SAP deletion promotes malignant insulinoma progression by inducing CXCL12 secretion from CAFs via the CXCR4/p38/ERK signalling pathway.

Malignant insulinoma is an extremely rare type of functioning pancreatic neuroendocrine tumour with a high degree of malignancy and a high incidence of metastasis. However, it is still unclear how malignant insulinomas develop and metastasize. Serum amyloid P component (SAP), a member of the pentraxin protein family, is an acute-phase protein secreted by liver cells. The role of SAP in insulinoma and the related mechanism are still unknown. To determine the effect of SAP on insulinoma, we crossed Rip1-Tag2 mice, which spontaneously develop insulinoma, and SAP knockout (KO) mice to generate Rip1-Tag2;SAP-/- mice. We found that SAP deletion significantly promoted the growth, invasion and metastasis of malignant insulinoma through C-X-C motif chemokine ligand 12 (CXCL12) secreted by cancer-associated fibroblasts (CAFs). Further study showed that SAP deletion promoted CXCL12 secretion by CAFs through the CXCR4/p38/ERK signalling pathway. These findings reveal a novel role and mechanism of SAP in malignant insulinoma and provide direct evidence that SAP may be a therapeutic agent for this disease.

Competitive Coordination of Sodium Ions for High-Voltage Sodium Metal Batteries with Fast Reaction Speed.

The unstable electrode-electrolyte interface and the narrow electrochemical window of normal electrolytes hinder the potential application of high-voltage sodium metal batteries. These problems are actually related to the solvation structure of the electrolyte, which is determined by the competition between cations coordinated with anions or solvent molecules. Herein, we design an electrolyte incorporating ethyl (2,2,2-trifluoroethyl) carbonate and fluoroethylene carbonate, which facilitates a pronounced level of cation-anion coordination within the solvation sheath by enthalpy changes to reduce the overall coordination of cation-solvents and increase sensitivity to salt concentration. Such an electrolyte regulated by competitive coordination leads to highly reversible sodium plating/stripping with extended cycle life and a high Coulombic efficiency of 98.0%, which is the highest reported so far in Na||Cu cells with ester-based electrolytes. Moreover, 4.5 V high-voltage Na||Na3V2(PO4)2F3 cells exhibit a high rate capability up to 20 C and an impressive cycling stability with an 87.1% capacity retention after 250 cycles with limited Na. The proposed strategy of solvation structure modification by regulating the competitive coordination of the cation provides a new direction to achieve stable sodium metal batteries with high energy density and can be further extended to other battery systems by controlling enthalpy changes of the solvation structure.

The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Augmented reality system based on the integration of polarization-independent metalens and micro-LEDs.

Augmented reality (AR), a technology that superimposes virtual information onto a user's direct view of real-world scenes, is considered one of the next-generation display technologies and has been attracting considerable attention. Here, we propose a flat optic AR system that synergistically integrates a polarization-independent metalens with micro light-emitting diodes (LEDs). A key component is a meticulously designed metalens with a numerical aperture of 0.25, providing a simulated focusing efficiency of approximately 76.5% at a wavelength of 532 nm. Furthermore, the laser measurement system substantiates that the fabricated metalens achieves a focusing efficiency of 70.8%. By exploiting the reversibility of light characteristics, the metalens transforms the divergent light from green micro-LEDs into a collimated beam that passes through the pupil and images on the retina. Monochromatic pixels with a size of 5×5 µm2 and a pitch of 10 µm can be distinctly resolved with a power efficiency of 50%. This work illustrates the feasibility of integrating the metalens with microdisplays, realizing a high-efficiency AR device without the need for additional optical components and showcasing great potential for the development of near-eye display applications.

Early Wnt Signaling Activation Promotes Inner Ear Differentiation via Cell Caudalization in Mouse Stem Cell-Derived Organoids.

