Multicomponent Synthesis of Imidazole-Based Ionizable Lipids for Highly Efficient and Spleen-Selective Messenger RNA Delivery.

The spleen emerges as a pivotal target for mRNA delivery, prompting a continual quest for specialized and efficient lipid nanoparticles (LNPs) designed to enhance spleen-selective transfection efficiency. Here we report imidazole-containing ionizable lipids (IMILs) that demonstrate a pronounced preference for mRNA delivery into the spleen with exceptional transfection efficiency. We optimized IMIL structures by constructing and screening a multidimensional IMIL library containing multiple heads, tails, and linkers to perform a structure-activity correlation analysis. Following high-throughput in vivo screening, we identified A3B7C2 as a top-performing IMIL in spleen-specific mRNA delivery via the formulated LNPs, achieving a remarkable 98% proportion of splenic transfection. Moreover, A3B7C2-based LNPs are particularly potent in splenic dendritic cell transfection. Comparative analyses revealed that A3B7C2-based LNPs achieved a notable 2.8-fold and 12.9-fold increase in splenic mRNA transfection compared to SM102 and DLin-MC3-DMA lipid formulations, respectively. Additionally, our approach yielded an 18.3-fold enhancement in splenic mRNA expression compared to the SORT method without introducing additional anionic lipids. Collectively, these IMILs highlight promising avenues for further research in spleen-selective mRNA delivery. This work offers valuable insights for the swift discovery and rational design of ionizable lipid candidates tailored for spleen-selective transfection, thereby facilitating the application of mRNA therapeutics in spleen-related interventions.

Health-Related Quality of Life in Patients with Inherited Ataxia in Ireland.

Inherited cerebellar ataxias (CA) are heterogeneous progressive neurological conditions associated with significant functional limitations. This study aimed to assess the implications of inherited CA on patients' self-reported quality of life (QoL) and impairments in work and activities. 129 individuals with ataxia responded to a survey focused on QoL. Health-related QoL was measured using the RAND 36-Item Short Form Survey. An adaptation of the validated Work Productivity and Activity Impairment questionnaire was used to assess the effect of health on work productivity and ability to perform activities over the past week. Nine percent of respondents were currently employed. Individuals with inherited ataxia experienced significant activity impairment, and 75% required professional or informal care. Health-related quality of life (HRQoL) was significantly worse in all areas for the individuals with inherited ataxia compared with Irish population normative values. Participants with Friedreich's ataxia (n = 56) demonstrated worse physical functioning then those with undetermined ataxia (n = 55). Female gender, younger age at symptom onset, current employment, retirement due to age or ataxia, and living in a long-term care facility were associated with higher sub-scores in different domains of HRQoL, while disease duration correlated with worse physical functioning sub-scores. This study is the first cross-sectional study on HRQoL in patients with inherited ataxia in Ireland. It highlights high rates of unemployment, difficulty with daily activities and physical functioning limitations, which is worse than comparative international studies. Given the limited therapeutic options currently available, optimising HRQoL is an important aspect of managing ataxia.

Dry-Spinning of Artificial Spider Silk Ribbons From Regenerated Natural Spidroin in an Organic Medium.

Natural spider silks with striking performances achieve extensive investigations. Nonetheless, a lack of consensus over the mechanism of the natural spinning hinders the development of artificial spinning methods where the regenerated spider silks generally show poor performances compared with the natural fibers. As is known, the Plateau-Rayleigh instability tends to break solution column into droplets and is considered a main challenge during fiber-spinning. Here in this study, by harnessing the viscoelastic properties of the regenerated spidroin dope solution via organic salt-zinc acetate (ZA), this outcome can be avoided, and dry-spinning of long and mechanically robust regenerated spider silk ribbons can be successfully realized. The as-obtained dry-spun spider silk ribbons show an enhanced modulus up to 14 ± 4 GPa and a toughness of ≈51 ± 9 MJ m-3 after the post-stretching treatment, which is even better than that of the pristine spider silk fibers. This facile and flexible strategy enriches the spinning methodologies which bypass the bottleneck of precisely mimicking the complex natural environment of the glands in spiders, shining a light to the spider-silk-based textile industrial applications.

