A transcription-independent mechanism determines rapid periodic fluctuations of BRCA1 expression.

BRCA1 expression is highly regulated to prevent genomic instability and tumorigenesis. Dysregulation of BRCA1 expression correlates closely with sporadic basal-like breast cancer and ovarian cancer. The most significant characteristic of BRCA1 regulation is periodic expression fluctuation throughout the cell cycle, which is important for the orderly progression of different DNA repair pathways throughout the various cell cycle phases and for further genomic stability. However, the underlying mechanism driving this phenomenon is poorly understood. Here, we demonstrate that RBM10-mediated RNA alternative splicing coupled to nonsense-mediated mRNA decay (AS-NMD), rather than transcription, determines the periodic fluctuations in G1/S-phase BRCA1 expression. Furthermore, AS-NMD broadly regulates the expression of period genes, such as DNA replication-related genes, in an uneconomical but more rapid manner. In summary, we identified an unexpected posttranscriptional mechanism distinct from canonical processes that mediates the rapid regulation of BRCA1 as well as other period gene expression during the G1/S-phase transition and provided insights into potential targets for cancer therapy.

C1QBP Promotes Homologous Recombination by Stabilizing MRE11 and Controlling the Assembly and Activation of MRE11/RAD50/NBS1 Complex.

MRE11 nuclease forms a trimeric complex (MRN) with RAD50 and NBS1 and plays a central role in preventing genomic instability. When DNA double-strand breaks (DSBs) occur, MRN is quickly recruited to the damage site and initiates DNA end resection; accordingly, MRE11 must be tightly regulated to avoid inefficient repair or nonspecific resection. Here, we show that MRE11 and RAD50 form a complex (MRC) with C1QBP, which stabilizes MRE11/RAD50, while inhibiting MRE11 nuclease activity by preventing its binding to DNA or chromatin. Upon DNA damage, ATM phosphorylates MRE11-S676/S678 to quickly dissociate the MRC complex. Either excess or insufficient C1QBP impedes the recruitment of MRE11 to DSBs and impairs the DNA damage response. C1QBP is highly expressed in breast cancer and positively correlates with MRE11 expression, and the inhibition of C1QBP enhances tumor regression with chemotherapy. By influencing MRE11 at multiple levels, C1QBP is, thus, an important player in the DNA damage response.

The ARK2N-CK2 complex initiates transcription-coupled repair through enhancing the interaction of CSB with lesion-stalled RNAPII.

Transcription is extremely important for cellular processes but can be hindered by RNA polymerase II (RNAPII) pausing and stalling. Cockayne syndrome protein B (CSB) promotes the progression of paused RNAPII or initiates transcription-coupled nucleotide excision repair (TC-NER) to remove stalled RNAPII. However, the specific mechanism by which CSB initiates TC-NER upon damage remains unclear. In this study, we identified the indispensable role of the ARK2N-CK2 complex in the CSB-mediated initiation of TC-NER. The ARK2N-CK2 complex is recruited to damage sites through CSB and then phosphorylates CSB. Phosphorylation of CSB enhances its binding to stalled RNAPII, prolonging the association of CSB with chromatin and promoting CSA-mediated ubiquitination of stalled RNAPII. Consistent with this finding, Ark2n-/- mice exhibit a phenotype resembling Cockayne syndrome. These findings shed light on the pivotal role of the ARK2N-CK2 complex in governing the fate of RNAPII through CSB, bridging a critical gap necessary for initiating TC-NER.

Neonatal microglia transplantation at early stage but not late stage after traumatic brain injury shows protective effects in mice.

