FOXA1 regulates ribosomal RNA transcription in prostate cancer.

BACKGROUND: Ribosome biogenesis is excessively activated in tumor cells, yet it is little known whether oncogenic transcription factors (TFs) are involved in the ribosomal RNA (rRNA) transactivation. METHODS: Nucleolar proteomics data and large-scale immunofluorescence were re-analyzed to jointly identify the proteins localized at nucleolus. RNA-Seq data of five prostate cancer (PCa) cohorts were combined and integrated with multi-dimensional data to define the upregulated nucleolar TFs in PCa tissues. Then, ChIP-Seq data of PCa cell lines and two PCa clinical cohorts were re-analyzed to reveal the TF binding patterns at ribosomal DNA (rDNA) repeats. The TF binding at rDNA was validated by ChIP-qPCR. The effect of the TF on rRNA transcription was determined by rDNA luciferase reporter, nascent RNA synthesis, and global protein translation assays. RESULTS: In this study, we reveal the role of oncogenic TF FOXA1 in regulating rRNA transcription within nucleolar organization regions. By analyzing human TFs in prostate cancer clinical datasets and nucleolar proteomics data, we identified that FOXA1 is partially localized in the nucleolus and correlated with global protein translation. Our extensive FOXA1 ChIP-Seq analysis provides robust evidence of FOXA1 binding across rDNA repeats in prostate cancer cell lines, primary tumors, and castration-resistant variants. Notably, FOXA1 occupancy at rDNA repeats correlates with histone modifications associated with active transcription, namely H3K27ac and H3K4me3. Reducing FOXA1 expression results in decreased transactivation at rDNA, subsequently diminishing global protein synthesis. CONCLUSIONS: Our results suggest FOXA1 regulates aberrant ribosome biogenesis downstream of oncogenic signaling in prostate cancer.

Application of Vitreoscilla Hemoglobin as a Green and Efficient Biocatalyst for the Synthesis of Benzoxazoles in Water.

We report an efficient and eco-friendly method for the Vitreoscilla hemoglobin (VHb)-catalyzed synthesis of benzoxazoles in water at room temperature. tert-Butyl hydroperoxide and 2,2,6,6-tetramethyl-1-piperidinyloxy were used as oxidant and radical scavenger, respectively. A total of 27 functionally diverse benzoxazoles were prepared in moderate to high yields (62 %-94 %) by the annulation reaction of phenols with amines in the presence of VHb in 1 h. Thus, this method is highly viable for practical applications. This work broadens the application of hemoglobin to organic synthesis.

Preoperative and intraoperative tirofiban during endovascular thrombectomy in large vessel occlusion stroke due to large artery atherosclerosis.

BACKGROUND AND PURPOSE: The aim of this study is to investigate the efficacy and safety of preoperative versus intraoperative tirofiban in patients with large vessel occlusion (LVO) due to large artery atherosclerosis (LAA). METHODS: This is a retrospective multicenter cohort study based on the RESCUE-RE (Registration Study for Critical Care of Acute Ischemic Stroke After Recanalization) trial enrolling patients with anterior circulation LVO classified as LAA within 24 h of onset. Patients were divided into three groups: preoperative tirofiban (PT), intraoperative tirofiban (IT), and no tirofiban (NT). Propensity score matching (PSM) was used to balance baseline characteristics. The efficacy outcomes included 90-day functional independence (modified Rankin Scale score = 0-2) and early partial recanalization (EPR; defined as a modified Thrombolysis in Cerebral Infarction score = 1-2a). The safety outcomes included symptomatic intracranial hemorrhage (sICH). RESULTS: A total of 104 matched triplets were obtained through PSM. Compared with NT, PT increased 90-day functional independence (60.8% vs. 42.3%, p = 0.008) and EPR (42.7% vs. 18.3%, p < 0.001) rate, with a tendency to increase the asymptomatic intracranial hemorrhage (aICH) proportion (28.8% vs. 18.3%, p = 0.072). Compared with IT, PT had a higher 90-day functional independence (60.8% vs. 45.2%, p = 0.025) and EPR (42.7% vs. 20.2%, p = 0.001) rate, with no significant difference in sICH (14.4% vs. 7.7%, p = 0.122) and aICH (28.8% vs. 21.2%, p = 0.200). Compared with NT, IT had a lower 90-day mortality rate (9.6% vs. 24.0%, p = 0.005). CONCLUSIONS: Tirofiban shows good adjuvant therapy potential in acute ischemic stroke-LVO due to LAA patients. PT is associated with higher rates of EPR and better therapeutic efficacy. In addition, EPR may be a potential way to improve prognosis.