The inner ear is derived from the otic placode, one of the numerous cranial sensory placodes that emerges from the pre-placodal ectoderm (PPE) along its anterior-posterior axis. However, the molecular dynamics underlying how the PPE is regionalized are poorly resolved. We used stem cell-derived organoids to investigate the effects of Wnt signaling on early PPE differentiation and found that modulating Wnt signaling significantly increased inner ear organoid induction efficiency and reproducibility. Alongside single-cell RNA sequencing, our data reveal that the canonical Wnt signaling pathway leads to PPE regionalization and, more specifically, medium Wnt levels during the early stage induce (1) expansion of the caudal neural plate border (NPB), which serves as a precursor for the posterior PPE, and (2) a caudal microenvironment that is required for otic specification. Our data further demonstrate Wnt-mediated induction of rostral and caudal cells in organoids and more broadly suggest that Wnt signaling is critical for anterior-posterior patterning in the PPE.

Association between screen time and self-reported balance disorders in middle-aged and older adults: national health and nutrition examination survey.

BACKGROUND: Balance disorders can give rise to sensations of instability, lightheadedness, vertigo, disequilibrium, or syncope, ultimately leading to grave medical, physical, emotional, and societal ramifications. These conditions are highly prevalent among individuals aged 40 and above. Screen time encompasses activities associated with television viewing, video game playing, and non-work-related computer usage. Prolonged screen exposure may engender a spectrum of health issues and even elevate overall mortality rates. However, the available evidence on the potential link between excessive screen time and balance dysfunction remains limited. AIMS: The primary aim of this study was to explore the possible association between prolonged screen exposure and impaired balance function. METHODS: This cross-sectional study utilized data from participants who completed a comprehensive questionnaire in the NHANES database between 1999 and 2002, all of whom were aged over 40 and under 85 years. Participants' screen time was categorized into two groups (< 4 h/d and ≥4 h/d) for subsequent data analysis. Logistic regression, combined with propensity score matching (PSM), was employed to investigate the correlation between screen time and balance disorders. RESULTS: A total of 5176 participants were enrolled in this study, comprising 2,586 men and 2,590 women, with a prevalence rate of balance disorders at 25.7% (1331/5176). The incidence of balance disorders was found to be significantly higher among individuals who spent 4 hours or more per day on screen time compared to those with less screen time (P<0.001). Multivariate logistic analysis conducted on the unmatched cohort revealed a significant association between screen time and balance disorders, with an odds ratio (OR) 1.8 (95%CI 1.57 ∼ 2.05). These findings remained consistent even after adjusting for confounding factors, yielding an OR 1.43 (95%CI 1.24 ∼ 1.66). Moreover, the association persisted when employing various multivariate analyses such as propensity score matching adjusted model, standardized mortality ratio weighting model and pairwise algorithmic model; all resulting in ORs ranging from 1.38 to 1.43 and p-values < 0.001. CONCLUSIONS: After controlling for all covariates, screen time (watching TV, playing video games, and using computers outside of work) was associated with balance dysfunction among middle-aged and older adults. This finding may offer a possible idea for the prevention of dizziness and balance disorders. Nevertheless, additional research is imperative to further validate these results.

Regulation and drug modulation of a voltage-gated sodium channel: Pivotal role of the S4-S5 linker in activation and slow inactivation.

Voltage-gated sodium (NaV) channels control excitable cell functions. While structural investigations have revealed conformation details of different functional states, the mechanisms of both activation and slow inactivation remain unclear. Here, we identify residue T140 in the S4-S5 linker of the bacterial voltage-gated sodium channel NaChBac as critical for channel activation and drug effects on inactivation. Mutations at T140 either attenuate activation or render the channel nonfunctional. Propofol, a clinical anesthetic known to inhibit NaChBac by promoting slow inactivation, binds to a pocket between the S4-S5 linker and S6 helix in a conformation-dependent manner. Using 19F-NMR to quantify site-specific binding by saturation transfer differences (STDs), we found strong STDs in inactivated, but not activated, NaChBac. Molecular dynamics simulations show a highly dynamic pocket in the activated conformation, limiting STD buildup. In contrast, drug binding to this pocket promotes and stabilizes the inactivated states. Our results provide direct experimental evidence showing distinctly different associations between the S4-S5 linker and S6 helix in activated and inactivated states. Specifically, an exchange occurs between interaction partners T140 and N234 of the same subunit in activation, and T140 and N225 of the domain-swapped subunit in slow inactivation. The drug action on slow inactivation of prokaryotic NaV channels seems to have a mechanism similar to the recently proposed "door-wedge" action of the isoleucine-phenylalanine-methionine (IFM) motif on the fast inactivation of eukaryotic NaV channels. Elucidating this gating mechanism points to a possible direction for conformation-dependent drug development.