The transplantation of neonatal microglia suppresses neuroinflammation caused by traumatic brain injury (TBI). This research aimed to explore the optimal time point of neonatal microglia transplantation for the best effect on the improvement of long-term cognitive function and inflammatory response in mouse models. qPCR and immunoblotting showed that the level of Iba1 gradually increased to the highest on day 7 and then gradually declined in TBI mice. Furthermore, it was observed that the level of CD86 and TNF-α increased to the highest after 7 days and subsequently was maintained until day 21, whereas the level of CD206 and IL-10 increased to the highest after 24 h and subsequently decreased until day 21 by qPCR and enzyme-linked immunosorbent assay. Afterward, it was shown that the neonatal microglia transplantation within 1 h significantly attenuated anxiety-like behavior and improved cognitive impairments in TBI mice. Mechanism exploration showed that the neonatal microglia could significantly decrease the level of cleaved caspase-3, M1/M2 polarization, and inflammatory cytokine (TNF-α) while increasing the level of anti-inflammatory factor IL-10 in TBI mice after transplantation within 1 h. Here, our findings demonstrated that neonatal microglia transplantation within 1 h significantly attenuated anxiety-like behavior and cognitive impairments caused by TBI.NEW & NOTEWORTHY The study demonstrated that neonatal microglia transplantation within 1 h significantly inhibited the pathogenesis of traumatic brain injury (TBI) in mouse models through inhibition of M1 polarization and promotion of M2 polarization.

Critical Review of Pd-Catalyzed Reduction Process for Treatment of Waterborne Pollutants.

Catalyzed reduction processes have been recognized as important and supplementary technologies for water treatment, with the specific aims of resource recovery, enhancement of bio/chemical-treatability of persistent organic pollutants, and safe handling of oxygenate ions. Palladium (Pd) has been widely used as a catalyst/electrocatalyst in these reduction processes. However, due to the limited reserves and high cost of Pd, it is essential to gain a better understanding of the Pd-catalyzed decontamination process to design affordable and sustainable Pd catalysts. This review provides a systematic summary of recent advances in understanding Pd-catalyzed reductive decontamination processes and designing Pd-based nanocatalysts for the reductive treatment of water-borne pollutants, with special focus on the interactions and transformation mechanisms of pollutant molecules on Pd catalysts at the atomic scale. The discussion begins by examining the adsorption of pollutants onto Pd sites from a thermodynamic viewpoint. This is followed by an explanation of the molecular-level reaction mechanism, demonstrating how electron-donors participate in the reductive transformation of pollutants. Next, the influence of the Pd reactive site structure on catalytic performance is explored. Additionally, the process of Pd-catalyzed reduction in facilitating the oxidation of pollutants is briefly discussed. The longevity of Pd catalysts, a crucial factor in determining their practicality, is also examined. Finally, we argue for increased attention to mechanism study, as well as precise construction of Pd sites under batch synthesis conditions, and the use of Pd-based catalysts/electrocatalysts in the treatment of concentrated pollutants to facilitate resource recovery.

Schizandrin A attenuates early brain injury following subarachnoid hemorrhage through suppressing neuroinflammation.

BACKGROUND: Early brain injury (EBI) is the vital factor in determining the outcome of subarachnoid hemorrhage (SAH). Schizandrin A (Sch A), the bioactive ingredient extracted from Schisandra chinensis, has been proved to exert beneficial effects in multiple human diseases. However, the effect of Sch A on SAH remains unknown. The current study was designed to explored role and mechanism of Sch A in the pathophysiological process of EBI following SAH. METHOD: A total of 74 male C57BL/6 J mice were subjected to endovascular perforation to establish the SAH model. Different dosages of Sch A were administrated post-modeling. The post-modeling assessments included neurological test, brain water content, RT-PCR, immunofluorescence, Nissl staining. Oxygenated hemoglobin was introduced into microglia to establish a SAH model in vitro. RESULT: Sch A significantly alleviated SAH-induced brain edema and neurological impairment. Moreover, application of Sch A remarkably inhibited SAH-induced neuroinflammation, evidenced by the decreased microglial activation and downregulated TNF-α, IL-1ß and IL-6 and expression. Additionally, Sch A, both in vivo and in vitro, protected neurons against SAH-induced inflammatory injury. Mechanismly, administration of Sch A inhibited miR-155/NF-κB axis and attenuated neuroinflammation, as well as alleviating neuronal injury. CONCLUSION: Our data suggested that Sch A could attenuated EBI following SAH via modulating neuroinflammation. The anti-inflammatory effect was exerted, at least partly through the miR-155/NF-κB axis, which may shed light on a possible therapeutic target for SAH.

Total contents, fractionation and bioaccessibility of nine heavy metals in household dust from 14 cities in China.