Effects of 3-month Qigong exercise on heart rate variability and respiration in anxious college students.

OBJECTIVE: This longitudinal study aimed to investigate the effects of Qigong on the anxiety state, heart rate variability (HRV), and breathing of anxious college students. METHODS: A total of 37 individuals (18-25 years old) were randomly allocated to the control (n = 19) and intervention (n = 18) groups. Qigong interventions were conducted five times weekly for 12 weeks, with each session lasting 60 min. Hamilton Anxiety Scale, Fatigue Scale 14, Pittsburgh Sleep Quality Index, and 36-item Short Form Survey, HRV, and respiration data were collected before and after the 3-month intervention. RESULTS: Individuals who participated in the three-month Qigong exercise intervention showed a significant reduction in anxiety, particularly mental anxiety (p < 0.05). Subjects in the intervention group presented a decrease in skin temperature (p < 0.05) and an increase in blood volume pulsation (p < 0.05). Meanwhile, HRV exhibited a significant increase in the standard deviation of interbeat interval before and after comparisons (p < 0.05) and between the two groups (p = 0.039) and a reduction in the normalized low-frequency power after the intervention. Moreover, the intervention group experienced increased abdominal breathing depth and abdominal breathing per minute (p < 0.05). CONCLUSION: These findings indicate that Qigong is an effective mind-body exercise strategy for relieving anxiety. HRV and breathing were improved accordingly among college students after the completion of the 3-month Qigong program.

Targeting the gut microbiota to alleviate chemotherapy-induced toxicity in cancer.

Despite ongoing breakthroughs in novel anticancer therapies, chemotherapy remains a mainstream therapeutic modality in different types of cancer. Unfortunately, chemotherapy-related toxicity (CRT) often leads to dose limitation, and even results in treatment termination. Over the past few years, accumulating evidence has indicated that the gut microbiota is extensively engaged in various toxicities initiated by chemotherapeutic drugs, either directly or indirectly. The gut microbiota can now be targeted to reduce the toxicity of chemotherapy. In the current review, we summarized the clinical relationship between the gut microbiota and CRT, as well as the critical role of the gut microbiota in the occurrence and development of CRT. We then summarized the key mechanisms by which the gut microbiota modulates CRT. Furthermore, currently available strategies to mitigate CRT by targeting the gut microbiota were summarized and discussed. This review offers a novel perspective for the mitigation of diverse chemotherapy-associated toxic reactions in cancer patients and the future development of innovative drugs or functional supplements to alleviate CRT via targeting the gut microbiota.

Iron vacancies engineering of FexC@NC hybrids toward enhanced lithium-ion storage properties.

Defect engineering have profound influence on the energy storage properties of electrode hybrids by adjusting their intrinsic electronic characteristics. For iron carbide based materials, however, the effect of defect (especially cation vacancies) toward their electrochemical performance are still unclear. Herein, the feasible and scalable synthesis of FexC@NC with 3D honeycomb-like carbon architecture and abundant Fe vacancies via template etching is reported. Such structure enable outstanding lithium-ion storage properties owing to hierarchical pores, improved intrinsic electrochemical activity, as well as the introduction of more active sites. As a result, the FexC@NC-2 presents a high reversible specific capacity of 1079 mAh g-1after 1000 cycles. Moreover, an excellent cycling stability can be achieved via maintaining a high-capacity retention (689 mAh g-1, 98.4%) over 1000 cycles at 5 A g-1. This study provides a feasible strategy for developing high-performance hybrids with hierarchical pore and rich defects structures.

Efficient synthesis of cyano-containing multi-substituted indoles catalyzed by lipase.

