Structural basis of SecA-mediated protein translocation.

Secretory proteins are cotranslationally or posttranslationally translocated across lipid membranes via a protein-conducting channel named SecY in prokaryotes and Sec61 in eukaryotes. The vast majority of secretory proteins in bacteria are driven through the channel posttranslationally by SecA, a highly conserved ATPase. How a polypeptide chain is moved by SecA through the SecY channel is poorly understood. Here, we report electron cryomicroscopy structures of the active SecA-SecY translocon with a polypeptide substrate. The substrate is captured in different translocation states when clamped by SecA with different nucleotides. Upon binding of an ATP analog, SecA undergoes global conformational changes to push the polypeptide substrate toward the channel in a way similar to how the RecA-like helicases translocate their nucleic acid substrates. The movements of the polypeptide substrates in the SecA-SecY translocon share a similar structural basis to those in the ribosome-SecY complex during cotranslational translocation.

Investing in mini-livestock production for food security and carbon neutrality in China.

Future food farming technology faces challenges that must integrate the core goal of keeping the global temperature increase within 1.5 °C without reducing food security and nutrition. Here, we show that boosting the production of insects and earthworms based on food waste and livestock manure to provide food and feed in China will greatly contribute to meeting the country's food security and carbon neutrality pledges. By substituting domestic products with mini-livestock (defined as earthworms and insects produced for food or feed) protein and utilizing the recovered land for bioenergy production plus carbon capture and storage, China's agricultural sector could become carbon-neutral and reduce feed protein imports to near zero. This structural change may lead to reducing greenhouse gas emissions by 2,350 Tg CO2eq per year globally when both domestic and imported products are substituted. Overall, the success of mini-livestock protein production in achieving carbon neutrality and food security for China and its major trading partners depends on how the substitution strategies will be implemented and how the recovered agricultural land will be managed, e.g., free use for afforestation and bioenergy or by restricting this land to food crop use. Using China as an example, this study also demonstrates the potential of mini-livestock for decreasing the environmental burden of food production in general.

Two novel sesquiterpenes and one new monoterpene from the aerial part of Artemisia tournefortiana.

Two novel sesquiterpenes and one new monoterpene, together with eight reported compounds were isolated from dichloromethane-soluble extract of the aerial part of Artemisia tournefortiana Reichb. Their relative and absolute structures were elucidated based on the analysis of 1D and 2D NMR spectra, HRESIMS, and calculated electronic circular dichroism (ECD). Two sesquiterpenes (1 and 2) showed no inhibition effect in anti-inflammatory and cytotoxic activity tests. Three new terpenes (1-3) were tested for antibacterial activity, compounds 2 and 3 showed moderate antibacterial activities with minimum inhibitory concentrations (MICs) between 264 and 556 µg/ml.

Nanoscale Hotspot-Induced Emitters in DNA Origami-Assisted Nanoantennas.

We report the observation of hotspot-induced emitters and photoluminescence enhancement of up to 42-fold from DNA origami-assisted plasmonic dimer nanoantennas upon excess polarized laser illumination. The presence of DNA and laser polarization alignment along the dimer axis are critical for the generation of bright emitters responsible for the observed PL increase. The emission spectrum reveals characteristic Raman peaks of amorphous carbon, suggesting the formation of carbon-based emitters in the nanoantenna due to the plasmonic hotspots at the longitudinal antenna resonance.

Predicting the Pharmacokinetics of Orally Administered Drugs across BCS Classes 1-4 by Virtual Bioequivalence Model.

To evaluate the influence of solubility and permeability on the pharmacokinetic prediction performance of orally administered drugs using avirtual bioequivalence (VBE) model, a total of 23 orally administered drugs covering Biopharmaceutics Classification System (BCS) classes 1-4 were selected. A VBE model (i.e., a physiologically based pharmacokinetic model integrated with dissolution data) based on a B2O simulator was applied for pharmacokinetic (PK) prediction in a virtual population. Parameter sensitivity analysis was used for input parameter selection. The predictive performances of PK parameters (i.e., AUC0-t, Cmax, and Tmax), PK profiles, and bioequivalence (BE) results were evaluated using the twofold error, average fold error (AFE), absolute average fold error (AAFE), and BE reassessment metrics. All models successfully simulated the mean PK profiles, with AAFE < 2 and AFE ranging from 0.58 to 1.66. As for the PK parameters, except for the time of peak concentration, Tmax, of isosorbide mononitrate, other simulated PK parameters were all within a twofold error. The simulated PK behaviors were comparable to the observed ones, both for test (T) and reference (R) products, and the simulated T/R arithmetic mean ratios were all within 0.88-1.16 of the observed values. These four evaluation metrics were distributed equally among BCS class 1-4 drugs. The VBE model showed powerful performance to predict the PK behavior of orally administered drugs with various combinations of solubility and permeability, irrespective of the BCS category.

