Schwann cell-derived extracellular vesicles promote memory impairment associated with chronic neuropathic pain.

BACKGROUND: The pathogenesis of memory impairment, a common complication of chronic neuropathic pain (CNP), has not been fully elucidated. Schwann cell (SC)-derived extracellular vesicles (EVs) contribute to remote organ injury. Here, we showed that SC-EVs may mediate pathological communication between SCs and hippocampal neurons in the context of CNP. METHODS: We used an adeno-associated virus harboring the SC-specific promoter Mpz and expressing the CD63-GFP gene to track SC-EVs transport. microRNA (miRNA) expression profiles of EVs and gain-of-function and loss-of-function regulatory experiments revealed that miR-142-5p was the main cargo of SC-EVs. Next, luciferase reporter gene and phenotyping experiments confirmed the direct targets of miR-142-5p. RESULTS: The contents and granule sizes of plasma EVs were significantly greater in rats with chronic sciatic nerve constriction injury (CCI)than in sham rats. Administration of the EV biogenesis inhibitor GW4869 ameliorated memory impairment in CCI rats and reversed CCI-associated dendritic spine damage. Notably, during CCI stress, SC-EVs could be transferred into the brain through the circulation and accumulate in the hippocampal CA1-CA3 regions. miR-142-5p was the main cargo wrapped in SC-EVs and mediated the development of CCI-associated memory impairment. Furthermore, α-actinin-4 (ACTN4), ELAV-like protein 4 (ELAVL4) and ubiquitin-specific peptidase 9 X-linked (USP9X) were demonstrated to be important downstream target genes for miR-142-5p-mediated regulation of dendritic spine damage in hippocampal neurons from CCI rats. CONCLUSION: Together, these findings suggest that SCs-EVs and/or their cargo miR-142-5p may be potential therapeutic targets for memory impairment associated with CNP.

Recent Advances in Automated Structure-Based De Novo Drug Design.

As the number of determined and predicted protein structures and the size of druglike 'make-on-demand' libraries soar, the time-consuming nature of structure-based computer-aided drug design calls for innovative computational algorithms. De novo drug design introduces in silico heuristics to accelerate searching in the vast chemical space. This review focuses on recent advances in structure-based de novo drug design, ranging from conventional fragment-based methods, evolutionary algorithms, and Metropolis Monte Carlo methods to deep generative models. Due to the historical limitation of de novo drug design generating readily available drug-like molecules, we highlight the synthetic accessibility efforts in each category and the benchmarking strategies taken to validate the proposed framework.

Iso-E-Codelock: A Rebuilding-free Electrochemical Chip with a Customizable Decoding Probe for Real-Time and Portable Pathogen Diagnostics.

In order to realize portable pathogen diagnostics with easier quantitation, digitization and integration, we develop a ready-to-use electrochemical sensing strategy (Iso-E-Codelock) for real-time detection of isothermal nucleic acid amplification. Bridged by a branched DNA as codelock, the isothermal amplicon is transduced into increased current of an electrochemical probe, holding multiple advantages of high sensitivity, high selectivity, signal-on response, "zero" background and one-pot operation. Through a self-designed portable instrument (BioAlex PHE-T), the detection can be implemented on a multichannel microchip and output real-time amplification curves just like an expensive commercial PCR machine. The microchip is a rebuilding-free and disposable component. The branch codelock probe can be customized for different targets and designs. Such high performance and flexibility have been demonstrated utilizing four virus (SARS-CoV-2, African swine fever, FluA and FluB) genes as targets, and two branch (3-way and 4-way) DNAs as codelock probes.

CRISPR/Cas12a-Responsive Hydrogels for Conjugation-Free and Universal Indicator Release in Colorimetric Detection.