Single-Splint, 2-Jaw Orthognathic Surgery for Correction of Facial Asymmetry: 3-Dimensional Planning and Surgical Execution.

Three-dimensional (3D) planning of orthognathic surgery (OGS) improves the treatment of facial asymmetry and malocclusion, but no consensus exists among clinicians regarding technical details. This study verified the consistency of authors' workflow and strategies between 3D planning and surgical execution for facial asymmetry. This retrospective study recruited consecutive patients (n=54) with nonsyndromic facial asymmetry associated with malocclusion. The stepwise workflow included orthodontic treatment, 3D imaging-based evaluation, planning, and transferring the virtual of single-splint 2-jaw OGS to actual surgery in all patients. Seven landmark-based measurements were selected for postoperative assessment of facial symmetry. Fifty patients had no anesthetic/surgical-related episode and procedure-related complications. Others experienced wound infection (n=1), transient TMJ discomfort (n=1), and facial numbness (n=3). Two cases had minor residual asymmetry (cheek and chin, respectively), but did not request revisionary bone or soft tissue surgery. Comparisons between the planned and postoperative 3D images with quantitative measurement revealed acceptable outcome data. The results showed a significant increase in facial symmetry at 7 landmark-based postoperative measurements for both male and female. This 3D-assisted pathway of OGS permitted achievement of consistent satisfactory results in managing facial asymmetry, with low rate of complications and secondary management.

Palladium-Catalyzed Three-Component 1,4-Alkoxyarylation Reaction of [60]Fullerene.

The palladium-catalyzed three-component alkoxyarylation reaction of [60]fullerene with primary/secondary alcohols and aryl iodides generates a series of 1,4-(alkoxy)(aryl)[60]fullerene derivatives. Plausible reaction pathways for the formation of 1,4-(alkoxy)(aryl)[60]fullerenes are proposed. In addition, the electrochemical properties of the synthesized 1,4-alkoxyarylation adducts are investigated.

Design of a Highly Sensitive Reduced Graphene Oxide/Graphene Oxide@Cellulose Acetate/Thermoplastic Polyurethane Flexible Sensor.

As a substitute for rigid sensors, flexible sensing materials have been greatly developed in recent years, but maintaining the stability of conductive fillers and the stability of micro-strain sensing is still a major challenge. In this experiment, we innovatively prepared a polyurethane-based cellulose acetate composite membrane (CA/TPU) with abundant mesopores through electrospinning. Then, we reduced graphene oxide (rGO)-as a conductive filler-and graphene oxide (GO)-as an insulating layer-which were successively and firmly anchored on the CA/TPU nanofiber membrane with the ultrasonic impregnation method, to obtain an rGO/GO@CA/TPU sensor with a GF of 3.006 under a very small strain of 0.5%. The flexibility of the film and its high sensitivity under extremely low strains enables the detection of subtle human motions (such as finger bending, joint motion, etc.), making it suitable for potential application in wearable electronic devices.

Antimicrobial activity of a quaternized BODIPY against Staphylococcus strains.

A novel BODIPY derivative was designed for biomedical applications. Its mono-quaternized structure ensured its water-solubility and suitable amphiphilicity. Showing no singlet oxygen generation to avoid damage to healthy cells, this new derivative proved to be an extremely promising antimicrobial agent, with activity equal or superior to ampicillin against MRS Staphylococcus strains with no short-term resistance issue. Its activity against MSS Staphylococcus strains was largely superior to those of ampicillin and reached the activity of vancomycin against MSS S. epidermidis. This latter result is in particular extremely promising for the treatment of hospital-acquired infections. Also the fluorescence properties of BODIPY allowed imaging of the uptake.

Selection of reference genes for microRNA quantitative expression analysis in Chinese perch, Siniperca chuatsi.

