A Universal Aptamer for Influenza A Viruses: Selection, Recognition, and Infection Inhibition.

It is crucial to develop universal inhibitors for viral inhibition due to the rapid mutation of viruses. Herein, a universal aptamer inhibitor was developed that enabled a single DNA molecule to recognize several hemeagglutinin (HA) protein subtypes, inducing broad neutralization against influenza A viruses (IAVs). Through a multi-channel enrichment (MCE) strategy, a high-affinity aptamer named UHA-2 was obtained, with its dissociation constants (Kd) for three different HA proteins being 1.5 ± 0.2 nM (H5N1), 3.7 ± 0.4 nM (H7N9), and 10.1 ± 1.1 nM (H9N2). The UHA-2 aptamer had a universal inhibition effect, by which it could broadly neutralize influenza A H5N1, H7N9, H9N2, H1N1, and H3N2 viruses. Universal aptamer inhibitors have the advantages of acquisition in vitro, stability, simple structure, small size, etc. This study not only develops a novel universal aptamer to achieve a broad inhibition effect on various IAVs, but also opens up an efficient strategy for the development of universal inhibitors against viruses.

Recent developments in ionization techniques for single-cell mass spectrometry.

The variation among individual cells plays a significant role in many biological functions. Single-cell analysis is advantageous for gaining insight into intricate biochemical mechanisms rarely accessible when studying tissues as a whole. However, measurement on a unicellular scale is still challenging due to unicellular complex composition, minute substance quantities, and considerable differences in compound concentrations. Mass spectrometry has recently gained extensive attention in unicellular analytical fields due to its exceptional sensitivity, throughput, and compound identification abilities. At present, single-cell mass spectrometry primarily concentrates on the enhancement of ionization methods. The principal ionization approaches encompass nanoelectrospray ionization (nano-ESI), laser desorption ionization (LDI), secondary ion mass spectrometry (SIMS), and inductively coupled plasma (ICP). This article summarizes the most recent advancements in ionization techniques and explores their potential directions within the field of single-cell mass spectrometry.

Trajectory of pain threshold and its association with acute pain after thoracic surgery: a prospective observational study.

BACKGROUND: Postoperative analgesic management is an ongoing challenge. The pain threshold (PT) is an objective index that reflects the body's sensitivity to pain and can be used for quantitative pain assessment. We hypothesized that the PT is correlated with postoperative pain and can thus be used to guide postoperative pain management. METHODS: This study involved 93 patients who underwent thoracoscopic surgery from December 2019 to February 2020. The PT was measured with transcutaneous electrical stimulation before surgery (T0) and at 1 h (T1), 6 h (T6), and 24 h (T24) after surgery. The visual analogue scale (VAS) score was used to evaluate the severity of postoperative pain at the same time. The PT variation (PTV) after surgery was calculated as the ratio of the postoperative PT to preoperative PT. RESULTS: The postoperative PT was higher than the preoperative PT and showed a downward trend within 24 h after surgery; the PTV also showed a downward trend within 24 h after surgery. PT-T1 was negatively correlated with VAS-T1 at rest and during motion (rest: VAS-T1r = - 0.274, P = 0.008; motion: VAS-T1r = - 0.298, P = 0.004). PTV-T1 was negatively correlated with VAS-T1 during motion (r = - 0.213, P = 0.04). Lower VAS-T1 scores (< 4) at rest and during motion were associated with higher PT-T1 (rest: t = 2.452, P = 0.016; motion: t = 2.138, P = 0.035). The intraoperative sufentanil dose was associated with a postoperative increase in PTV-T1. Increased rescue analgesic administration was associated with PTV elevation. However, the incidence of dizziness in patients with moderate PTV-T24 was lower than that in patients with high or low PTV-T24 (χ2 = 8.297, P = 0.015). CONCLUSIONS: The postoperative PT was higher than the preoperative PT and showed a downward trend within 24 h after surgery; PTV also showed a downward trend within 24 h after surgery. The PT and PTV were negatively correlated with the pain intensity at rest and during motion and were associated with perioperative analgesic consumption and the incidence of adverse events.