Recent advances have demonstrated the significant potential and advantages to repurpose existing point-of-care reactions/devices to realize portable detection of nonoriginal targets, e.g., pathogen genes. However, pursuing this aim usually requires protein indicator-nucleic acid conjugation via a covalent bond, which may bring drawbacks such as high cost, complicated procedure, and annoying component rebuilding. Herein, we developed a conjugation-free, effective, and universal detection platform called CRIs-gel (CRISPR/Cas12a-Responsive Indicators@RCA hydrogels). Various protein indicators are pre-encapsulated into the hydrogels made of effective and high-yield rolling circle amplification (RCA). Upon a targeting sequence binding with its antisense crRNA, CRISPR/Cas12a starts its trans-cleavage activity to crush the hydrogel, which may directly release the indicator for downstream readout. Two proteins, amylase (GA) and human chorionic gonadotropin (hCG), are successfully used as model indicators to trigger the downstream amylum-I2 color change and pregnancy test strip response. After coupling with upstream isothermal nucleic acid amplification, both portable readouts may detect as few as 2 copies/µL genetic sequences of influenza A virus (FluA), human papilloma virus (HPV), SARS-CoV-2, and influenza B virus (FluB). This conjugation-free CRIs-gel platform is thus simple, sensitive, and universal and can provide innovative insights for portable point-of-care testing (POCT) development.

Multiplex detection of clinical pathogen nucleic acids via a three-way junction structure-based nucleic acid circuit.

Nucleic acid testing technology has made considerable progress in the last few years. However, there are still many challenges in the clinical application of multiple nucleic acid assays, such as how to ensure accurate results, increase speed and decrease cost. Herein, a three-way junction structure has been introduced to specifically translate analytes of loop-mediated isothermal amplification to a catalytic hairpin assembly. For different analyses, a well-optimized nucleic acid circuit can be directly applied to detection, through only one-component replacement, which only not avoids duplicate sequence design but also saves detection cost. Thanks to this design, multiple and logical analysis can be easily realized in a single reaction with ultra-high sensitivity and selectivity. In this paper, Mycoplasma pneumoniae and Streptococcus pneumoniae can be clearly distinguished from the clinical mixed sample with negative control or one analyte in one tube single fluorescence channel. The fair experimental results of actual clinical samples provide a strong support for the possibility of clinical application of this methodology.

Impact of Regional Anesthesia on Subjective Quality of Recovery in Patients Undergoing Thoracic Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVES: Regional anesthesia can be effective for managing pain after thoracic surgery. This study evaluated whether it can also improve patient-reported quality of recovery (QoR) after such surgery. DESIGN: Meta-analysis of randomized controlled trials. SETTING: Postoperative care. INTERVENTION: Perioperative regional anesthesia. PATIENTS: Adults undergoing thoracic surgery. MEASUREMENTS AND MAIN RESULTS: The primary outcome was total QoR scores 24 hours after surgery. Secondary outcomes were postoperative opioid consumption, pain scores, pulmonary function, respiratory complications, and other adverse effects. Eight studies were identified, of which 6 involving 532 patients receiving video-assisted thoracic surgery were included in the quantitative analysis of QoR. Regional anesthesia significantly improved QoR-40 score (mean difference 9.48; 95% CI 3.53-15.44; I2 = 89%; 4 trials involving 296 patients) and QoR-15 score (mean difference 6.7; 95% CI 2.58-10.82; I2 = 0%; 2 trials involving 236 patients). Regional anesthesia also significantly reduced postoperative opioid consumption and the incidence of nausea and vomiting. Insufficient data were available to meta-analyze the effects of regional anesthesia on postoperative pulmonary function or respiratory complications. CONCLUSIONS: The available evidence suggests that regional anesthesia can enhance QoR after video-assisted thoracic surgery. Future studies should confirm and extend these findings.

Resolution Potential of Necrotic Cell Death Pathways.

During tissue damage caused by infection or sterile inflammation, not only damage-associated molecular patterns (DAMPs), but also resolution-associated molecular patterns (RAMPs) can be activated. These dying cell-associated factors stimulate immune cells localized in the tissue environment and induce the production of inflammatory mediators or specialized proresolving mediators (SPMs). Within the current prospect of science, apoptotic cell death is considered the main initiator of resolution. However, more RAMPs are likely to be released during necrotic cell death than during apoptosis, similar to what has been observed for DAMPs. The inflammatory potential of many regulated forms of necrotic cell death modalities, such as pyroptosis, necroptosis, ferroptosis, netosis, and parthanatos, have been widely studied in necroinflammation, but their possible role in resolution is less considered. In this review, we aim to summarize the relationship between necrotic cell death and resolution, as well as present the current available data regarding the involvement of certain forms of regulated necrotic cell death in necroresolution.

