<b>Long Noncoding RNA LINC02453 Inhibits HIV-1 Replication by Binding with SEC13 to Regulate the Viral Productive Cycle</b>

Emerging evidence underscores the pivotal role of long noncoding RNAs (lncRNAs) as crucial regulators within the HIV life cycle. However, the precise functions and detailed mechanisms by which lncRNAs operate in HIV-1 highly exposed but persistently seronegative individuals (HESN) remain currently unknown. In our study, we found that LncRNA LINC02453 was highly expressed in HESN and typical progressors. Moreover, LINC02453 was identified as a novel lncRNA associated with heightened resistance to HIV-1. Located within the nucleus, LINC02453 demonstrated interaction with the RNA-binding protein SEC13, a component of the nuclear pore complex. And this interaction facilitated the promotion of HIV-1 replication by regulating key processes such as viral late reverse transcription, transportation to the nucleus and viral DNA integration processes within the nucleus. Furthermore, the promotion could be rescued by LINC02453 overexpression. Our findings suggest that LINC02453 may serve as a prospective target for the development of innovative anti-HIV therapeutics.</p

Toxicity Decreases with the Decay of Environmentally Persistent Free Radicals in Particulate Matter from Incomplete Solid Fuel Burning

Environmentally persistent free radicals (EPFRs) have been linked to the generation of reactive oxygen species (ROS) and adverse health effects. However, there remains a knowledge gap regarding the dynamic changes in reactivity and toxicity during the decay process of EPFRs emitted from incomplete solid fuel burning, which are identified as a primary source of EPFRs. Here, we report the decay behavior of EPFRs in particulate matter (PM) emitted from typical solid fuel burning and the associated ROS generation and cytotoxic effects. The EPFRs in freshly produced PM first undergo rapid exponential decay with lifetimes ranging from 15 to 97 h and are categorized as fast-decay EPFRs. The relative content of fast-decay EPFRs was 40.5 ± 15.3%, while the remaining portion, defined as slow-decay EPFRs, displayed an extremely slow rate of decay. ROS generation and cytotoxicity decreased by 38.8 ± 11.4% and 62.5 ± 12.6%, respectively, following the depletion of fast-decay EPFRs, which were further demonstrated to be responsible for the variations in PM reactivity and toxicity. These new findings underscore the importance of considering the decay process of EPFRs in assessments of PM toxicity

Toxic Potencies of Particulate Matter from Typical Industrial Plants Mediated with Acidity via Metal Dissolution

Acidity is an important property of particulate matter (PM) in the atmosphere, but its association with PM toxicity remains unclear. Here, this study quantitively reports the effect of the acidity level on PM toxicity via pH-control experiments and cellular analysis. Oxidative stress and cytotoxicity potencies of acidified PM samples at pH of 1–2 were up to 2.8–5.2 and 2.1–13.2 times higher than those at pH of 8–11, respectively. The toxic potencies of PM samples from real-world smoke plumes at the pH of 2.3 were 9.1–18.2 times greater than those at the pH of 5.6, demonstrating a trend similar to that of acidified PM samples. Furthermore, the impact of acidity on PM toxicity was manifested by promoting metal dissolution. The dramatic increase by 2–3 orders of magnitude in water-soluble metal content dominated the variation in PM toxicity. The significant correlation between sulfate, the pH value, water-soluble Fe, IC20, and EC1.5 (p < 0.05) suggested that acidic sulfate could enhance toxic potencies by dissolving insoluble metals. The findings uncover the superficial association between sulfate and adverse health outcomes in epidemiological research and highlight the control of wet smoke plume emissions to mitigate the toxicity effects of acidity

Variable Valence State of Trace Elements Regulating Toxic Potencies of Inorganic Particulate Matter

Trace element is known to be one major component in determining particulate matter (PM) toxicities. However, there is still no accurate assessment of the toxic potency of the mixed valences. Here, we reported the oxidative stress and cytotoxicity potencies of 14 trace elements in their various valence states and estimated the toxic gaps of inorganic PM resulting from variations in element valences. Substantial discrepancies of up to 3 orders of magnitude in toxic potencies were observed among their different valences. When considering their abundance in PM, the toxicity gaps are estimated to range from 5 to 6 times between the greatest and weakest toxic valence states in the inorganic PM emitted from industrial sources, with iron contributing to 65.5%–91.0% of the overall gaps. Furthermore, the relative toxic variation of inorganic PM shows a significant correlation with the additive toxicities of Fe(II) and Fe(III) ions during aging process. The finding highlights that the multiple coexisting valence states of trace elements in PM need to be taken into account when estimating their toxic potencies