Newcastle Disease Virus (NDV)-based vaccine candidate against SARS-CoV-2 Omicron by intranasal immunization.

Despite global vaccination efforts, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve and spread globally. Currently, the development of affordable vaccine against Omicron variant of concern (VOC) is necessary. Here, we assessed the safety and immunogenicity of a SARS-CoV-2 vaccine consisting of a live Newcastle disease virus vector expressing the spike (S) protein of Omicron BA.1 administrated intranasally (IN) or intramuscularly (IM) in Golden Syrian hamster model. Immunogenicity studies showed that the prime-boost regimen elicited high antibody titers and the modified S antigen (Sm-F) could induce robust antibody response in low dosage immunization through IN route. Sera of the immunized hamsters provided effective cross-neutralizing activity against different Omicron variants, the prototype and delta strains of SARS-CoV-2. Moreover, the vaccine could provide complete immunoprotection in hamsters against the Omicron BA.1 challenge by either intranasal or intramuscular immunization. Overall, our study provides an alternative nasal vaccine against the SARS-CoV-2 Omicron variants.

Mechanisms of inhibition of human monoclonal antibodies in immune thrombotic thrombocytopenic purpura.

Antibody binding to a plasma metalloprotease, a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 (ADAMTS13), is necessary for the development of immune thrombotic thrombocytopenic purpura (iTTP). Inhibition of ADAMTS13-mediated von Willebrand factor (VWF) cleavage by such antibodies clearly plays a role in the pathophysiology of the disease, although the mechanisms by which they inhibit ADAMTS13 enzymatic function are not fully understood. At least some immunoglobulin G-type antibodies appear to affect the conformational accessibility of ADAMTS13 domains involved in both substrate recognition and inhibitory antibody binding. We used single-chain fragments of the variable region previously identified via phage display from patients with iTTP to explore the mechanisms of action of inhibitory human monoclonal antibodies. Using recombinant full-length ADAMTS13, truncated ADAMTS13 variants, and native ADAMTS13 in normal human plasma, we found that, regardless of the conditions tested, all 3 inhibitory monoclonal antibodies tested affected enzyme turnover rate much more than substrate recognition of VWF. Hydrogen-to-deuterium exchange plus mass spectrometry experiments with each of these inhibitory antibodies demonstrated that residues in the active site of the catalytic domain of ADAMTS13 are differentially exposed to solvent in the presence and absence of monoclonal antibody binding. These results support the hypothesis that inhibition of ADAMTS13 in iTTP may not necessarily occur because the antibodies directly prevent VWF binding, but instead because of allosteric effects that impair VWF cleavage, likely by affecting the conformation of the catalytic center in the protease domain of ADAMTS13. Our findings provide novel insight into the mechanism of autoantibody-mediated inhibition of ADAMTS13 and pathogenesis of iTTP.

Differences in multielement concentrations in rice (Oryza sativa L.) between longevity and non-longevity areas in China and their relations with lifespan indicators.