A Rebuilding-Free Nucleic Acid Detection Strategy Enables Ultrasensitive Genotyping, N-in-1 Logic Screening and Accurate Multiplex Assay of Dangerous Pathogens.

Sensitive, rapid and low-cost nucleic acid detection is critical for controlling infectious pathogens. Here, we develop a ready-to-use and multimodal detection based on a rebuilding-free, ultrasensitive and selective strategy named dual hairpin ligation-induced isothermal amplification pro (DHLApro). Taking influenza A, influenza B, MERS-CoV, SARS-CoV-2 as model targets, we demonstrate DHLApro provides ≈zM level ultra-sensitivity, being equaling to 0.45 copy/µL in original sample. By simply changing the recognition module, a set of DHLApro components can be applied to a new target without performance loss. Moreover, DHLApro innovatively allows flexible logic/multiplex assay using one set of primer, for example, the "N pathogens-in-1" OR gate screening and accurate multi-channel multiplex assay. Compared with traditional methods, the cost of this logic/multiplex assay has been largely reduced and the cross-interference between the multiple primer sets is also avoided.

CLIPON: A CRISPR-Enabled Strategy that Turns Commercial Pregnancy Test Strips into General Point-of-Need Test Devices.

Desirable biosensing assays need to be sensitive, specific, cost-effective, instrument-free, and versatile. Herein we report a new strategy termed CLIPON (CRISPR and Large DNA assembly Induced Pregnancy strips for signal-ON detection) that can deliver these traits. CLIPON integrates a commercial pregnancy test strip (PTS) with four biological elements: the human chorionic gonadotropin (hCG), CRISPR-Cas12a, crRNA and cauliflower-like large-sized DNA assemblies (CLD). CLIPON uses the Cas12a/crRNA complex both to recognize a target of interest and to release CLD-bound hCG so that target presence can translate into a colorimetric signal on the PTS. We demonstrate the versatility of CLIPON through sensitive and specific detection of HPV genomic DNA, SARS-CoV-2 genomic RNA and adenosine. We also engineer a cell phone app and a hand-held microchip to achieve signal quantification. CLIPON represents an attractive option for biosensing and point-of-care diagnostics.

Establishment of Dual Hairpin Ligation-Induced Isothermal Amplification for Universal, Accurate, and Flexible Nucleic Acid Detection.

Isothermal amplifications have found their potentials in applications of portable nucleic acid diagnostics. However, there are still several certain deficiencies existing in the current amplification methods, including high false-positive signals, limited range of targets, difficult primer design, and so forth. Here, we report an effective solution via the development of dual hairpin ligation-induced isothermal amplification (DHLA) consisting of (1) the formation of a dual hairpin probe (DHP) based on sequence specific hybridization and ligation and (2) exponential isothermal amplification of DHP in the presence of polymerase and primers. Taking both microRNA and virus RNA as model targets, DHLA is proven to be accurate, flexible, and applicable to most deoxyribonucleic acid and ribonucleic acid targets ranging from ∼20 to hundreds of nt. The detection limit is down to the ∼aM level without a false-positive signal. More importantly, the whole detection can be directly applied to a new target via a slight change in the DHP sequence, without redesigning the primer set. This unique property not only simplifies the process for new reaction development but also enables flexible multiprobe strategies to achieve antidegradation analysis.

SARS-CoV-2 Point-of-Care (POC) Diagnosis Based on Commercial Pregnancy Test Strips and a Palm-Size Microfluidic Device.