The potential health risk caused by long-term exposure to heavy metals in household dust is not only depended on their total content, but also bioaccessibility. In this study, twenty-one dust samples were collected from residential buildings, schools, and laboratories in 14 provincial-capital/industrial cities of China, aiming to evaluate the total contents, fractionation, bioaccessibility and health risks of nine heavy metals (As, Cd, Cr, Ni, Pb, Mn, Zn, Fe, and Cu). Results showed that the highest levels of Cd, Cr, Ni and Zn were found in laboratory dust, As, Pb and Mn in school dust, and Fe and Cu in residential dust, indicating different source profiles of the heavy metals. The mean bioaccessibility of the heavy metals across all samples as evaluated using SBRC (Solubility Bioavailability Research Consortium), IVG (In Vitro Gastrointestinal), and PBET (Physiologically Based Extraction Test) assays was 58.4%, 32.4% and 17.2% in gastric phase (GP), and 24.9%, 21.9% and 9.39% in intestinal phase (IP), respectively. Cadmium had the highest content in the fractions of E1+C2 (43.7%), as determined by sequential extraction, and Pb, Mn, and Zn had a higher content in E1+C2+F3 (64.2%, 67.2%, 78.8%), resulting in a higher bioaccessibility of these heavy metals than others. Moreover, the bioaccessibility of most heavy metals was inversely related to dust pH (R = -0.18 in GP; -0.18 in IP; P < 0.01) and particle size, while a positive correlation was observed with total organic carbon (R = 0.40 in GP; 0.38 in IP; P < 0.01). The exposure risk calculated by the highest bioaccessibility was generally lower than that calculated by the total content. However, Pb in one school dust sample had an unacceptable carcinogenic risk (adult risk = 1.19 × 10-4; child risk = 1.08 × 10-4). This study suggests that bioaccessibility of heavy metals in household dust is likely related to geochemical fractions and physical/chemical properties. Further research is needed to explore the sources of bioaccessible heavy metals in household dust.

Association between serum uric acid and deep venous thrombosis in European populations: A two-sample Mendelian randomization study.

BACKGROUND AND AIM: Previous experimental and observational studies showed that serum uric acid (SUA) was associated with deep venous thrombosis (DVT), but the causal relationship is unclear. This study aimed to explore the potential causal association between SUA and DVT. METHODS AND RESULTS: We designed a two-sample Mendelian randomization (MR) analysis by using summary-level data from large genome-wide association studies performed in European individuals. A total of 14 SUA-related single-nucleotide polymorphisms (SNPs) (P value < 5 × 10-8) were identified as instrumental variables. The inverse variance weighted method was used as the primary method to compute the odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for per standard deviation increase in SUA. MR Egger, weighted median, weighted mode, and simple mode were also applied to test the robustness of the results. We found no significant causal effects of serum uric acid on deep venous thrombosis (odds ratio [OR]: 1.000, 95 % confidence interval [CI]: 0.998-1.002, p = 0.78) by using inverse variance weighted. MR analyses based on other methods showed similar results. CONCLUSIONS: There was no potential causal associations between higher genetically predicted SUA levels and increased risk of deep venous thrombosis. Further, MR studies with more valid SNPs and more DVT cases are needed. Validation of the findings is also recommended.

Visual outcomes and optimal timing for repeat surgery in cases of postoperative hematoma following transsphenoidal surgery for pituitary neuroendocrine tumors: A retrospective cohort study.