Effectiveness of a multicomponent activity and horticultural intervention for the hospitalized older adults: A randomized controlled trial: Effectiveness of Intervention for the Hospitalized Older Adults.

This study evaluated the effectiveness of different intervention programs in improving function among hospitalized older individuals using the Comprehensive Geriatric Assessment (CGA). A randomized controlled trial consisted of three groups: routine care, horticulture, and multicomponent activities (n = 32 each). Horticultural and multicomponent activity interventions showed beneficial effects on the CGA in hospitalized older individuals, particularly regarding cognitive function and quality-of-life. Additionally, horticultural activities significantly contributed to the perception of older adults' health status. We recommend to select older patients in geriatric wards with long-term hospitalization and adjust the frequency of activities or choose a single intervention program to provide long-term and effective intervention effects.

Stereodivergent Total Synthesis of Tacaman Alkaloids.

This paper describes a concise, asymmetric and stereodivergent total synthesis of tacaman alkaloids. A key step in this synthesis is the biocatalytic Baeyer-Villiger oxidation of cyclohexanone, which was developed to produce seven-membered lactones and establish the required stereochemistry at the C14 position (92% yield, 99% ee, 500 mg scale). Cis- and trans-tetracyclic indoloquinolizidine scaffolds were rapidly synthesized through an acid-triggered, tunable acyl-Pictet-Spengler type cyclization cascade, serving as the pivotal reaction for building the alkaloid skeleton. Computational results revealed that hydrogen bonding was crucial in stabilizing intermediates and inducing different addition reactions during the acyl-Pictet-Spengler cyclization cascade. By strategically using these two reactions and the late-stage diversification of the functionalized indoloquinolizidine core, the asymmetric total syntheses of eight tacaman alkaloids were achieved. This study may potentially advance research related to the medicinal chemistry of tacaman alkaloids.

Directing Highly Ordered and Dense Li Deposition to Achieve Stable Li Metal Batteries.

Li metal anode is promising to achieve high-energy-density battery. However, it has rapid capacity fading due to the generation of inactive Li (dead Li), especially at high current density. This study reveals that the random distribution of Li nuclei leads to large uncertainty for the further growth behavior on Cu foil. Here, periodical regulation of Li nucleation sites on Cu foil by ordered lithiophilic micro-grooves is proposed to precisely manipulate the Li deposition morphology. The management of Li deposits in the lithiophilic grooves can induce high pressure on the Li particles, leading to the formation of dense Li structure and smooth surface without dendrite growth. Li deposits comprising tightly packed large Li particles largely reduce the side reaction and the generation of isolated metallic Li at high current density. Less dead Li accumulating on the substrate significantly prolongs the cycling life of full cells with limited Li inventory. The precise manipulation of the Li deposition on Cu is promising for high-energy and stable Li metal batteries.

Transcriptomic data recover a new superfamily-level phylogeny of Cucujiformia (Coleoptera, Polyphaga).

Cucujiformia, the largest taxon in the order Coleoptera, exhibits extraordinary morphological, ecological, and behavioral diversity. This infraorder is currently divided into seven superfamilies, but considerably incongruent relationships among superfamilies have been reported by recent phylogenomic studies. Here, we combined the 21 newly sequenced transcriptomes representing six superfamilies with nine previously published cucujiform genomes/transcriptomes to elucidate the phylogeny and evolution of Cucujiformia. The monophyly of each of five superfamilies were consistently supported by all phylogenetic analyses based on the twelve datasets (matrix occupancy, amino acid and nucleotide data) and the two analytical methods (maximum likelihood method and Bayesian inference). Both the amino acid datasets and the RY recoded nucleotide datasets recovered the monophyly of Cucujoidea. Topology test results statistically supported the following robust superfamily-level phylogeny in Cucujiformia: (Coccinelloidea, (Cleroidea, (Tenebrionoidea, (Cucujoidea, (Chrysomeloidea, Curculionoidea))))). Our divergence time analyses recovered a Permian origin of Cucujiformia and a Jurassic-Cretaceous origin of most superfamilies. The diversification of phytophagous beetles that occurred in the Cretaceous can be attributed to its co-evolution with angiosperms, supporting the hypothesis of a Cretaceous Terrestrial Revolution.