Coronavirus diseases such as the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pose serious threats. Portable and accurate nucleic acid detection is still an urgent need to achieve on-site virus screening and timely infection control. Herein, we have developed an on-site, semiautomatic detection system, aiming at simultaneously overcoming the shortcomings suffered by various commercially available assays, such as low accuracy, poor portability, instrument dependency, and labor intensity. Ultrasensitive isothermal amplification [i.e., reverse transcription loop-mediated isothermal amplification (RT-LAMP)] was applied to generate intensified SARS-CoV-2 RNA signals, which were then transduced to portable commercial pregnancy test strips (PTSs) via ultraspecific human chorionic gonadotropin (hCG)-conjugated toehold-mediated strand exchange (TMSE) probes (hCG-P). The entire detection was integrated into a four-channel, palm-size microfluidic device, named the microfluidic point-of-care (POC) diagnosis system based on the PTS (MPSP) detection system. It provides rapid, cost-effective, and sensitive detection, of which the lowest concentration of detection was 0.5 copy/µL of SARS-CoV-2 RNA, regardless of the presence of other similar viruses, even highly similar severe acute respiratory syndrome coronavirus (SARS-CoV). The successful detection of the authentic samples from different resources evaluated the practical application. The commercial PTS provides a colorimetric visible signal, which is instrument- and optimization-free. Therefore, this MPSP system can be immediately used for SARS-CoV-2 emergency detection, and it is worthy of further optimization to achieve full automation and detection for other infectious diseases.

Berry Cell Vitality Assessment and the Effect on Wine Sensory Traits Based on Chemical Fingerprinting, Canopy Architecture and Machine Learning Modelling.

Berry cell death assessment can become one of the most objective parameters to assess important berry quality traits, such as aroma profiles that can be passed to the wine in the winemaking process. At the moment, the only practical tool to assess berry cell death in the field is using portable near-infrared spectroscopy (NIR) and machine learning (ML) models. This research tested the NIR and ML approach and developed supervised regression ML models using Shiraz and Chardonnay berries and wines from a vineyard located in Yarra Valley, Victoria, Australia. An ML model was developed using NIR measurements from intact berries as inputs to estimate berry cell death (BCD), living tissue (LT) (Model 1). Furthermore, canopy architecture parameters obtained from cover photography of grapevine canopies and computer vision analysis were also tested as inputs to develop ML models to assess BCD and LT (Model 2) and the intensity of sensory descriptors based on visual and aroma profiles of wines for Chardonnay (Model 3) and Shiraz (Model 4). The results showed high accuracy and performance of models developed based on correlation coefficient (R) and slope (b) (M1: R = 0.87; b = 0.82; M2: R = 0.98; b = 0.93; M3: R = 0.99; b = 0.99; M4: R = 0.99; b = 1.00). Models developed based on canopy architecture, and computer vision can be used to automatically estimate the vigor and berry and wine quality traits using proximal remote sensing and with visible cameras as the payload of unmanned aerial vehicles (UAV).

Efficiency and safety of desloratadine in combination with compound glycyrrhizin in the treatment of chronic urticaria: a meta-analysis and systematic review of randomised controlled trials.

CONTEXT: Desloratadine, an H1 receptor antagonist, is suggested as an effective first-line drug for chronic urticarial (CU). However, the efficacy of desloratadine alone is limited, and the recurrence rate of CU is relatively high. OBJECTIVE: We sought to evaluate the efficacy and clinical feasibility of desloratadine in combination with compound glycyrrhizin in the treatment of CU. MATERIALS AND METHODS: A systematic literature search was conducted in the databases of the China National Knowledge Infrastructure Database, VIP, WanFang, PubMed, and Web of Science using subject terms: "Chronic urticaria", "Loratadine", and "Compound glycyrrhizin". Randomised controlled trials (RCTs) that compared the efficiency and safety of the combination treatment with desloratadine alone starting from January 1, 2014 until February 10, 2021 were selected by two co-first authors independently, and the extracted data were analysed using Rev Man 5.3 software. RESULTS: Fourteen RCTs were included in our meta-analysis with a total of 1501 patients. The results showed that the combination treatment yielded a better treatment effect (total response rate: RR = 1.23, 95% CI: 1.17 to 1.29, p < 0.00001; cure rate: RR = 1.50, 95% CI: 1.30 to 1.73, p < 0.00001), lower recurrence rate as well as superior immune improvement than the treatment with desloratadine alone. In addition, there was no significant difference in the safety of the two treatments. DISCUSSION AND CONCLUSION: The combination of desloratadine and compound glycyrrhizin is a promising treatment for CU and is associated with decreased serum IgE level and improved proportions of CD4+ T and CD8+ T cells.