BACKGROUND: Indoles are important bioactive compounds that have been extensively studied in organic chemistry. In this work, a green and efficient process for the synthesis of Indoles from 1,3-diketones with fumaronitrile was developed. RESULTS: Under optimal conditions (1,3-diketones (0.5 mmol), fumaronitrile (1 mmol), water (2 ml), lipase (15 mg), 30 °C, 24 h), high yields and satisfactory regioselectivity of cyano-containing multi-substituted indoles could be obtained when CRL (C. rugosa lipase) was used as the catalyst. CONCLUSION: This enzymatic method demonstrates the great potential for the synthesis of indoles and extends the application of enzyme in organic synthesis.

An ensemble optimizer with a stacking ensemble surrogate model for identification of groundwater contamination source.

The application of the simulation-optimization method for groundwater contamination source identification (GCSI) encounters two main challenges: the substantial time cost of calling the simulation model, and the limitations on the accuracy of identification results due to the complexity, nonlinearity, and ill-posed nature of the inverse problem. To address these issues, we have innovatively developed an inversion framework based on ensemble learning strategies. This framework comprises a stacking ensemble model (SEM), which integrates three distinct machine learning models (Extremely Randomized Trees, Adaptive Boosting, and Bidirectional Gated Recurrent Unit), and an ensemble optimizer (E-GKSEEFO), which combines two newly proposed swarm intelligence optimizers (Genghis Khan Shark Optimizer and Electric Eel Foraging Optimizer). Specifically, the SEM serves as a surrogate model for the groundwater numerical simulation model. Compared to the original simulation model, it significantly reduces time cost while maintaining accuracy. The E-GKSEEFO, functioning as the search strategy for the optimization model, greatly enhances the accuracy of the optimization results. We have verified the performance of the SEM-E-GKSEEFO ensemble inversion framework through two hypothetical scenarios derived from an actual coal gangue pile. The results are as follows. (1) The SEM exhibits improved fitting performance compared to single machine learning models when dealing with high-dimensional nonlinear data from GCSI. (2) The E-GKSEEFO achieves significantly higher accuracy in the identification results of GCSI than individual optimizers. These findings affirm the effectiveness and superiority of the proposed SEM-E-GKSEEFO ensemble inversion framework.

Influence of intelligent management mode based on Internet of Things on self-management ability and prognosis of elderly patients with hypertensive heart disease: An observational study.

Hypertensive heart disease was difficult to cure with drugs, and most patients had poor compliance, leading to recurrent disease and poor quality of life. The intelligent management mode based on the Internet of Things avoided the excessive dependence of the elderly patients on medical institutions in the traditional medical model and enabled patients to monitor themselves. This study aimed to explore the impact on self-management ability and prognosis of elderly patients with hypertensive heart disease. A total of 150 elderly patients with hypertensive heart disease who received treatment from April 2020 to April 2022 were selected and divided into control group (n = 75 cases) and observation group (n = 75 cases) by random number table method. The control group was given routine intervention, and the observation group was given intelligent management mode based on the Internet of Things. Blood pressure fluctuation, self-management ability, and prognosis of the 2 groups were compared after intervention. After the intervention of the intelligent management mode based on the Internet of Things, the systolic and diastolic blood pressure levels in the observation group were lower than those in the control group (P < .05). After intervention, the scores of self-management ability in diet control, self-care skills, rehabilitation exercise, and self-monitoring in observation group were higher than those in control group (P < .05). After intervention, the total incidence of chest tightness, dyspnea, arrhythmia, edema, and nausea in the observation group was 5 (6.67%), which was significantly lower than that in the control group 12 (16.00%) (P < .05). The application of intelligent management mode based on the Internet of Things could effectively improve patients' blood pressure level, improve patients' self-management ability, and significantly improve the prognosis, which was worthy of popularization and application.

Directed evolution of Escherichia coli surface-displayed Vitreoscilla hemoglobin as an artificial metalloenzyme for the synthesis of 5-imino-1,2,4-thiadiazoles.