Geographical distribution pattern of centenarians in China runs counter to the global trend, and centenarians are mainly distributed in low-latitude South China but rarely in high-latitude North China. To investigate the effect of the elemental content of rice on the differences between the longevity areas and the non-longevity areas in China, the multielement concentrations in 84 rice samples collected from 28 counties/cities were measured, of which 37 belonged to the longevity areas in South China (SLs), 36 belonged to non-longevity areas in South China (SNLs), and 11 belonged to non-longevity areas in North China (NNLs). The concentrations of 29 different elements (Ca, K, Mg, Na, P, S, Se, As, Ba, Cr, Cu, Fe, Mn, Mo, Ni, Sr, Ti, Zn Cd, Co, Li, Pb, Tl, Cs, Ga, In, Rb, U and Bi) in rice samples were determined by ICP-OES, ICP-MS and HG-AFS. Notably, the concentrations of macroelements in SLs rice samples (3682.92 mg/kg) were significantly higher than those of SNLs (3046.62 mg/kg) and NNLs (2590.38 mg/kg) (p < 0.05). The concentrations of essential microelements in rice samples of SLs (38.87 mg/kg) and NNLs (41.79 mg/kg) were not significantly different, but both significantly higher than those of SNLs (31.91 mg/kg) (p < 0.05). Significant differences were also found in the concentrations of K, Mg, Na, P, S, Cu, Mn, Mo, Ni, Pb, Tl, In and Cs in rice among SLs, SNLs and NNLs (p < 0.05). The rice samples of SLs had the characteristic of higher concentrations of K, Mg, P, Mn and Ni. Thus, rice intake in SLs provided greater proportions of the dietary mineral requirements than those in SNLs and NNLs. Besides, the concentrations of K, Mg, P, Ni and Ti in rice, especially K, were demonstrated to be significantly positively correlated with lifespan indicators (p < 0.05), while the concentrations of Ga, Cd, In and U in rice were negatively correlated with lifespan indicators. Our findings are expected to provide a basis for reasonable dietary mineral element intakes and promote understanding of the relationships between natural environment and regional longevity in China.

A novel method for fabrication of coated microneedles with homogeneous and controllable drug dosage for transdermal drug delivery.

Over the years, scientists have been focused on the development of microneedle coating process to coat a broad range of therapeutic agents onto the surface of the solid microneedles for effective drug delivery. The precise dose control, content uniformity as well as large-scale production of coated microneedles are still the core issues that have been the interest of researchers in this topic. To this end, a repeatable method that involved a micro-molding process was demonstrated for mass fabrication of coated microneedles with homogeneous and controllable drug loading under mild conditions. In this system, the dissolvable drug carriers with precise dosage were first mounted onto the solid microneedles and then exposed to the high moisture condition to finally obtain the coated microneedle with uniform and precise drug loading. Using the microneedle molds with the volume of 4.71 nL, 8.24 nL, 10.47 nL, and 12.56 nL per cavity, the drug loadings were precisely controlled at 4.8 ng, 6.4 ng, 9.3 ng, and 13.5 ng per needle, with the standard deviation of 0.09, 0.01, 0.07, and 0.53%, respectively. Mechanical property tests showed that the coated microneedles are strong enough for reliable skin insertion, and with in vivo trials in diabetic mice, we further confirmed the similar hypoglycaemic effect of insulin-coated microneedles to subcutaneous injection. Taken together, the micro-molding-based fabrication process has practical merits in the mass production of coated microneedles with homogeneous and controllable drug loading, facilitating the clinical translation of the microneedle technique.

Nickel-Catalyzed anti-Markovnikov Hydrodifluoroalkylation of Unactivated Alkenes.

An efficient Ni-catalyzed hydrodifluoroalkylation of unactivated alkenes with bromodifluoroacetate by using PhSiH3 as hydride source was developed. The transformation affords aliphatic difluorides with anti-Markovnikov regioselectivity. A wide range of highly remote alkenes, simple alkenes, drug molecules, commercially available CF2 precursors, and even nonfluorinated substrates are competent in this reaction under mild conditions, demonstrating the practicability of the strategy. Moreover, mechanistic studies indicated that the difluoroalkyl radical might be a key intermediate to this transformation.

To survive or to thrive? China's luxury hotel restaurants entering O2O food delivery platforms amid the COVID-19 crisis.

COVID-19 presents luxury hotels with an unenviable task of maneuvering to secure survival. One of the contingency measures of China's five-star hotels is to salvage revenues by entering online-to-offline (O2O) food delivery platforms. However, both opportunities and risks will ensue. Study 1 has content analyzed customer reviews on the largest O2O food delivery platform in China to probe the key factors of concern. The results show that taste, freshness, and brand credibility remain salient, as in dine-in experiences, while packaging and delivery quality emerge as a result of the integration of the O2O platform, and hygiene due to the COVID-19 pandemic. Interestingly, interaction quality between restaurant staff and customers still plays significant roles with the online channel. Study 2 has further deepened the understanding of luxury restaurants' O2O services through semi-structured interviews with F&B professionals. The results have paved the way for hotel operators to employ tactics on O2O platforms.