Nonlinear Optical Signal Generation Mediated by a Plasmonic Azimuthally Chirped Grating.

Plasmonic gratings are simple and effective platforms for nonlinear signal generation since they provide a well-defined momentum for photon-plasmon coupling and local hot spots for frequency conversion. Here, a plasmonic azimuthally chirped grating (ACG), which provides spatially resolved broadband momentum for photon-plasmon coupling, was exploited to investigate the plasmonic enhancement effect in two nonlinear optical processes, namely two-photon photoluminescence (TPPL) and second harmonic generation (SHG). The spatial distributions of the nonlinear signals were determined experimentally by hyperspectral mapping with ultrashort pulsed excitation. The experimental spatial distributions of nonlinear signals agree very well with the analytical prediction based on photon-plasmon coupling with the momentum of the ACG, revealing the "antenna" function of the grating in plasmonic nonlinear signal generation. This work highlights the importance of the antenna effect of the gratings for nonlinear signal generation and provides insight into the enhancement mechanism of plasmonic gratings in addition to local hot spot engineering.

Atomically Smooth Single-Crystalline Platform for Low-Loss Plasmonic Nanocavities.

Nanoparticle-on-mirror plasmonic nanocavities, capable of extreme optical confinement and enhancement, have triggered state-of-the-art progress in nanophotonics and development of applications in enhanced spectroscopies. However, the optical quality factor and thus performance of these nanoconstructs are undermined by the granular polycrystalline metal films (especially when they are optically thin) used as a mirror. Here, we report an atomically smooth single-crystalline platform for low-loss nanocavities using chemically synthesized gold microflakes as a mirror. Nanocavities constructed using gold nanorods on such microflakes exhibit a rich structure of plasmonic modes, which are highly sensitive to the thickness of optically thin (down to ∼15 nm) microflakes. The microflakes endow nanocavities with significantly improved quality factor (∼2 times) and scattering intensity (∼3 times) compared with their counterparts based on deposited films. The developed low-loss nanocavities further allow for the integration with a mature platform of fiber optics, opening opportunities for realizing nanocavity-based miniaturized photonic devices for practical applications.

Enhanced Tensile Properties, Biostability, and Biocompatibility of Siloxane-Cross-Linked Polyurethane Containing Ordered Hard Segments for Durable Implant Application.

This work developed a series of siloxane-modified polyurethane (PU-Si) containing ordered hard segments by a facile method. The polyaddition between poly(ε-caprolactone) and excess diurethane diisocyanate was carried out to synthesize a polyurethane prepolymer with terminal isocyanate groups, which was then end-capped by 3-aminopropyl triethoxysilane to produce alkoxysilane-terminated polyurethane; the target products of PU-Si were obtained with hydrolysis and the condensation of alkoxysilane groups. The chemical structures were confirmed by FT-IR and XPS, and the effect of the siloxane content or cross-linked degree on the physicochemical properties of the PU-Si films was investigated in detail. The formation of the network structure linked by Si-O-Si bonds and interchain denser hydrogen bonds endowed PU-Si films with fine phase compatibility, low crystallinity, high thermal stability, and excellent tensile properties. Due to the high cross-linked degree and low interfacial energy, the films displayed a high surface water contact angle and low equilibrium water absorption, which resulted in slow hydrolytic degradation rates. Furthermore, the evaluation of protein adsorption and platelet adhesion on the PU-Si film surface presented high resistance to biofouling, indicating superior surface biocompatibility. Consequently, the siloxane-cross-linked polyurethane, which possessed excellent tensile properties, high biostability, and superior biocompatibility, showed great potential to be explored as biomaterials for durable implants.