OBJECTIVE: To investigate the visual outcomes and optimal timing for repeat surgery in cases of postoperative hematoma following transsphenoidal surgery for pituitary neuroendocrine tumors (PitNETs). METHODS: A retrospective study was conducted on 28 patients who developed evident postoperative hematoma out of a total of 9,010 patients. The hematomas were classified into three types based on their CT appearance. Type 1a - mild high density with no tension, Type 1b - thin-layer high density; Type 2a - solid high density with large empty cavities, Type 2b - solid high density with small empty cavities; Type 3 -solid high density with no cavity showing high tension. Patient data were collected for analysis. RESULTS: The study cohort comprised 10 female and 18 male patients, with a mean age of 51.5±11.9 years. Most patients presented with large adenomas (median diameter 36mm). Postoperative visual sight improved in 12 patients, remained stable in 11 patients, and worsened in 5 patients. Notably, no patients experienced worsened visual sight beyond twenty-four hours after the operation. Among the five patients with visual deterioration, four had CT type 3 hematoma (4/6, 66.7%), and one had CT type 2b hematoma (1/9, 11.1%). Patients in the type 3 CT group were significantly more prone to experience visual deterioration compared to those in the type 2 group (odds ratio [OR] 2.154 [95% CI 1.858-611.014], P=.027). Four patients underwent repeat surgery after visual deterioration, resulting in visual improvement following a prolonged recovery period. Postoperative hematoma had limited impact on pituitary dysfunction and hyponatremia. CONCLUSION: Our study reveals a significant association between postoperative hematoma CT types and visual deterioration. For patients with stable visual sight and type 1 or 2a hematoma, conservative strategies may be considered. Conversely, type 2b and 3 patients are at higher risk of visual deterioration, especially within the first 24 hours after the operation. Consequently, early reoperation before vision worsens may be a prudent approach to reduce risks and improve visual outcomes, particularly in type 3 patients.

Researching the CNN Collaborative Inference Mechanism for Heterogeneous Edge Devices.

Convolutional Neural Networks (CNNs) have been widely applied in various edge computing devices based on intelligent sensors. However, due to the high computational demands of CNN tasks, the limited computing resources of edge intelligent terminal devices, and significant architectural differences among these devices, it is challenging for edge devices to independently execute inference tasks locally. Collaborative inference among edge terminal devices can effectively utilize idle computing and storage resources and optimize latency characteristics, thus significantly addressing the challenges posed by the computational intensity of CNNs. This paper targets efficient collaborative execution of CNN inference tasks among heterogeneous and resource-constrained edge terminal devices. We propose a pre-partitioning deployment method for CNNs based on critical operator layers, and optimize the system bottleneck latency during pipeline parallelism using data compression, queuing, and "micro-shifting" techniques. Experimental results demonstrate that our method achieves significant acceleration in CNN inference within heterogeneous environments, improving performance by 71.6% compared to existing popular frameworks.

Particle morphology and soil properties affect the retention of copper oxide nanoparticles in agricultural soils.

The interaction between nanoscale copper oxides (nano-CuOs) and soil matrix significantly affects their fate and transport in soils. This study investigates the retention of nano-CuOs and Cu2+ ions in ten typical agricultural soils by employing the Freundlich adsorption model. Retention of nano-CuOs and Cu2+ in soils was well fitted by the Freundlich model. The retention parameters (KD, KF, and N) followed an order of CuO NTs > CuO NPs > Cu2+, highlighting significant impact of nano-CuOs morphology. The KF and N values of CuO NPs/Cu2+ were positively correlated with soil pH and electrical conductivity (EC), but exhibited a weaker correlation for CuO NTs. Soil pH and/or EC could be used to predict KF and N values of CuO NPs or CuO NTs, with additional clay content should be included for Cu2+.The different relationship between retention parameters and soil properties may suggest that CuO NTs retention mainly caused by agglomeration, whereas adsorption and agglomeration were of equal importance to CuO NPs. The amendment of Ca2+ at low and medium concentration promoted retention of nano-CuOs in alkaline soils, but reduced at high concentration. These findings provided critical insights into the fate of nano-CuOs in soil environments, with significant implications for environmental risk assessment and soil remediation strategies.

Novel patient-derived xenograft and cell line models for therapeutic screening in NF2-associated schwannoma.