Synthesis of small molecules targeting paclitaxel-induced MyD88 expression in triple-negative breast cancer cell lines.

Acquired paclitaxel (PTX) chemoresistance in triple-negative breast cancer (TNBC) can be inferred from the overexpression of toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) proteins and the activation of the TLR4/MyD88 cascading signalling pathway. Finding a new inhibitor that can attenuate the activation of this pathway is a novel strategy for reducing PTX chemoresistance. In this study, a series of small molecule compounds were synthesised and tested in combination with PTX against TNBC cells. The trimethoxy-substituted compound significantly decreased MyD88 overexpression and improved PTX activity in MDA-MB-231TLR4+ cells but not in HCCTLR4- cells. On the contrary, the trifluoromethyl-substituted compound with PTX synergistically improved the growth inhibition in both TNBC subtypes. The fluorescence titrations indicated that both compounds could bind with MD2 with good and comparable binding affinities. This was further supported by docking analysis, in which both compounds fit perfectly well and form some critical binding interactions with MD2, an essential lipid-binding accessory to TLR4 involved in activating the TLR-4/MyD88-dependent pathway.

[Effect of Long-time Postnatal Exposure to Sevoflurane on Causing Attention-deficit/Hyperactivity Disorder in Rats].

OBJECTIVE: To investigate whether long-term exposure to inhaled sevoflurane, a volatile anesthetic, causes abnormal activities and memory impairment related to attention-deficit/hyperactivity disorder (ADHD) in neonatal rats. METHODS: On postnatal day 5 (P5), Sprague-Dawley rats were randomly assigned to two sevoflurane subgroups and two control subgroups and underwent experimental intervention. The two sevoflurane (SEVO) subgroups were exposed to 3% sevoflurane for 2 h and 4 h respectively, while the two control subgroups were given pure oxygen for the same amount and duration. Behavioral tests, including open-field test (OFT), five-choice serial reaction time task (5-CSRTT), fear-conditioning (FC) and Morris water maze (MWM), were applied to evaluate changes in cognition, memory, anxiety and ADHD-related behavioral changes in the rats in adolescence (-P25) and in adulthood (-P65). RESULTS: In OFT, the SEVO 2 h and SEVO 4 h subgroups displayed activity level and exploratory behaviors similar to those of the control subgroups on P21 and P61, with no statistically significant difference identified in the data. 5-CSRTT results on P25 and P65 indicated no statistically significant difference between the SEVO subgroups and the control subgroups in regard to ADHD-related abnormal behaviors, including number of immature reaction, rate of correct response and omission rate. In the FC experiment, SEVO 4 h group had a shorter freezing period and longer period of freezing latency ( P=0.029) in comparison to the control groups. The results of the MWM test showed that the escape latency period of rats in the SEVO 4 h group was significantly prolonged on the second day and the third day, compared to the control groups ( P<0.05). The average swimming speed of SEVO groups did no exhibit any statistically significant difference on P69 or P76. The time the SEVO 4 h group spent in the target quadrant was significantly shorter than that of the control group ( P=0.039) and percentage of distance traveled in the target quadrant was significantly reduced compared to that the control group ( P=0.048). CONCLUSION: The findings suggest that four hours of inhaled sevoflurane exposure in neonate rats may cause memory impairment, but does no increase risks for ADHD-related abnormal activities.

In Situ Identification and Spatial Mapping of Microplastic Standards in Paramecia by Secondary-Ion Mass Spectrometry Imaging.

