-PKcs depended on Hsp90α N-terminal nucleotide binding domain. Transcription factor SP1 regulates the transcription of PRKDC (gene name of DNA-PKcs) and is a client protein of Hsp90. Inhibition of Hsp90 N-terminal by STA9090 decreased the location of Hsp90α in nucleus, Hsp90α-SP1 interaction, SP1 level, and the binding of Hsp90α/SP1 at the proximal promoter region of PRKDC Because hyperthermia induces DSBs with increases level of DNA-PKcs, combined STA9090 treatment with hyperthermia effectively delayed the tumor growth and significantly decreased DNA-PKcs levels in xenografts model. Consistently, inhibition of Hsp90 increased the number of heat shock-induced γ-H2AX foci and delayed the repair of DSBs. Altogether, our results suggest that Hsp90 inhibitor STA9090 decreases DNA-PKcs protein stability and PRKDC mRNA level, which provide a theoretical basis for the promising combination therapy of hyperthermia and Hsp90 inhibitor in HCC.