Artificial metalloenzymes (ArMs) are constructed by anchoring organometallic catalysts to an evolvable protein scaffold. They present the advantages of both components and exhibit considerable potential for the in vivo catalysis of new-to-nature reactions. Herein, Escherichia coli surface-displayed Vitreoscilla hemoglobin (VHbSD-Co) that anchored the cobalt porphyrin cofactor instead of the original heme cofactor was used as an artificial thiourea oxidase (ATOase) to synthesize 5-imino-1,2,4-thiadiazoles. After two rounds of directed evolution using combinatorial active-site saturation test/iterative saturation mutagenesis (CAST/ISM) strategy, the evolved six-site mutation VHbSD-Co (6SM-VHbSD-Co) exhibited significant improvement in catalytic activity, with a broad substrate scope (31 examples) and high yields with whole cells. This study shows the potential of using VHb ArMs in new-to-nature reactions and demonstrates the applicability of E. coli surface-displayed methods to enhance catalytic properties through the substitution of porphyrin cofactors in hemoproteins in vivo.

Bioassessment of Macroinvertebrate Communities Influenced by Gradients of Human Activities.

This study explores the impact of anthropogenic land use changes on the macroinvertebrate community structure in the streams of the Cangshan Mountains. Through field collections of macroinvertebrates, measurement of water environments, and delineation of riparian zone land use in eight streams, we analyzed the relationship between land use types, stream water environments, and macroinvertebrate diversities. The results demonstrate urban land use type and water temperature are the key environmental factors driving the differences in macroinvertebrate communities up-, mid-, and downstream. The disturbed streams had lower aquatic biodiversity than those in their natural state, showing a decrease in disturbance-sensitive aquatic insect taxa and a more similar community structure. In the natural woodland area, species distributions may be constrained by watershed segmentation and present more complex community characteristics.

Switching engineered Vitreoscilla hemoglobin into carbene transferase for enantioselective SH insertion.

An attractive strategy for efficiently forming CS bonds is through the use of diazo compounds SH insertion. However, achieving good enantioselective control in this reaction within a biocatalytic system has proven to be challenging. This study aimed to enhance the activity and enantioselectivity of to enable asymmetric SH insertion. The researchers conducted site-saturation mutagenesis (SSM) on 5 amino acid residues located around the iron carbenoid intermediate within a distance of 5 Å, followed by iterative saturation mutagenesis (ISM) of beneficial mutants. Through this process, the beneficial variant VHbSH(P54R/V98W) was identified through screening with 4-(methylmercapto) phenol as the substrate. This variant exhibited up to 4-fold higher catalytic efficiency and 6-fold higher enantioselectivity compared to the wild-type VHb. Computational studies were also conducted to elucidate the detailed mechanism of this asymmetric SH insertion, explaining how active-site residues accelerate this transformation and provide stereocontrol.

Structural elucidation of a capsular polysaccharide from Bacteroides uniformis and its ameliorative impact on DSS-induced colitis in mice.

Capsular polysaccharides derived from Bacteroides species have emerged as potential mitigators of intestinal inflammation in murine models. However, research on capsular polysaccharides from B. uniformis, a Bacteroides species with reduced abundance in colons of patients with ulcerative colitis, remains scarce. In this study, we extracted a neutral polysaccharide component from B. uniformis ATCC8492, termed BUCPS1B, using ultrasonic disruption, ethanol precipitation, and anion exchange chromatography. Structural characterization revealed BUCPS1B as a water-soluble polysaccharide with an α-1,4-glucan main chain adorned with minor substituent sugar residues. BUCPS1B alleviated intestinal inflammation in a mouse model of colitis and induced polarization of macrophages into M2-type. Furthermore, BUCPS1B modulated the gut microbiota composition, increased the abundance of the probiotic Akkermansia muciniphila and altered the gut metabolic profile to promote phenylalanine and short chain fatty acids metabolism. BUCPS1B is therefore a promising candidate to prevent inflammation and augment intestinal health.

YAP represses the TEAD-NF-κB complex and inhibits the growth of clear cell renal cell carcinoma.