Microplastics (MPs) are universally present in the ecosystem and pose great threats to the environment and living organisms. Research studies have shown that small MPs (<50 µm in diameter) are especially toxic and account for more than half of all MPs collected in the Atlantic Ocean. Nevertheless, current methods for the detection and analysis of MPs are incapable of achieving rapid and in situ analysis of small MPs in the biota to ultimately enable the study of their biological effects. In this work, we report a method that allows rapid in situ identification and spatial mapping of small MPs directly from paramecia with high accuracy by acquiring chemical composition information using secondary-ion mass spectrometry (SIMS) imaging. Specifically, six types of common MPs (polymethyl methacrylate, polyvinyl chloride, polypropylene, polyethylene terephthalate, polyglycidyl methacrylate, and polyamide 6) with a diameter of 1-50 µm were simultaneously imaged with high chemical specificity at a spatial resolution of 700 nm. In situ spatial mapping of a group of MPs ingested by paramecia was performed using SIMS fragments specific to the plastic composition with no sample pretreatment, revealing the aggregation of MPs in paramecia after ingestion. Compared with existing methods, one additional advantage of the developed method is that the MPs and the organism can be analyzed in the same experimental workflow to record their fingerprint spectra, acquiring biochemical information to evaluate MP fate, toxicity, and the MP-biota interaction.

Pharmacokinetic and pharmacodynamic properties of ciprofol emulsion in Chinese subjects: a single center, open-label, single-arm dose-escalation phase 1 study.

We conducted a single-center, single-arm, open-label, dose-escalation phase 1 clinical trial to evaluate the tolerability of a single intravenous injection of ciprofol emulsion for the induction of short-term general anesthesia. Four doses of ciprofol (0.15 mg/kg, n = 2; 0.4 mg/kg, n = 10; 0.6 mg/kg, n = 6; 0.9 mg/kg, n = 6) were administered. Twenty-four subjects were enrolled, with 18 subjects in the 0.4 to 0.9 mg/kg dosage groups included in the data analysis. In total, 37 mild and 4 moderate adverse events (AEs), including 9 abnormal limb movements (3 moderate cases), 8 cases of sinus bradycardia, 11 cases of prolonged QTcF interval (including 1 moderate case), and 1 case of hypotension, were found, but no serious AEs were reported. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores rapidly decreased after ciprofol administration. The duration of recovery of the verbal response, loss of verbal response duration, the duration of MOAA/S ≤1 and the duration until the return of responsiveness were all increased in a dose-dependent manner. The durations of bispectral index values <60 (6, 8 and 12 min) were similar to the durations of loss of verbal response (6, 8 and 14 min) and MOAA/S ≤1 (5, 5.5 and 13.5 min) in the 0.4, 0.6 and 0.9 mg/kg dose groups, respectively. The plasma concentration reached a peak value approximately 2 min after injection in the 0.4-0.9 mg/kg groups and all subjects fully recovered after ciprofol administration, with the shortest time being 9.2 min in the 0.4 mg/kg group. A ciprofol dosing regimen of 0.4-0.9 mg/kg was well-tolerated and exhibited rapid onset and recovery properties.

Autophagy-related long non-coding RNA signature for ovarian cancer.

OBJECTIVE: Ovarian cancer (OC) affects nearly 22,000 women annually in the United States and ranks fifth in cancer deaths, largely because of being diagnosed at an advanced stage. Autophagy is the cellular process of self-degrading damaged or degenerate proteins and organelles. Long non-coding RNAs (lncRNAs) are a group of RNA molecules whose transcripts are greater than 200 nt but are not translated into proteins. However, just a small number of autophagy-related lncRNAs have been explored in depth. METHODS: We used RNA sequencing data from The Cancer Genome Atlas (TCGA) and autophagy datasets to identify dysfunctional autophagy-related lncRNAs and provide potential useful biomarkers for OC diagnosis and prognosis. RESULTS: Seventeen differentially expressed lncRNAs (AC010186.3, AC006001.2, LBX2-AS1, SNHG17, AC011445.1, AC083880.1, MIR193BHG, AC025259.3, HCG14, AC007114.1, AC108673.2, USP30-AS1, AC010336.5, LINC01132, AC006333.2, LINC00665 and AC027348.1) were selected as independent prognostic factors for OC patients. Functional annotation of the data was performed through gene set enrichment analysis (GSEA). The results suggested that the high-risk group was mainly enriched in specific tumor-related and metabolism pathways. CONCLUSION: Based on the online databases, we identified novel autophagy-related lncRNAs for the prognosis of ovarian cancer.