Data_Sheet_1_Nilotinib in Parkinson's disease: A systematic review and meta-analysis.docx

BackgroundNilotinib, which inhibits cellular Abelson tyrosine kinase, may be an effective treatment for patients with Parkinson's disease (PD). The purpose of this study is to evaluate the outcomes of different doses of nilotinib in patients with PD.MethodsWe searched PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Clinical Trials from inception to 7 March 2022 to identify all randomized controlled trials (RCTs) of nilotinib reporting outcomes of interest in patients with PD. Outcomes included tolerability, efficacy, safety, and CSF biomarker levels. Review manager 5.4 software was used to analyze all data.ResultsThree RCTs with a total of 163 patients were included. No significant difference was found between 150 mg nilotinib or 300 mg nilotinib and placebo in terms of tolerability, adverse events, or HVA levels. 300 mg nilotinib showed significantly higher Movement Disorder Society Unified Parkinson's Disease Rating Scale III (MDS-UPDRS III) scores [SMD = 0.52, 95%CI = (0.12, 0.92), P = 0.01] and 3,4-dihydroxyphenylacetic acid (DOPAC) levels [SMD = 0.52, 95%CI = (0.12, 0.92), P = 0.01], and lower α-synuclein levels [SMD = −2.16, 95%CI = (−3.38, −1.84), P ConclusionsAlthough our study demonstrated favorable tolerability and safety of different doses of nilotinib, and improvement in part of CSF biomarker levels of 300 mg nilotinib, the poor efficacy on motor outcomes indicated that nilotinib had no advantages in the clinic.</p

Data_Sheet_1_Exploring brain network oscillations during seizures in drug-naïve patients with juvenile absence epilepsy.docx

ObjectiveWe aimed to investigate the brain network activity during seizures in patients with untreated juvenile absence epilepsy.MethodsThirty-six juvenile absence epilepsy (JAE) patients with a current high frequency of seizures (more than five seizures during a 2 h EEG examination) were included. Each participant underwent a 2 h video EEG examination. Five 10 s EEG epochs for inter-ictal, pre-ictal, and post-ictal, and five 5 s EEG epochs for ictal states were extracted. Five 10 s resting-state EEG epochs for each participant from a sex- and age-matched healthy control (HC) were enrolled. The topological parameters of the brain networks were calculated using a graph theory analysis.ResultsCompared with the resting state of the HC group, the global efficiency, local efficiency, and clustering coefficients of the JAE group decreased in the inter-ictal state. In addition, the ictal state showed significantly increased global and local efficiency and clustering coefficients (p ConclusionThe present study supported the idea that the changes in the EEG brain networks in JAE patients are characterized by decreased global and local efficiency and clustering coefficient in the alpha band. Moreover, the onset of seizures is accompanied by excessively enhanced network efficiency. JAE patients with different ictal discharge patterns may have different functional network oscillations.</p

MicroRNA-3646 Contributes to Docetaxel Resistance in Human Breast Cancer Cells by GSK-3β/β-Catenin Signaling Pathway