Treatment of schwannomas in patients with neurofibromatosis type 2 (NF2) is extremely unsatisfactory, and innovative therapeutic approaches are urgently needed. However, the lack of clinically relevant NF2-associated schwannoma models has severely hampered drug discovery in this rare disease. Here we report the first establishment and characterization of patient-derived xenograft (PDX) and cell line models of NF2-associated schwannoma, which recapitulates the morphological and histopathological features of patient tumors, retain patient NF2 mutations, and maintain gene expression profiles resembling patient tumor profiles with the preservation of multiple key signaling pathways commonly dysregulated in human schwannomas. Using gene expression profiling, we identified elevated PI3K/AKT/mTOR networks in human NF2-associated vestibular schwannomas. Using high-throughput screening of 157 inhibitors targeting the PI3K/AKT/mTOR pathways in vitro, we identified a dozen inhibitors (such as BEZ235, LY2090314, and AZD8055) with significant growth-suppressive effects. Interestingly, we observed that three cell lines displayed differential therapeutic responses to PI3K/AKT/mTOR inhibitors. Furthermore, we demonstrated that two orally bioavailable inhibitors, AZD8055 and PQR309, suppressed NF2-associated schwannoma growth both in vitro and in vivo. In conclusion, our novel patient-derived models of NF2-associated schwannoma closely mimic the phenotypes and genotypes of patient tumors, making them reliable preclinical tools for testing novel personalized therapies. © 2022 The Pathological Society of Great Britain and Ireland.

Arsenic Ingested Early in Life Is More Readily Absorbed: Mechanistic Insights from Gut Microbiota, Gut Metabolites, and Intestinal Morphology and Functions.

Early-life arsenic (As) exposure is a particular health concern. However, it is unknown if As ingested early in life is more readily absorbed from the gastrointestinal (GI) tract, i.e., higher in oral bioavailability. Here, weanling (3-week) and adult (6-week-old) female mice were exposed to arsenate in the diet (10 µg g-1) over a 3-week period with As oral bioavailability estimated using As urinary excretion as the bioavailability endpoint. The As urinary excretion factor was 1.54-fold higher in weanling mice compared to adult mice (82.2 ± 7.29 versus 53.1 ± 3.73%), while weanling mice also showed 2.28-, 1.50-, 1.48-, and 1.89-fold higher As concentration in small intestine tissue, blood, liver, and kidneys, demonstrating significantly higher As oral bioavailability of early-life exposure. Compared to adult mice, weanling mice significantly differed in gut microbiota, but the difference did not lead to remarkable differences in As biotransformation in the GI tract or tissue and in overall gut metabolite composition. Although the expression of several metabolites (e.g., atrolactic acid, hydroxyphenyllactic acid, and xanthine) was up-regulated in weanling mice, they had limited ability to elevate As solubility in the intestinal tract. Compared to adult mice, the intestinal barrier function and intestinal expression of phosphate transporters responsible for arsenate absorption were similar in weanling mice. However, the small intestine of weanling mice was characterized by more defined intestinal villi with greater length and smaller width, providing a greater surface area for As to be absorbed across the GI barrier. The results highlight that early-life As exposure can be more readily absorbed, advancing the understanding of its health risk.

LONG-TERM EVOLUTION OF MYOPIC RETINOSCHISIS WITH A DOME-SHAPED MACULA AND PREDICTORS OF PROGRESSION AND VISUAL PROGNOSIS.

PURPOSE: To study the long-term natural course of myopic retinoschisis (MRS) with a dome-shaped macula (DSM) and to identify the factors affecting its development and visual prognosis. METHODS: In this retrospective case series study, we followed 25 MRS eyes with a DSM and 68 MRS eyes without a DSM for at least two years and observed changes in optical coherence tomography morphologic features and best-corrected visual acuity. RESULTS: During the mean follow-up of 48.3 ± 13.24 months, the difference in the rate of MRS progression between the DSM and non-DSM groups was not significant ( P = 0.7462). In the DSM group, the patients whose MRS progressed were older and had a higher refractive error than those whose MRS was stable or improved ( P = 0.0301 and 0.0166, respectively). The patients whose DSM was located in the central fovea had a significantly higher progression rate than those whose DSM was located in the parafovea ( P = 0.0421). For all DSM eyes, BCVA did not decrease significantly in eyes with extrafoveal retinoschisis ( P = 0.2500), patients whose best-corrected visual acuity decreased more than two lines had a greater central foveal thickness initially than those whose best-corrected visual acuity decreased less than two lines during the follow-up period ( P = 0.0478). CONCLUSION: A DSM did not delay the progression of MRS. The development of MRS in DSM eyes was associated with age, myopic degree, and DSM location. A higher schisis cavity predicted visual deterioration, and a DSM protected visual function in extrafoveal MRS eyes during the follow-up period.