Effects of Propofol on Perioperative Sleep Quality in Patients Undergoing Gastrointestinal Endoscopy: A Prospective Cohort Study.

PURPOSE: Some patients experience sleep disturbances after endoscopy performed under sedation. This study aimed to evaluate the effects of propofol on sleep quality after gastrointestinal endoscopy (GE). DESIGN: This study was a prospective cohort study. METHODS: This study enrolled 880 patients who underwent GE. Patients who chose to undergo GE under sedation received intravenous propofol, whereas the control group did not. The Pittsburgh Sleep Quality Index (PSQI) was measured before GE (PSQI-1) and 3 weeks (PSQI-2) after GE. The Groningen Sleep Score Scale (GSQS) was used before GE (GSQS-1) and 1 (GSQS-2) and 7 days (GSQS-3) after GE. FINDINGS: There was a significant increase in GSQS scores from baseline to days 1 and 7 after GE (GSQS-2 vs GSQS-1, P < .001, GSQS-3 vs GSQS-1, P = .008). However, no significant changes were observed in the control group (GSQS-2 vs GSQS-1, P = .38, GSQS-3 vs GSQS-1, P = .66). On day 21, there were no significant changes in the baseline PSQI scores over time in either group (sedation group, P = .96; control group, P = .95). CONCLUSIONS: GE with propofol sedation negatively affected sleep quality for 7 days after GE but not 3 weeks after GE.

Clinical trials of orphan drugs in China over the decade 2012-2022: Opportunities and challenges.

Rare diseases refer to diseases with very low prevalence. Along with the support of national policies and improvement of research capability, a new landscape for orphan drug is emerging in China. To identity unmet clinical needs and provide insight on the development of orphan drugs, we reviewed the changes over time of orphan drug clinical trials in China from 2012 to 2022. A total of 261 trials of 40 drugs were initiated, of which 66.3% trials were sponsored by Chinese local pharmaceutical enterprises. Among the 261 trials, chemical drugs (about 63.6%) and biological products (35.6%) account for the high proportions, and traditional Chinese medicine (0.8%) was the least; the indications mainly focused on homozygous hypercholesterolemia, hemophilia, multiple sclerosis and idiopathic pulmonary fibrosis; single-arm study design was applied to 50% of the clinical trials, with an average sample size of 52 participants. Additionally, totally 122 trials were completed by January 2022, of which the average duration time was 15.7 months for new drug and 3.5 months for generic drug, respectively. The trends over time illustrated that remarkable progress has been achieved in development of orphan drugs in China since 2012. Given the large patient pool and the rising capability of innovation, it is believed that China will contribute more to the global drug pipelines for rare diseases.

From "Aha!" to "Haha!" Using Humor to Cope with Negative Stimuli.

Humor has been considered an effective emotion regulation strategy, and some behavioral studies have examined its superior effects on negative emotion regulation. However, its neural mechanisms remain unknown. Our functional magnetic resonance imaging study directly compared the emotion regulation effects and neural bases of humorous coping (reappraisal) and ordinary reappraisal following exposure to negative pictures. The behavioral results suggested that humorous reappraisal was more effective in downregulating negative emotions and upregulating positive emotions both in the short and long term. We also found 2 cooperative neural pathways involved in coping with negative stimuli by means of humor: the "hippocampal-thalamic-frontal pathway" and the "amygdala-cerebellar pathway." The former is associated with the restructuring of mental representations of negative situations and accompanied by an insightful ("Aha!") experience, while the latter is associated with humorous emotional release and accompanied by an expression of laughter ("Haha!"). Furthermore, the degree of hippocampal functional connectivity with both the thalamus and frontal cortex was positively correlated with changes in positive emotion, and this result implied that the degree of emotion regulation could be strongly directly related to the depth of cognitive reconstruction. These findings highlight that regulating negative emotions with humor involves cognitive restructuring and the release of positive emotions.

Pharmacokinetic/pharmacodynamic analysis of high-dose tigecycline, by Monte Carlo simulation, in plasma and sputum of patients with hospital-acquired pneumonia.