Homogeneous and Universal Detection of Various Targets with a Dual-Step Transduced Toehold Switch Sensor.

Toehold switch sensors represent a class of new advances that allow specific targets to trigger in situ expression of a protein reporter. Although they offer unique advantages of a label-free nature and high portability, they generally require repeated sequence design, high expenditure, and laborious optimization of toehold switch sequences according to different targets. To simplify the sensing process further and to improve its practicability, we innovatively introduce a dual-step pre-transduction upon traditional toehold switch sensor. Through two successive toehold-mediated strand-displacement reactions that are initiated, respectively, by a linear and an associative trigger, different DNAs, RNAs, or ligands of functional nucleic acids can be generally transduced into the input of one high-performance toehold switch sensor. This advance greatly increases the target range. Furthermore, the whole process is signal-on, homogeneous, and free of any requirements for complicated operations such as probe labeling, separation, and reconstruction of the toehold switch, being promising and practical even in portable or point-of-care assays.

(Cyclopentadienone)iron-Catalyzed Transfer Dehydrogenation of Symmetrical and Unsymmetrical Diols to Lactones.

Air-stable iron carbonyl compounds bearing cyclopentadienone ligands with varying substitution were explored as catalysts in dehydrogenative diol lactonization reactions using acetone as both the solvent and hydrogen acceptor. Two catalysts with trimethylsilyl groups in the 2- and 5-positions, [2,5-(SiMe3)2-3,4-(CH2)4(η4-C4C═O)]Fe(CO)3 (1) and [2,5-(SiMe3)2-3,4-(CH2)3(η4-C4C═O)]Fe(CO)3 (2), were found to be the most active, with 2 being the most selective in the lactonization of diols containing both primary and secondary alcohols. Lactones containing five-, six-, and seven-membered rings were successfully synthesized, and no over-oxidations to carboxylic acids were detected. The lactonization of unsymmetrical diols containing two primary alcohols occurred with catalyst 1, but selectivity was low based on alcohol electronics and modest based on alcohol sterics. Evidence for a transfer dehydrogenation mechanism was found, and insight into the origin of selectivity in the lactonization of 1°/2° diols was obtained. Additionally, spectroscopic evidence for a trimethylamine-ligated iron species formed in solution during the reaction was discovered.

Pt-Like Oxygen Reduction Activity Induced by Cost-Effective MnFeO2 /N-Carbon.

The development of effective and affordable electrocatalysts for the oxygen reduction reaction (ORR) is critical for the renewable-energy technologies. Here, we present a new manganese iron oxide (MnFeO2 ) as a cost-effective material for the ORR with Pt-like electrochemical properties. Pyrolysis of hybrid agar hydrogel on NaCl nanocrystals furnishes a unique structure in which the active MnFeO2 particles are uniformly immobilized in the nitrogen-doped porous carbon aerogels (MnFeO2 /NPC). Nitrogen-doped carbon is introduced to construct porous mass-transfer channels and reduce self-aggregation of the MnFeO2 particles. It is found that the formation of the MnFeO2 phase greatly depends on the pyrolysis temperature. Benefiting from the synergy of MnFeO2 and NPC, the MnFeO2 /NPC can actually be as good as the Pt/C catalyst for the ORR, with an onset-potential of 0.98 V and a half-wave potential of 0.86 V, combined with demonstrating a superior stability and tolerance to methanol.

Hydrogel-Derived Honeycomb Ni3 S4 /N,P-C as an Efficient Oxygen Evolution Catalyst.