Enhanced virulence of genetically engineered Autographa californica nucleopolyhedrovirus owing to accelerated viral DNA replication aided by inserted ascovirus genes.

Genetic engineering technology is an ideal method to improve insecticidal efficiency by combining the advantages of different pathogenic microorganisms. Thus, six ascovirus genes were introduced into the genomic DNA of Autographa californica nucleopolyhedrovirus (AcMNPV) to possibly transfer the intrinsically valuable insecticidal properties from ascovirus to baculovirus. The viral budded virus (BV) production and viral DNA replication ability of AcMNPV-111 and AcMNPV-165 were significantly stronger than that of AcMNPV-Egfp (used as the wild-type virus in this study), whereas AcMNPV-33 had reduced ones. AcMNPV-111 and AcMNPV-165 also exhibited excellent insecticidal efficiency in the in vivo bioassays: AcMNPV-111 showed a 24.1% decrease in the LT50 value and AcMNPV-165 exhibited a 56.3% decrease in the LD50 value compared with AcMNPV-Egfp against the 3rd instar of Spodoptera exigua larvae, respectively. Furthermore, the size of the occlusion bodies (OBs) of AcMNPV-33, AcMNPV-111, and AcMNPV-165 were significantly increased compared to that of AcMNPV-Egfp. AcMNPV-111 and AcMNPV-165 had stable virulence against the 2nd to 4th instars tested larvae and higher OB yield than AcMNPV-Egfp in the 3rd and 4th instar larvae. Correlation and regression analyses indicated that it is better to use 5 OBs/larva virus to infect the 2nd instar larvae to produce AcMNPV-111 and 50 OBs/larva virus to infect the 3rd instar larvae to produce AcMNPV-165. The results of this study obtained recombinant viruses with enhanced virulence and exhibited a diversity of ascovirus gene function based on the baculovirus platform, which provided a novel strategy for the improvement of baculovirus as a biological insecticide.

Furfural Derivatives and Phenolic Constituents in Stemona tuberosa Lour.

Chemical investigation on the water-soluble constituents of Stemona tuberosa Lour. resulted in the isolation of a previously undescribed furfural derivative namely (S)-5-((R)-hydroxy(5-(hydroxymethyl)furan-2-yl)methyl)-5-methylfuran-2(5H)-one and twenty-five known compounds from the water decoction of the dried root tubers. Their structures were determined by analysis of the extensive spectroscopic data, including 1D/2D NMR, HR-ESI-MS, and ORD, as well as the ECD simulation and comparison. Most of them were phenolic and among them, four compounds were isolated from Stemona plants for the first time. This study uncovers diverse constituents from water decoction of S. tuberosa dedicated for its quality control and allows for the exploitation of chemical markers with potential significance for discrimination of Stemona plants.

Induction Mechanism of Ferroptosis, Necroptosis, and Pyroptosis: A Novel Therapeutic Target in Nervous System Diseases.

In recent years, three emerging cell deaths, ferroptosis, necroptosis and pyroptosis, have gradually attracted everyone's attention, and they also play an important role in the occurrence and development of various diseases. Ferroptosis is an idiographic iron-dependent form regulated cell death with the hallmark of accumulation of the intracellular reactive oxygen species (ROS). Necroptosis is a form of regulated necrotic cell death mediated by the receptor-interacting protein kinase 1(RIPK1) and receptor-interacting protein kinase 3RIPK3. Pyroptosis, also known as cell inflammatory necrosis, is a programmed cell necrosis mediated by Gasdermin D (GSDMD). It is manifested by the continuous swelling of the cells until the cell membrane ruptures, resulting in the release of the cell contents and the activation of a strong inflammatory response. Neurological disorders remain a clinical challenge and patients do not respond well to conventional treatments. Nerve cell death can aggravate the occurrence and development of neurological diseases. This article reviews the specific mechanisms of these three types of cell death and their relationship with neurological diseases and the evidence for the role of the three types of cell death in neurological diseases; understanding these pathways and their mechanisms is helpful for the treatment of neurological diseases.