The Hippo pathway is generally understood to inhibit tumor growth by phosphorylating the transcriptional cofactor YAP to sequester it to the cytoplasm and reduce the formation of YAP-TEAD transcriptional complexes. Aberrant activation of YAP occurs in various cancers. However, we found a tumor-suppressive function of YAP in clear cell renal cell carcinoma (ccRCC). Using cell cultures, xenografts, and patient-derived explant models, we found that the inhibition of upstream Hippo-pathway kinases MST1 and MST2 or expression of a constitutively active YAP mutant impeded ccRCC proliferation and decreased gene expression mediated by the transcription factor NF-κB. Mechanistically, the NF-κB subunit p65 bound to the transcriptional cofactor TEAD to facilitate NF-κB-target gene expression that promoted cell proliferation. However, by competing for TEAD, YAP disrupted its interaction with NF-κB and prompted the dissociation of p65 from target gene promoters, thereby inhibiting NF-κB transcriptional programs. This cross-talk between the Hippo and NF-κB pathways in ccRCC suggests that targeting the Hippo-YAP axis in an atypical manner-that is, by activating YAP-may be a strategy for slowing tumor growth in patients.

Atrial myxoma embolization of the basilar artery presenting with a convulsive seizure: Case report.

BACKGROUND: Basilar artery occlusion (BAO) is a rare cause of convulsive seizure. Such patients who are treated for epilepsy will miss the optimal time for treatment. Atrial myxoma is a rare cause of stroke and should be surgically removed as soon as possible after diagnosis. CASE SUMMARY: We report a patient who presented with convulsions as the initial symptom and was diagnosed with BAO by computed tomographic angiography. After transthoracic echocardiogram, the cause of the disease was diagnosed as atrial myxoma. The patient recovered well after endovascular treatment and resection of the atrial myxoma. CONCLUSION: A small number of patients with BAO present with convulsive seizures. It is very important to make a timely diagnosis. Direct thrombaspiration may be the best choice for basilar artery cardioembolization, and thrombectomy for distal moderate vascular occlusion in posterior circulation is feasible. Atrial myxoma is a rare cause of cardioembolic stroke and should be resected as soon as possible to prevent further embolic complications.

Inactivation of microglia dampens blood-brain barrier permeability and loss of dopaminergic neurons in paraquat-lesioned mice.

Prior studies indicated the involvement of neuroinflammation in the dopaminergic neurodegeneration in mice of paraquat (PQ)-induced Parkinson's disease (PD), but the underlying mechanisms remain to be elucidated. The present study explored whether microglia-mediated inflammation disrupted blood-brain barrier (BBB) and its related mechanism. C57BL/6 mice were injected intraperitoneally with PQ, twice a week for six weeks, following with or without minocycline (intraperitoneal injection, once every two days). The microglial activation, BBB permeability, expression of tight junctions (TJs) proteins and matrix metalloproteinase (MMP), as well as the loss of dopaminergic neurons and neurological deficits assessment, were evaluated. Minocycline efficiently restrained nigral microglial activation induced by PQ in mice. PQ-induced increase of EB content in the brain and excessive expression of zonula occludin-1 (ZO-1), claudin-5 and occludin were significantly dampened by minocycline treatment. Inhibition of microglial activation by minocycline greatly ameliorated the loss of dopaminergic neurons and neurological dysfunctions in PQ-exposed mice. Also, microglial inactivation downregulated the expression of MMP-2/9 in PQ-lesioned mice. These findings suggested the potential protection of suppressing microglia-mediated neuroinflammation against dopaminergic neurodegeneration through attenuating BBB disruption in a mouse of PQ-induced PD, and MMP-2/9 might involve in the contribution, which needs to be verified in future study.

Engineering of Dual-Function Vitreoscilla Hemoglobin: A One-Pot Strategy for the Synthesis of Unnatural α-Amino Acids.

Despite a well-developed and growing body of work on the directed evolution of hemoproteins, the potential of hemoproteins to catalyze non-natural reactions remains underexplored. This paper reports a new biocatalytic strategy for the one-pot synthesis of unnatural α-amino acids. Engineered variants of dual-function Vitreoscilla hemoglobin were found to efficiently catalyze N-H insertion and C-H sp3 alkylation, providing moderate to excellent yields (57%-95%) of unnatural α-amino acid derivatives and turnover numbers (1425-2375).

Differential Roles of CD36 in Regulating Muscle Insulin Response Depend on Palmitic Acid Load.