WHAT IS KNOWN AND OBJECTIVE: To Investigate the pharmacokinetic/pharmacodynamic (PK/PD) parameters of high-dose tigecycline in plasma and sputum of patients with hospital-acquired pneumonia (HAP), and provide a therapeutic regimen of multidrug-resistant bacteria (MDRB) infections. METHODS: Blood/sputum samples were collected at intervals after tigecycline had reached a steady-state. Tigecycline concentrations in specimens were determined by high-performance liquid chromatography (HLPC), PK parameters were evaluated by WinNonlin software using a non-compartment model. The probability of target attainments (PTAs) at different minimal inhibitory concentrations (MICs) were calculated for achieving the PK/PD index with Crystal Ball software by 10,000-patient Monte Carlo Simulation. RESULTS: In plasma, the maximum concentration (Cmax ) and area under the concentration-time curve from 0 to 12 h (AUC0-12h ) were 2.21 ± 0.17 mg/L and 15.29 ± 1.13 h mg/L, respectively. In sputum, they were 2.48 ± 0.21 mg/L and 19.46 ± 1.82 h mg/L, respectively. The mean lung penetration rate was 127.27%. At the MIC ≤4 mg/L, the PTAs in plasma and sputum were 100.00%. When the MIC increased to 8 mg/L, the PTAs in plasma and sputum mostly were < 90.00% according to two criteria. WHAT IS NEW AND CONCLUSION: In this study, we explored PK/PD of high-dose tigecycline in plasma and sputum. From a PK/PD perspective, high-dose tigecycline had greater therapeutic outcomes in HAP treatment caused by MDRB. Antimicrobial-drug concentrations should be determined to optimize their clinical use.

A Review on Gold Nanotriangles: Synthesis, Self-Assembly and Their Applications.

Gold nanoparticles (AuNPs) with interesting optical properties have attracted much attention in recent years. The synthesis and plasmonic properties of AuNPs with a controllable size and shape have been extensively investigated. Among these AuNPs, gold nanotriangles (AuNTs) exhibited unique optical and plasmonic properties due to their special triangular anisotropy. Indeed, AuNTs showed promising applications in optoelectronics, optical sensing, imaging and other fields. However, only few reviews about these applications have been reported. Herein, we comprehensively reviewed the synthesis and self-assembly of AuNTs and their applications in recent years. The preparation protocols of AuNTs are mainly categorized into chemical synthesis, biosynthesis and physical-stimulus-induced synthesis. The comparison between the advantages and disadvantages of various synthetic strategies are discussed. Furthermore, the specific surface modification of AuNTs and their self-assembly into different dimensional nano- or microstructures by various interparticle interactions are introduced. Based on the unique physical properties of AuNTs and their assemblies, the applications towards chemical biology and sensing were developed. Finally, the future development of AuNTs is prospected.

Penalized and constrained LAD estimation in fixed and high dimension.

Recently, many literatures have proved that prior information and structure in many application fields can be formulated as constraints on regression coefficients. Following these work, we propose a L 1 penalized LAD estimation with some linear constraints in this paper. Different from constrained lasso, our estimation performs well when heavy-tailed errors or outliers are found in the response. In theory, we show that the proposed estimation enjoys the Oracle property with adjusted normal variance when the dimension of the estimated coefficients p is fixed. And when p is much greater than the sample size n, the error bound of proposed estimation is sharper than k log ( p ) / n . It is worth noting the result is true for a wide range of noise distribution, even for the Cauchy distribution. In algorithm, we not only consider an typical linear programming to solve proposed estimation in fixed dimension , but also present an nested alternating direction method of multipliers (ADMM) in high dimension. Simulation and application to real data also confirm that proposed estimation is an effective alternative when constrained lasso is unreliable.

Prolonged infusion of linezolid is associated with improved pharmacokinetic/pharmacodynamic (PK/PD) profiles in patients with external ventricular drains.