Computer-Aided Prediction of the Interactions of Viral Proteases with Antiviral Drugs: Antiviral Potential of Broad-Spectrum Drugs.

Human society is facing the threat of various viruses. Proteases are promising targets for the treatment of viral infections. In this study, we collected and profiled 170 protease sequences from 125 viruses that infect humans. Approximately 73 of them are viral 3-chymotrypsin-like proteases (3CLpro), and 11 are pepsin-like aspartic proteases (PAPs). Their sequences, structures, and substrate characteristics were carefully analyzed to identify their conserved nature for proposing a pan-3CLpro or pan-PAPs inhibitor design strategy. To achieve this, we used computational prediction and modeling methods to predict the binding complex structures for those 73 3CLpro with 4 protease inhibitors of SARS-CoV-2 and 11 protease inhibitors of HCV. Similarly, the complex structures for the 11 viral PAPs with 9 protease inhibitors of HIV were also obtained. The binding affinities between these compounds and proteins were also evaluated to assess their pan-protease inhibition via MM-GBSA. Based on the drugs targeting viral 3CLpro and PAPs, repositioning of the active compounds identified several potential uses for these drug molecules. As a result, Compounds 1-2, modified based on the structures of Ray1216 and Asunaprevir, indicate potential inhibition of DENV protease according to our computational simulation results. These studies offer ideas and insights for future research in the design of broad-spectrum antiviral drugs.

Aptamer-Induced-Dimerization Strategy Attenuates AßO Toxicity through Modulating the Trophic Activity of PrPC Signaling.

Current therapeutic strategies for Alzheimer's disease (AD) mainly focus on amyloid ß oligomer (AßO) formation or clearance. However, most of them have failed to yield good clinical results. There is an urgent need to explore an alternative therapeutic target for AD treatments. Recent studies have indicated that the cellular prion protein (PrPC) is one of the cell-surface receptors of AßO that mediates related neurotoxicity. Besides, as a neuroprotective protein, the dimerization of PrPC seems to be critical for its trophic activity. We presume that modulating PrPC receptor activity could be another potential approach to abrogate AßO toxicity. In the present work, using an aptamer-induced dimerization (AID) strategy, we enforce PrPC dimerization and modulate its neurotrophic signaling. The AID strategy can attenuate AßO toxic action by (i) interfering with AßO-PrPC interaction and promoting neuroprotective shedding of PrPC; (ii) preventing the AßO-induced mitochondrial dysfunction and the caspase-3-induced apoptosis; and (iii) reducing the secretion of inflammatory cytokines and relieving the neuroinflammation microenvironment. Our findings suggest that the strategy targeting PrPC signaling may shed light on validating new therapeutic strategies in AD.

Phosphoproteomic analysis of FAC overload-triggered human hepatic cells reveals G2/M phase arrest.

Hepatic iron overload is a universal phenomenon in patients with myelodysplastic syndromes (MDS) who undergo bone marrow transplantation and may experience the toxicity of peri- and post-bone marrow transplantation. To clarify the mechanisms of iron overload-triggered liver injury, we determined the effects of iron overload on changes in protein phosphorylation in human hepatocyte cell line HH4 in vitro by using a phosphoproteomics approach. The hepatocytes were exposed to high concentrations of ferric ammonium citrate (FAC) to build up an iron overload model in vitro. Changes in protein phosphorylation initiated by iron overloading were studied by 2D-LC/MS. We identified 335 differentially expressed phosphorylated proteins under the condition of excess hepatocyte iron, 11% of which were related to cell cycle progression. The results of phosphoproteomics showed that iron overload induced 10.9 times increase in Thr 14/Tyr 15-phosphorylated Cdk1 in HH4 cells. Flow cytometry analysis revealed that FAC-treated HH4 cells showed significant G2/M phase arrest. Our subsequent RT-PCR and Western blot experiments indicated that FAC-induced G2/M phase arrest was related to the activation of p53-p21-Cdk1, p53-14-3-3 sigma-Cdk1, and 14-3-3 gamma pathway. Our findings demonstrate the first evidence that iron overload causes G2/M arrest in HH4 hepatocytes.