Technological process optimization and measurement of image quality of the electrically bifocal metalens.

This Letter describes the design procedure and process optimization of the electrically bifocal metalens. In our design, horizontal and vertical polarization is manipulated by applying a suitable voltage to a twisted nematic liquid crystal (TN-LC) cell. Each nanostructure is designed to be a rectangular prism, making different polarizations of light experience various phase delays, thus causing bi-focus. We selected lithographical methods to fabricate our metalens because of the minimum physical size, which can be as small as 50 nm, and the maximum aspect ratio, which is as high as 15. Furthermore, to increase the tolerance and make the sidewall vertical and smooth, we coated different characteristics of photoresist sensitivity to the upper and lower layers. After the development, the mushroom-type photoresist makes Ni easier to strip while in the lift-off process, thus increasing the quality of the whole metalens. Our experiment shows that the focal lengths and focusing efficiencies corresponding to the two polarizations are similar to the simulation results. The proposed electrically modulated bifocal metalens can be utilized in different applications and combined with other optical components.

Identification of cuticular protein genes and analysis of their roles in phosphine resistance of the rusty grain beetle Cryptolestes ferrugineus.

The rusty grain beetle, Cryptolestes ferrugineus (Stephens) is one of the most economically important stored grain pests, and it has evolved the high resistance to phosphine. Cuticular proteins (CPs) are the major structural components of insect cuticle, and previous studies have confirmed that CPs were involved in insecticide resistance. However, the CPs of C. ferrugineus are still poorly characterized, and thus we conducted transcriptome-wide identification of CP genes and analyze their possible relationships with phosphine resistance in this pest. In this study, a total of 122 putative CPs were annotated in the C. ferrugineus transcriptome data by blasting with the known CPs of Tribolium castaneum. The analysis of conserved motifs revealed these CPs of C. ferrugineus belonging to 9 different families, including 87 CPR, 13 CPAP1, 7 CPAP3, 3 Tweedle, 1 CPLCA, 1 CPLCG, 5 CPLCP, 2 CPCFC, and 3 CPFL proteins. The further phylogenetic analysis showed the different evolutionary patterns of CPs. Namely, we found some CPs (CPR family) formed species-specific protein clusters, indicating these CPs might occur independently among insect taxa, and while some other CPs (CPAP1 and CPAP3 family) shared a closer correlation based on the architecture of protein domains. Subsequently, the previous RNA-seq data were applied to establish the expression profiles of CPs in a phosphine susceptible and resistant populations of C. ferrugineus, and a large amount of CP genes were found to be over-expressed in resistant insects. Lastly, an up-regulated CP gene (CPR family) was selected for the further functional analysis, and after this gene was silenced via RNA interference (RNAi), the sensitivity to phosphine was significantly enhanced in C. ferrugineus. In conclusion, the present results provided us an overview of C. ferrugineus CPs, and which suggested that the CPs might play the critical roles in phosphine resistance.

Multi-conformers caused by conformational change of A-ring in the C18- and C19-N-dealkyl diterpenoid alkaloids.

This paper describes a rare phenomenon of multi-conformers caused by conformational change of A-ring in the C18- and C19- N-dealkyl diterpenoid alkaloids. The possible reasons for the generation of multiple conformational isomers are complex, which could be affected by the substituents at C-1, C-3, C-13, C-14, and C-15, pH, solvents, the intramolecular hydrogen bond between 1α-OCH3/1α-OH and N-H groups, acid-base treatment, preparation methods, and work-up procedures.

A Socket Seal Technique With the Use of Autologous Dental Roots for Socket Seal: A Case Series.