Real-time quantitative reverse transcription PCR (RT-qPCR) is one of the most effective and sensitive techniques in gene expression assay, for which selection of reference genes is a prerequisite. In teleost species, such as Chinese perch, the expression profiling of miRNAs as reference genes for RT-qPCR has not been intensively studied. In the present study, the expression profiles of six miRNAs (miR-101a, miR-146a, miR-22a, miR-23a, miR-26a and let-7a) and one small nuclear RNA (U6) were assayed with RT-qPCR in different adult tissues, developmental stages and growth conditions of Chinese perch, Siniperca chuatsi. The analyses revealed that embryonic developmental stage is an important variability factor in the expression stability of miRNAs. All six miRNAs exhibited better expression consistency than U6 in most of the conditions examined, and therefore, they may be more suitable as a reference gene for miRNA quantification. When different tissues and developmental stages were considered, miR-22a demonstrated the most consistent expression pattern, and the best combination of reference genes was miR-22a and miR-23a. Our study offers useful data for selecting miRNAs as reference genes for RT-qPCR analysis of miRNAs in teleost fishes under different conditions.

Topological Defect-Regulated Porous Carbon Anodes with Fast Interfacial and Bulk Kinetics for High-Rate and High-Energy-Density Potassium-Ion Batteries.

Carbonaceous materials are regarded as one of the most promising anodes for potassium-ion batteries (PIBs), but their rate capabilities are largely limited by the slow solid-state potassium diffusion kinetics inside anode and sluggish interfacial potassium ion transfer process. Herein, high-rate and high-capacity PIBs are demonstrated by facile topological defect-regulation of the microstructure of carbon anodes. The carbon lattice of the as-obtained porous carbon nanosheets (CNSs) with abundant topological defects (TDPCNSs) holds relatively high potassium adsorption energy yet low potassium migration barrier, thereby enabling efficient storage and diffusion of potassium inside graphitic layers. Moreover, the topological defects can induce preferential decomposition of anions, leading to the formation of high potassium ion conductive solid electrolyte interphase (SEI) film with decreased potassium ion de-solvation and transfer barrier. Additionally, the dominant sp2-hybridized carbon conjugated skeleton of TDPCNSs enables high electrical conductivity (39.4 S cm-1) and relatively low potassium storage potential. As a result, the as-constructed TDPCNSs anode demonstrates high potassium storage capacity (504 mA h g-1 at 0.1 A g-1), remarkable rate capability (118 mA h g-1 at 40 A g-1), as well as long-term cycling stability.

Emergence of eravacycline heteroresistance in carbapenem-resistant Acinetobacter baumannii isolates in China.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is resistant to almost all antibiotics. Eravacycline, a newer treatment option, has the potential to treat CRAB infections, however, the mechanism by which CRAB isolates develop resistance to eravacycline has yet to be clarified. This study sought to investigate the features and mechanisms of eravacycline heteroresistance among CRAB clinical isolates. A total of 287 isolates were collected in China from 2020 to 2022. The minimum inhibitory concentration (MIC) of eravacycline and other clinically available agents against A. baumannii were determined using broth microdilution. The frequency of eravacycline heteroresistance was determined by population analysis profiling (PAP). Mutations and expression levels of resistance genes in heteroresistant isolates were determined by polymerase chain reaction (PCR) and quantitative real-time PCR (qRT-PCR), respectively. Antisense RNA silencing was used to validate the function of eravacycline heteroresistant candidate genes. Twenty-five eravacycline heteroresistant isolates (17.36%) were detected among 144 CRAB isolates with eravacycline MIC values ≤4 mg/L while no eravacycline heteroresistant strains were detected in carbapenem-susceptible A. baumannii (CSAB) isolates. All eravacycline heteroresistant strains contained OXA-23 carbapenemase and the predominant multilocus sequence typing (MLST) was ST208 (72%). Cross-resistance was observed between eravacycline, tigecycline, and levofloxacin in the resistant subpopulations. The addition of efflux pump inhibitors significantly reduced the eravacycline MIC in resistant subpopulations and weakened the formation of eravacycline heteroresistance in CRAB isolates. The expression levels of adeABC and adeRS were significantly higher in resistant subpopulations than in eravacycline heteroresistant parental strains (P < 0.05). An ISAba1 insertion in the adeS gene was identified in 40% (10/25) of the resistant subpopulations. Decreasing the expression of adeABC or adeRS by antisense RNA silencing significantly inhibited eravacycline heteroresistance. In conclusion, this study identified the emergence of eravacycline heteroresistance in CRAB isolates in China, which is associated with high expression of AdeABC and AdeRS.

Absorption and scattering of light from ensembles of randomly oriented aggregates.