Immune reconstitution inflammatory syndrome associated with Pneumocystis pneumonia in a patient with AIDS.

Immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral treatment for human immunodeficiency virus (HIV) infection has a wide variety of causes. Delayed diagnosis and treatment of IRIS is fatal. We report a case of a 21-year-old man with HIV infection and Pneumocystis jirovecii pneumonia. The patient presented with fever and dyspnea with deterioration of pulmonary infiltrations 5 days after starting antiretroviral treatment. We reached the diagnosis of IRIS based on radial endobronchial ultrasound (EBUS)-guided lung biopsy. In conclusion, radial EBUS-guided lung biopsy via bronchoscopy is a valuable and minimally invasive technique for the rapid diagnosis of IRIS-associated Pneumocystis jirovecii pneumonia.

Postoperative Elevations of Neutrophil-to-lymphocyte and Platelet-to-lymphocyte Ratios Predict Postoperative Pulmonary Complications in Non-small Cell Lung Cancer Patients: A Retrospective Cohort Study.

The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) are found to increase in patients who develop postoperative complications (PCs). The aim of the present study was to explore the association of the perioperative changes of NLR (ΔNLR) and PLR (ΔPLR) with PCs in non-small cell lung cancer (NSCLC). Clinical data of 509 patients, who were diagnosed with NSCLC and underwent thoracoscopic radical resection between January 1, 2014 and July 31, 2016 at the Department of Thoracic Surgery, West China Hospital, were reviewed. Patients were divided into PC and non-PC groups, and clinical characteristics including ΔNLR and ΔPLR were compared between them. The optimal cut-off values of ΔNLR and ΔPLR were determined by receiver operating characteristics (ROC) curves and patients were assigned to high ΔNLR/ΔPLR and low ΔNLR/ΔPLR groups in terms of the cut-off values. Clinicopathologic characteristics and the incidence of different PCs were compared between the dichotomized groups. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors for PCs. The results showed that the ΔNLR and ΔPLR in the PC group were signifcantly higher than those in the non-PC group (P<0.001 for both). The optimal cutoff values of ΔNLR and ΔPLR were 6.6 and 49, respectively. Patients with ΔNLR>6.6 or ΔPLR>49 were more likely to experience postoperative pulmonary complications (PPCs) (P<0.001 for both). Multivariate logistic regression analysis demonstrated that smoking [odds ratio (OR): 2.450, 95% confdence interval (95% CI): 1.084-5.535, P=0.031)], tumor size (OR: 1.225, 95% CI: 1.047-1.433, P=0.011), ΔNLR>6.6 (OR: 2.453, 95% CI: 1.224-4.914, P=0.011) and ΔPLR>49 (OR: 2.231, 95% CI: 1.182-4.212, P=0.013) were predictive of PPCs. In conclusion, the ΔNLR and ΔPLR may act as novel predictors for PPCs in NSCLC patients undergoing thoracoscopic radical lung resection, and patients with ΔNLR>6.6 or ΔPLR>49 should be treated more actively to prevent or reduce PPCs.

Applications of hyperspectral imaging in the detection and diagnosis of solid tumors.

Hyperspectral imaging (HSI) is an emerging new technology in solid tumor diagnosis and detection. It incorporates traditional imaging and spectroscopy together to obtain both spatial and spectral information from tissues simultaneously in a non-invasive manner. This imaging modality is based on the principle that different tissues inherit different spectral reflectance responses that present as unique spectral fingerprints. HSI captures those composition-specific fingerprints to identify cancerous and normal tissues. It becomes a promising tool for performing tumor diagnosis and detection from the label-free histopathological examination to real-time intraoperative assistance. This review introduces the basic principles of HSI and summarizes its methodology and recent advances in solid tumor detection. In particular, the advantages of HSI applied to solid tumors are highlighted to show its potential for clinical use.