The possible role of fatty acid translocase (CD36) in the treatment of obesity has gained increasing research interest since researchers recognized its coordinated function in fatty acid uptake and oxidation. However, the effect of CD36 deficiency on intracellular insulin signaling is complex and its impact may depend on different nutritional stresses. Therefore, we investigated the various effects of CD36 deletion on insulin signaling in C2C12 myotubes with or without palmitic acid (PA) overload. In the present work, we reported the upregulated expression levels of CD36 in the skeletal muscle tissues of obese humans and mice as well as in C2C12 myotubes with PA stimulation. CD36 knockdown using RNA interference showed that insulin signaling was impaired in CD36-deficient C2C12 cells in the absence of PA loading, suggesting that CD36 is essential for the maintenance of insulin action, possibly resulting from increased mitochondrial dysfunction and endoplasmic reticulum (ER) stress; however, CD36 deletion improved insulin signaling in the presence of PA overload due to a reduction in lipid overaccumulation. In conclusion, we identified differential roles of CD36 in regulating muscle insulin response under conditions with and without PA overload, which provides supportive evidence for further research into therapeutic approaches to diabetes.

Efficacy and safety of early anticoagulation after endovascular treatment in patients with atrial fibrillation.

BACKGROUND: The timing for initiating anticoagulant therapy in acute ischaemic stroke (AIS) patients with atrial fibrillation who recanalised after endovascular treatment (EVT) is unclear. The objective of this study was to evaluate the effect of early anticoagulation after successful recanalisation in AIS patients with atrial fibrillation. METHODS: Patients with anterior circulation large vessel occlusion and atrial fibrillation who were successfully recanalised by EVT within 24 hours after stroke in the Registration Study for Critical Care of Acute Ischemic Stroke after Recanalization registry were analysed. Early anticoagulation was defined as the initiation of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) within 72 hours after EVT. Ultra-early anticoagulation was defined if it was initiated within 24 hours. The primary efficacy outcome was the score on the modified Rankin Scale (mRS) at day 90, and the primary safety outcome was symptomatic intracranial haemorrhage within 90 days. RESULTS: Overall, 257 patients were enrolled, of whom 141 (54.9%) initiated anticoagulation within 72 hours after EVT, including 111 within 24 hours. A significant shift towards better mRS scores at day 90 was associated with early anticoagulation (adjusted common OR 2.08 (95% CI 1.27 to 3.41)). Symptomatic intracranial haemorrhage was comparable between patients treated with early and routine anticoagulation (adjusted OR 0.20 (95% CI 0.02 to 2.18)). Comparison of different early anticoagulation regimens showed that ultra-early anticoagulation was more significantly associated with favourable functional outcomes (adjusted common OR 2.03 (95% CI 1.20 to 3.44)) and reduced the incidence of asymptomatic intracranial haemorrhage (OR 0.37 (95% CI 0.14 to 0.94)). CONCLUSIONS: In AIS patients with atrial fibrillation, early anticoagulation with UFH or LMWH after successful recanalisation is associated with favourable functional outcomes without increasing the risk of symptomatic intracranial haemorrhages. TRIAL REGISTRATION NUMBER: ChiCTR1900022154.

MYC reshapes CTCF-mediated chromatin architecture in prostate cancer.

MYC is a well characterized oncogenic transcription factor in prostate cancer, and CTCF is the main architectural protein of three-dimensional genome organization. However, the functional link between the two master regulators has not been reported. In this study, we find that MYC rewires prostate cancer chromatin architecture by interacting with CTCF protein. Through combining the H3K27ac, AR and CTCF HiChIP profiles with CRISPR deletion of a CTCF site upstream of MYC gene, we show that MYC activation leads to profound changes of CTCF-mediated chromatin looping. Mechanistically, MYC colocalizes with CTCF at a subset of genomic sites, and enhances CTCF occupancy at these loci. Consequently, the CTCF-mediated chromatin looping is potentiated by MYC activation, resulting in the disruption of enhancer-promoter looping at neuroendocrine lineage plasticity genes. Collectively, our findings define the function of MYC as a CTCF co-factor in three-dimensional genome organization.