OBJECTIVE: We previously investigated the pharmacokinetic and pharmacodynamic (PK/PD) parameters of routine linezolid infusions (1 h) in patients with external ventricular drains (EVD). The aim of the study was to determine whether extended linezolid infusions (200 mg/h for 3 h) were more efficacious than short linezolid infusions (600 mg/h for 1 h). METHODS: We collected cerebrospinal fluid (CSF) and plasma samples from 10 patients who received linezolid infusions after cerebral hemorrhage surgery with EVDs. Linezolid concentrations were measured by high-performance liquid chromatography (HPLC). A Monte Carlo simulation was used to measure the probability of target attainments (PTA) and the PK/PD indexes at four minimum inhibitory concentrations (MIC). RESULTS: When the same dose (600 mg) was given as an extended infusion (3 h), linezolid reached its maximum concentrations in the plasma and CSF at 3.00 h and 4.40 h, respectively. The mean penetration of linezolid in CSF was 41.31%. Using the parameter of AUC0-24 h/MIC ≥ 100, the plasma PTA provided good coverage at > 90% when MIC was ≤ 1 µg/mL, while the values were 0 in CSF. Using the parameter %T (time) > MIC ≥ 85%, the PTA in both the plasma and CSF provided good coverage when MIC ≤ 2 µg/mL. Compared with routine infusions, prolonged infusion times (3 h) showed increased PTA of linezolid. CONCLUSIONS: Prolonged infusion times increased the concentration of linezolid in the plasma, leading to improved therapeutic outcomes. However, this improvement did not exist in CSF. Lastly, the PK/PD indicator AUC/MIC ≥ 100 may be used to achieve improved outcomes in patients with critical infections.

Pharmacokinetic/pharmacodynamic analysis of meropenem, by Monte Carlo simulation, in both plasma and cerebrospinal fluid in patients with cerebral hemorrhage after external ventricular drainage
.

OBJECTIVE: Patients with cerebral hemorrhage are often prone to intracranial infection, and meropenem is recommended for treatment. But whether the widely used dosing regimen (1 g, 2-hour infusion, every 12 hours) is suitable for antibiotic therapy is still unclear. The purpose of this study was to perform pharmacokinetic/pharmacodynamic (PK/PD) analyses of meropenem in both plasma and cerebrospinal fluid (CSF) in these patients. MATERIALS AND METHODS: Ten patients were enrolled in the present study. The blood samples and CSF samples were taken at predetermined time points and determined by our previously developed HPLC method. Pharmacokinetic parameters were then calculated, and the probability of target attainment (PTA) was calculated by the time that drug concentrations were above the minimum inhibitory concentration (%T>MIC). RESULTS: The peak meropenem concentration (Cmax) of 17.79 ± 3.38 µg/mL in plasma was reached at 2 hours, and the area under the curve (AUC) was 46.95 ± 4.37 h×µg/mL. The Cmax of 6.51 ± 1.11 µg/mL in CSF was reached at 3.50 ± 0.53 hours, and the AUC was 24.53 ± 4.28 h×µg/mL. The average penetration rate of meropenem in these patients was 52.25%. In the case where the MIC value was ≤ 1 µg/mL and using 40%T>MIC as a PK/PD index, the PTA of meropenem in both plasma and CSF were able to provide good coverage with MIC ≤ 1 µg/mL. CONCLUSION: In conclusion, this is the first study on the PK/PD analysis of meropenem in both plasma and CSF in patients with cerebral hemorrhage. The results will assist in selecting appropriate dosing regimens of meropenem in these patients.

LSTM-Based VAE-GAN for Time-Series Anomaly Detection.

Time series anomaly detection is widely used to monitor the equipment sates through the data collected in the form of time series. At present, the deep learning method based on generative adversarial networks (GAN) has emerged for time series anomaly detection. However, this method needs to find the best mapping from real-time space to the latent space at the anomaly detection stage, which brings new errors and takes a long time. In this paper, we propose a long short-term memory-based variational autoencoder generation adversarial networks (LSTM-based VAE-GAN) method for time series anomaly detection, which effectively solves the above problems. Our method jointly trains the encoder, the generator and the discriminator to take advantage of the mapping ability of the encoder and the discrimination ability of the discriminator simultaneously. The long short-term memory (LSTM) networks are used as the encoder, the generator and the discriminator. At the anomaly detection stage, anomalies are detected based on reconstruction difference and discrimination results. Experimental results show that the proposed method can quickly and accurately detect anomalies.

Evidence of Cascaded Third-Harmonic Generation in Noncentrosymmetric Gold Nanoantennas.