<div><p>Acquisition of resistance to docetaxel (Doc) is one of the most important problems in treatment of breast cancer patients, but the underlying mechanisms are still not fully understood. In present study, Doc-resistant MDA-MB-231 and MCF-7 breast cancer cell lines (MDA-MB-231/Doc and MCF-7/Doc) were successfully established <i>in vitro</i> by gradually increasing Doc concentration on the basis of parental MDA-MB-231 and MCF-7 cell lines (MDA-MB-231/S and MCF-7/S). The potential miRNAs relevant to the Doc resistance were screened by miRNA microarray. We selected 5 upregulated miRNAs (has-miR-3646, has-miR-3658, has-miR-4438, has-miR-1246, and has-miR-574-3p) from the results of microarray for RT-qPCR validation. The results showed that expression level of miR-3646 in MDA-MB-231/Doc cells was significantly higher than in MDA-MB-231/S cells. Compared to MCF-7/S cells, miR-3646 expression was up-regulated in MCF-7/Doc cells. Further studies revealed that transfection of miR-3646 mimics into MDA-MB-231/S or MCF-7/S cells remarkably increased their drug resistance, in contrast, transfection of miR-3646 inhibitors into MDA-MB-231/Doc or MCF-7/Doc cells resulted in significant reduction of the drug resistance. By the pathway enrichment analyses for miR-3646, we found that GSK-3β/β-catenin signaling pathway was a significant pathway, in which GSK-3β was an essential member. RT-qPCR and Western blot results demonstrated that miR-3646 could regulate GSK-3β mRNA and protein expressions. Furthermore, a marked increase of both nuclear and cytoplasmic β-catenin expressions (with phosphorylated-β-catenin decrease) was observed in MDA-MB-231/Doc cells compared with MDA-MB-231/S cells, and their expression were positively related to miR-3646 and negatively correlated with GSK-3β. Taken together, our results suggest that miR-3646-mediated Doc resistance of breast cancer cells maybe, at least in part, through suppressing expression of GSK-3β and resultantly activating GSK-3β/β-catenin signaling pathway.</p></div

Violapyrones A–G, α‑Pyrone Derivatives from <i>Streptomyces violascens</i> Isolated from <i>Hylobates hoolock</i> Feces

Seven new 3,4,6-trisubstituted α-pyrone derivatives, violapyrones A–G (<b>1</b>–<b>7</b>), were isolated from <i>Streptomyces violascens</i> obtained from <i>Hylobates hoolock</i> feces. Their structures were elucidated on the basis of detailed spectroscopic analysis. The antimicrobial activities of <b>1</b>–<b>7</b> were evaluated against Gram-positive and Gram-negative bacteria and against fungi. Compounds <b>1</b>–<b>3</b> showed moderate antibacterial activities against <i>Bacillus subtilis</i> and <i>Staphylococcus aureus</i> with MIC values of 4–32 μg/mL

Cytotoxic Fusicoccane-Type Diterpenoids from <i>Streptomyces violascens</i> Isolated from <i>Ailuropoda melanoleuca</i> Feces

Six new fusicoccane-type diterpenoids (<b>2</b>–<b>7</b>) were isolated from the fermentation broth of <i>Streptomyces violascens</i>, which was isolated from <i>Ailuropoda melanoleuca</i> (giant panda) feces. The structures of these new compounds were elucidated by a detailed spectroscopic data and X-ray crystallographic analysis. Compounds <b>5</b>–<b>7</b> demonstrated cytotoxicity against five human cancer cell lines, with IC₅₀ values ranging from 3.5 ± 0.7 to 14.1 ± 0.8 μM. Cell adhesion, migration, and invasion assays showed that <b>6</b> inhibited the migration and invasion of human hepatocellular carcinoma SMMC7721 cells in a dose-dependent manner. Through further investigation, it was revealed that <b>6</b> inhibited the enzymatic activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), in addition to down-regulating the expressions of MMP-2 and MMP-9 at both the protein and mRNA levels to influence the migration and invasion of cancer cells

Cytotoxic Fusicoccane-Type Diterpenoids from <i>Streptomyces violascens</i> Isolated from <i>Ailuropoda melanoleuca</i> Feces

Six new fusicoccane-type diterpenoids (<b>2</b>–<b>7</b>) were isolated from the fermentation broth of <i>Streptomyces violascens</i>, which was isolated from <i>Ailuropoda melanoleuca</i> (giant panda) feces. The structures of these new compounds were elucidated by a detailed spectroscopic data and X-ray crystallographic analysis. Compounds <b>5</b>–<b>7</b> demonstrated cytotoxicity against five human cancer cell lines, with IC₅₀ values ranging from 3.5 ± 0.7 to 14.1 ± 0.8 μM. Cell adhesion, migration, and invasion assays showed that <b>6</b> inhibited the migration and invasion of human hepatocellular carcinoma SMMC7721 cells in a dose-dependent manner. Through further investigation, it was revealed that <b>6</b> inhibited the enzymatic activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), in addition to down-regulating the expressions of MMP-2 and MMP-9 at both the protein and mRNA levels to influence the migration and invasion of cancer cells