This paper presents one approach to the absorption and scattering of light from aggregates of primary particles. The primary particles are sphere-like and small compared to the wavelength, whereas the aggregate can be large compared to the wavelength. This situation applies to when soot particles formed in flames are measured using methods based on laser light. The method presented in this work, called generalized Rayleigh-Debye-Gans, leads to closed-form expressions for the scattered intensity and the absorbed power of an ensemble of aggregates with random positions and orientations. The expressions ensure a fast and accurate numerical evaluation of the scattering and absorption from ensembles of aggregates. The numerical results are compared with the ones obtained from the T-matrix method and the discrete dipole approximation method.

Peroxisome proliferator-activated receptor δ improves the features of atherosclerotic plaque vulnerability by regulating smooth muscle cell phenotypic switching.

BACKGROUND AND PURPOSE: Vascular smooth muscle cells (SMCs) undergo phenotypic switching during sustained inflammation, contributing to an unfavourable atherosclerotic plaque phenotype. PPARδ plays an important role in regulating SMC functions; however, its role in atherosclerotic plaque vulnerability remains unclear. Here, we explored the pathological roles of PPARδ in atherosclerotic plaque vulnerability in severe atherosclerosis and elucidated the underlying mechanisms. EXPERIMENTAL APPROACH: Plasma levels of PPARδ were measured in patients with acute coronary syndrome (ACS) and stable angina (SA). SMC contractile and synthetic phenotypic markers, endoplasmic reticulum (ER) stress, and features of atherosclerotic plaque vulnerability were analysed for the brachiocephalic artery of apolipoprotein E-knockout (ApoE-/- ) mice, fed a high-cholesterol diet (HCD) and treated with or without the PPARδ agonist GW501516. In vitro, the role of PPARδ was elucidated using human aortic SMCs (HASMCs). KEY RESULTS: Patients with ACS had significantly lower plasma PPARδ levels than those with SA. GW501516 reduced atherosclerotic plaque vulnerability, a synthetic SMC phenotype, ER stress markers, and NLRP3 inflammasome expression in HCD-fed ApoE-/- mice. ER stress suppressed PPARδ expression in HASMCs. PPARδ activation inhibited ER stress-induced synthetic phenotype development, ER stress-NLRP3 inflammasome axis activation and matrix metalloproteinase 2 (MMP2) expression in HASMCs. PPARδ inhibited NFκB signalling and alleviated ER stress-induced SMC phenotypic switching. CONCLUSIONS AND IMPLICATIONS: Low plasma PPARδ levels may be associated with atherosclerotic plaque vulnerability. Our findings provide new insights into the mechanisms underlying the protective effect of PPARδ on SMC phenotypic switching and improvement the features of atherosclerotic plaque vulnerability.

TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2.

Metastatic colorectal cancer (mCRC) is characterized by poorer prognosis of patients and limited therapeutic approach, partly due to the lack of effective target. Using mouse models and tumor organoids, this study reported a tripartite motif 21 (TRIM21) protein, exerting potential inhibitory effects on the invasion and metastasis of CRC. Mechanistically, TRIM21 directly interacted with and ubiquitinated MST2 at lysine 473 (K473) via K63-linkage. This ubiquitination enabled the formation of MST2 homodimer and enhanced its kinase activity, ultimately resulting in the functional inactivation of yes-associated protein (YAP) and inhibition of an epithelial-mesenchymal transition (EMT) feature. We identified that vilazodone, an antidepressant, directly bound to TRIM21 to exert effective anti-metastatic action both in vitro and in vivo. Collectively, these findings revealed a previously unrecognized interplay between TRIM21 and the Hippo-YAP signaling. These results suggested that vilazodone could be repositioned as an anti-tumor drug to inhibit CRC metastasis by targeting TRIM21.

Hydrogen phosphates play a critical structural role in amorphous calcium phosphates.

Amorphous calcium phosphate (ACP) is an intriguing mineral phase of calcium phosphate in its own right, in addition to its relevance in biomineralization. We hereby demonstrate that ACPs prepared by different synthetic routes such as the crosslinking of inorganic oligomers and polymer-induced liquid precursors have distinctive relative compositions of orthophosphate and hydrogen phosphate, and the extent of their hydrogen bonding with water. For all the ACPs or ACP-derived materials studied in this work, the species of hydrogen phosphate is the most important structural element. Depending on the synthetic pathways, orthophosphate and water, as well as their associated hydrogen bonds, may also play a role in the structural formation of ACPs.