The optimization of nonlinear optical processes on the nanoscale is a crucial step for the integration of complex functionalities into compact photonic devices and metasurfaces. In such systems, photon upconversion can be achieved with higher efficiencies via third-order processes, such as third-harmonic generation (THG), thanks to the resonantly enhanced volume currents. Conversely, second-order processes, such as second-harmonic generation (SHG), are often inhibited by the symmetry of metal lattices and of common nanoantenna geometries. SHG and THG processes in plasmonic nanostructures are generally treated independently because they typically represent small perturbations in the light-matter interaction mechanisms. In this work, we demonstrate that this paradigm does not hold for plasmon-enhanced nonlinear optics by providing evidence of a sum-frequency generation (SFG) process seeded by SHG, which sizably contributes to the overall THG yield. We address this mechanism by unveiling a characteristic fingerprint in the polarization state of the THG emission from gold noncentrosymmetric nanoantennas, which directly reflects the asymmetric distribution of second-harmonic fields within the structure and does not depend on the model one employs to describe photon upconversion. We suggest that such cascaded processes may also appear for structures that exhibit only moderate SHG yields. The presence of this peculiar mechanism in THG from plasmonic nanoantennas at telecommunication wavelengths allows us to gain further insight into the physics of plasmon-enhanced nonlinear optical processes. This could be crucial in the realization of nanoscale elements for photon conversion and manipulation operating at room temperature.

Superior emotional regulating effects of creative cognitive reappraisal.

Although the effects of cognitive reappraisal in regulating negative emotion are generally well documented, its regulatory effects are usually not very strong because the ordinary reappraisals employed in previous studies were insufficient to overcome the mental set or response bias toward negative situations. In this study, we developed a new strategy employing creative reappraisals that provides an insightful reinterpretation of the negative stimulus. We believe this approach, through adopting a guided (creative) reappraisal rather than self-generation strategy, will greatly improve the emotion regulation effect of reappraisal through activating the neural networks representing the process of deep and structural mental representational change accompanied by the feeling of positive emotion and mental reward. The behavioral results suggested that 1) regarding the transient regulatory effect, creative reappraisal resulted in a positive rating for standardized negative pictures; 2) creative reappraisal had a long-lasting effect in reducing negative affect. In parallel with these behavioral results, the imaging data indicated that 1) creative reappraisal was specifically associated with greater engagement of the amygdala and hippocampus as well as regions in the ventral striatum, and 2) the engagement of the amygdala predicted the transient regulatory effect of creative reappraisal, while the involvement of the hippocampus and the ventral striatum predicted long-term regulatory effects. These findings suggest that the superior regulatory effect of creative reappraisal could be mediated by amygdala-based salient emotional arousal, hippocampus-based new association formation, and striatum-based mental rewarding to lead to a novel and positive experience that could be kept in long-term memory. This research indicates the key role of creative insight in reappraisal and presents a novel and highly efficient reappraisal strategy.

Use of autologous platelet rich fibrin-based bioactive membrane in pressure ulcer healing in rats.

OBJECTIVE: To verify the feasibility of treating pressure ulcers (PUs) with autologous platelet-rich fibrin-based (PRF) bioactive membrane, both in vitro and in vivo. METHOD: An animal model using adult male Sprague-Dawley rats was used. Pressure was periodically exerted on the skin to induce localised ischaemia by using an external magnet and transplanted metal disc. After a PU developed, the rats were divided into two groups: a treatment group and a control group. Rats in the treatment group were then treated with PRF bioactive membrane every three days. RESULTS: A total of 20 rats were used in this study. At days three and seven, the PU area in the PRF bioactive membrane-treated group was significantly smaller than that in the control group, and after 14 days of treatment, the PUs in the PRF bioactive membrane treatment group had healed. Haemotoxylin and eosin staining, immunohistochemistry and Western blot results indicated that PRF bioactive membrane induced wound healing by increasing the thickness of the regenerated epidermis and by upregulating vascular endothelial growth factor expression. Further, we found that different concentrations of rat autologous PRF soluble factors extraction components could significantly promote rat aortic endothelial cell proliferation, wound healing and migration ability in vitro. CONCLUSION: Overall, results indicate that PRF bioactive membrane promotes PU healing in rats. Thus, it may represent a natural and effective wound-healing tool for use in the treatment of clinical skin PUs in humans in the future.