The development of high-efficiency electrocatalysts with low costs for the oxygen evolution reaction (OER) is essential, but remains challenging. Herein, a new synthetic process is proposed to prepare Ni3 S4 particles embedded in N,P-codoped honeycomb porous carbon aerogels (Ni3 S4 /N,P-HPC) through a hydrogel approach. The preparation of Ni3 S4 /N,P-HPC begins with the sol-gel polymerization of tripolyphosphate, chitosan, and guanidine polymer that contains metal-binding sites, allowing for the uniform incorporation of Ni ions into the gel matrix, freeze-drying, and subsequent carbonization under an inert atmosphere. This synthesis resolves difficulties in synthesizing the pure Ni3 S4 phase caused by the instability of Ni3 S4 at high temperature, while affording good control of the porous structure and N,P-doping of carbon aerogels. The synergy between the structural advantages of N,P-carbon aerogels (such as easily accessible active sites, high specific surface area, and excellent electron transport) and the intrinsic electrochemical properties of Ni3 S4 result in the outstanding OER performance of Ni3 S4 /N,P-HPC, with overpotentials as low as 0.37 V at 10 mA cm-2 . The work outlined herein offers a simple and effective method for the development of carbon-based electrocatalysts for renewable energy conversion.

Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation.

PURPOSE: Numerous studies have investigated the associations between methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss (RPL); however, the results remain controversial. The aim of this study is to drive a more precise estimation of association between MTHFR gene polymorphisms and risk of RPL. METHODS: We searched PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated Database for papers on MTHFR gene C677T and A1298C polymorphisms and RPL risk. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of association in the homozygous model, heterozygous model, dominant model, recessive model and an additive model. The software STATA (Version 13.0) was used for statistical analysis. RESULTS: Overall, 57 articles were included in the final meta-analysis. In maternal group the MTHFR C677T polymorphism showed pooled odds ratios for the homozygous comparison [OR = 2.285, 95 % CI (1.702, 3.067)] and the MTHFR A1298C polymorphism showed pooled odds ratios for recessive model [OR = 1.594, 95 % CI (1.136, 2.238)]. In fetal group the MTHFR C677T polymorphism showed pooled odds ratios for dominant model [OR = 1.037, 95 % CI (0.567, 1.894)] and the MTHFR A1298C polymorphism showed pooled odds ratios for dominant model [OR = 1.495, 95 % CI (1.102, 2.026)]. CONCLUSIONS: In summary, the results of our meta-analysis indicate that maternal and paternal MTHFR gene C677T and A1298C polymorphisms are associated with RPL. We also observed a significant association between fetal MTHFR A1298C polymorphism and RPL but not C677T.

Application of multimodal ultrasonography to predicting the acute kidney injury risk of patients with sepsis: artificial intelligence approach.

The occurrence of acute kidney injury in sepsis represents a common complication in hospitalized and critically injured patients, which is usually associated with an inauspicious prognosis. Thus, additional consequences, for instance, the risk of developing chronic kidney disease, can be coupled with significantly higher mortality. To intervene in advance in high-risk patients, improve poor prognosis, and further enhance the success rate of resuscitation, a diagnostic grading standard of acute kidney injury is employed to quantify. In the article, an artificial intelligence-based multimodal ultrasound imaging technique is conceived by incorporating conventional ultrasound, ultrasonography, and shear wave elastography examination approaches. The acquired focal lesion images in the kidney lumen are mapped into a knowledge map and then injected into feature mining of a multicenter clinical dataset to accomplish risk prediction for the occurrence of acute kidney injury. The clinical decision curve demonstrated that applying the constructed model can help patients whose threshold values range between 0.017 and 0.89 probabilities. Additionally, the metrics of model sensitivity, specificity, accuracy, and area under the curve (AUC) are computed as 67.9%, 82.48%, 76.86%, and 0.692%, respectively, which confirms that multimodal ultrasonography not only improves the diagnostic sensitivity of the constructed model but also dramatically raises the risk prediction capability, thus illustrating that the predictive model possesses promising validity and accuracy metrics.