Comparative assessment and novel strategy on methods for imputing proteomics data.

Missing values are a major issue in quantitative proteomics analysis. While many methods have been developed for imputing missing values in high-throughput proteomics data, a comparative assessment of imputation accuracy remains inconclusive, mainly because mechanisms contributing to true missing values are complex and existing evaluation methodologies are imperfect. Moreover, few studies have provided an outlook of future methodological development. We first re-evaluate the performance of eight representative methods targeting three typical missing mechanisms. These methods are compared on both simulated and masked missing values embedded within real proteomics datasets, and performance is evaluated using three quantitative measures. We then introduce fused regularization matrix factorization, a low-rank global matrix factorization framework, capable of integrating local similarity derived from additional data types. We also explore a biologically-inspired latent variable modeling strategy-convex analysis of mixtures-for missing value imputation and present preliminary experimental results. While some winners emerged from our comparative assessment, the evaluation is intrinsically imperfect because performance is evaluated indirectly on artificial missing or masked values not authentic missing values. Nevertheless, we show that our fused regularization matrix factorization provides a novel incorporation of external and local information, and the exploratory implementation of convex analysis of mixtures presents a biologically plausible new approach.

A novel in vitro angiogenesis model based on a microfluidic device.

Angiogenesis is very important for many physiological and pathological processes. However, the molecular mechanisms of angiogenesis are unclear. To elucidate the molecular mechanisms of angiogenesis and to develop treatments for "angiogenesis- dependent" diseases, it is essential to establish a suitable in vitro angiogenesis model. In this study, we created a novel in vitro angiogenesis model based on a microfluidic device. Our model provides an in vivo-like microenvironment for endothelial cells (ECs) cultures and monitors the response of ECs to changes in their microenvironment in real time. To evaluate the potential of this microfluidic device for researching angiogenesis, the effects of pro-angiogenic factors on ECs proliferation, migration and tube-like structure formation were investigated. Our results showed the proliferation rate of ECs in 3D matrix was significantly promoted by the pro-angiogenic factors (with an increase of 59.12%). With the stimulation of pro-angiogenic factors gradients, ECs directionally migrated into the Matrigel from low concentrations to high concentrations and consequently formed multi-cell chords and tube-like structures. These results suggest that the device can provide a suitable platform for elucidating the mechanisms of angiogenesis and for screening pro-angiogenic or anti-angiogenic drugs for "angiogenesis-dependent" diseases.

Preparation and Properties of Cassava Residue Cellulose Nanofibril/Cassava Starch Composite Films.

Because of its non-toxic, pollution-free, and low-cost advantages, environmentally-friendly packaging is receiving widespread attention. However, using simple technology to prepare environmentally-friendly packaging with excellent comprehensive performance is a difficult problem faced by the world. This paper reports a very simple and environmentally-friendly method. The hydroxyl groups of cellulose nanofibrils (CNFs) were modified by introducing malic acid and the silane coupling agent KH-550, and the modified CNF were added to cassava starch as a reinforcing agent to prepare film with excellent mechanical, hydrophobic, and barrier properties. In addition, due to the addition of malic acid and a silane coupling agent, the dispersibility and thermal stability of the modified CNFs became significantly better. By adjusting the order of adding the modifiers, the hydrophobicity of the CNFs and thermal stability were increased by 53.5% and 36.9% ± 2.7%, respectively. At the same time, the addition of modified CNFs increased the tensile strength, hydrophobicity, and water vapor transmission coefficient of the starch-based composite films by 1034%, 129.4%, and 35.95%, respectively. This material can be widely used in the packaging of food, cosmetics, pharmaceuticals, and medical consumables.

From Cellulose to Cellulose Nanofibrils-A Comprehensive Review of the Preparation and Modification of Cellulose Nanofibrils.

This review summarizes the preparation methods of cellulose nanofibrils (CNFs) and the progress in the research pertaining to their surface modification. Moreover, the preparation and surface modification of nanocellulose were comprehensively introduced based on the existing literature. The review focuses on the mechanical treatment of cellulose, the surface modification of fibrillated fibers during pretreatment, the surface modification of nanocellulose and the modification of CNFs and their functional application. In the past five years, research on cellulose nanofibrils has progressed with developments in nanomaterials research technology. The number of papers on nanocellulose alone has increased by six times. However, owing to its high energy consumption, high cost and challenging industrial production, the applications of nanocellulose remain limited. In addition, although nanofibrils exhibit strong biocompatibility and barrier and mechanical properties, their high hydrophilicity limits their practical application. Current research on cellulose nanofibrils has mainly focused on the industrial production of CNFs, their pretreatment and functional modification and their compatibility with other biomass materials. In the future, with the rapid development of modern science and technology, the demand for biodegradable biomass materials will continue to increase. Furthermore, research on bio-based nanomaterials is expected to advance in the direction of functionalization and popularization.

Avoiding Inferior Alveolar Nerve Injury during Osseous Genioplasty: A Guide for the Safe Zone by Three-Dimensional Virtual Imaging.

BACKGROUND: No consensus exists about the safest position for performing the osseous genioplasty, with 5 to 6 mm below the mental foramen being the most frequently recommended position. This study intends to generate a safe distance guide to minimize the risk of inferior alveolar nerve injury during osteotomy. METHODS: Pretreatment cone-beam computed tomography-derived three-dimensional models from adult patients with skeletal class I to III patterns and cleft lip/palate deformity who underwent orthodontic-surgical interventions (n = 317) were analyzed. A three-dimensional vertical distance between the inferior margin of the mental foramen and the lowest point of the inferior alveolar nerve canal was measured in each three-dimensional hemimandible (n = 634). Statistical analysis was performed to generate the safe distance guide in a stepwise fashion at 95, 99, and 99.99 percent confidence levels. RESULTS: Class III (4.35 ± 1.42 mm) and cleft lip/palate (4.42 ± 1.53 mm) groups presented significantly (p < 0.001) larger three-dimensional distances than class I (3.44 ± 1.54 mm) and class II (3.66 ± 1.51 mm) groups. By considering the 5- to 6-mm safe distance parameter, 6.4, 5.0, 10.6, 16, and 9.9 percent of hemimandibles were at risk of osteotomy-induced nerve injury in the class I, class II, class III, cleft lip/palate, and overall cohorts, respectively. Overall, the safe distance zone to perform the osteotomy was set at 7.06, 8.01, and 9.12 mm below the mental foramen, with risk probabilities of 2.5, 0.5, and 0.0005 percent, respectively. CONCLUSION: This study contributes to patient safety and surgeon practice by proving a safe distance guide for genioplasty.

Regulation of human Mcl-1 by a divergently-expressed antisense transcript.

Mcl-1 is a member of the Bcl-2 anti-apoptotic protein family with important roles in the development, lifespan and metabolism of lymphocytes, as well as oncogenesis. Mcl-1 displays the shortest half-life of all Bcl-2 family members, with miRNA interference and proteasomal degradation being major pathways for Mcl-1 downregulation. In this study, we have identified a previously undescribed control mechanism active at the RNA level. A divergently transcribed lncRNA LOC107985203 (named here mcl1-AS1) negatively modulated Mcl-1 expression resulting in downregulation of Mcl-1 at both mRNA and protein level in a time-dependent manner. Using reporter assays, we confirmed that the mcl1-AS1 lncRNA promoter was located within Mcl-1 coding region. We next placed mcl1-AS1 under tetracycline-inducible control and demonstrated decreased viability in HEK293 cells upon doxycycline induction. Inhibition of mcl1-AS1 with shRNA reversed drug sensitivity. Bioinformatics surveys predicted direct mcl1-AS1 lncRNA binding to Mcl-1 transcripts, suggesting its mechanism in Mcl-1 expression is at the transcriptional level, consistent with a common role for anti-sense transcripts. The identification of a bi-directional promoter and lncRNA controlling Mcl-1 expression will have implications for controlling Mcl-1 activity in cancer cells, or for the purpose of enhancing the lifespan and quality of anti-cancer T lymphocytes.