The literature identified variations in socket seal surgery, each with limitations. This case series aimed to observe the outcome of using autologous dental root (ADR) for socket sealing on socket preservation (SP). A total of 9 patients with 15 extraction sockets were documented. After flapless extraction, the xenograft or alloplastic grafts were placed in the sockets. Autologous dental roots were prepared extraorally and applied to seal the socket entrance. All SP sites healed uneventfully. Cone-beam computed tomography (CBCT) scan was performed after 4-6 months of healing to evaluate ridge dimensions. The preserved alveolar ridge profiles were verified on CBCT scans and during implant surgery. Implants were placed successfully with a reduced need for guided bone regeneration. Histological biopsy specimens were examined in 3 cases. The histological examination demonstrated vital bone formation and osseointegration of graft particles. All patients completed the final restorations and were monitored for 15.56 ± 9.08 months after functional loading. The favorable clinical outcomes support the use of ADR for SP procedures. It was not only accepted to patients but also easy to perform with low complication rates. The ADR technique is thus a feasible method for socket seal surgery.

Association between the occurrence of buccally displaced canine and palatal and craniofacial morphology in adolescents.

The main objective of the present research study is to evaluate the association between the occurrence of buccally displaced canine (BDC) and the palatal as well as the craniofacial morphology in adolescents in accordance at the early permanent dentition. As the experimental group, 100 adolescents of Chinese ethnicity (mean age 13.05 years) with crowding and buccally displaced canine (BDC-c) were selected in comparison with the same number of candidates (mean age 12.59 years) without BDC and crowding as control group. Digital dental casts and cephalograms were collected for three dimensional (3D) and cephalometric measurements. An independent sample T-test was used to compare the cephalometric values between the two groups. Logistic regression as commonly statistical methods used in empirical study including categorical dependent variables was used to identify the joint effects of the dental variables' 3D measurements. When comparing the groups with above analysis, patients with BDC showed a statistically significant narrower and higher palatal vault. For the cephalometric variables, the anterior cranial base length, sagittal position of the maxilla (SNA), sagittal position of the mandible (SNB), and skeletal relationship between maxilla and mandible (ANB) appeared to be smaller, whilst palatal plane angle (SN-PP), Frankfort-mandibular plane angle (FMA), anterior facial height, and lower facial height were larger in BDC-c control group (p < 0.05). A smaller inter-first premolar width was significant in the prediction model (p = 0.002). This study highlights that BDC-c participants in early permanent dentition exhibited a narrower dental arch and higher palatal vault, of which a smaller inter-first premolar width would significantly increase the occurrence of BDC.

[Current research status and application prospect of numerical simulation in traditional Chinese medicine drying].

With the rapid development of computer technology, numerical simulation has gradually become an important method to study drying process and improve drying equipment. Using computer to simulate the drying process of traditional Chinese medicine(TCM) is characterized by intuitiveness, scientificity, and low cost, which serves as an auxiliary means for technical innovation in TCM drying. This paper summarizes the theories of different drying methods and the research status of numerical simulation in drying, introduces the modeling methods and software of numerical simulation, and expounds the significance of numerical simulation modeling in shortening the research and development cycle, improving drying equipment, and optimizing drying parameters. However, the current numerical simulation method for drying process has problems, such as low accuracy, lack of quantitative indicators for the control of simulation results on the process, and insufficient in-depth research on the mechanism of drug quality changes. Furthermore, this paper put forward the application prospect of numerical simulation in TCM drying, providing reference for the further study of numerical simulation in this field.

[Application prospect of reaction engineering approach in studying drying behavior of single droplet during spray drying of traditional Chinese medicine].

Spray drying technology is one of the most commonly used unit operations in the production of traditional Chinese medicine(TCM) preparations, offering advantages such as short drying time and uniform product quality. However, due to the properties of TCM extracts, such as high viscosity, strong hygroscopicity, and poor flowability, there is limited scope to solve the problems of wall adhesion and clumping in spray drying from the macroscopic perspective of pharmaceutical production. Therefore, it has become a trend to study and optimize the spray drying process from the microscopic point of view by investigating single droplet evaporation behavior. Based on the reaction engineering approach(REA), the single droplet drying system, as a novel method for studying droplets, collects parameter data on individual TCM droplets during the drying process and uses the REA to process the data and establish predictive models. This approach is crucial for understanding the mechanism of TCM spray drying. This paper summarized and analyzed the cha-racteristics of various single droplet systems, the application of REA in single droplet drying systems, and its significance in optimizing the process, predicting drying states, and shortening the development cycle in the field of TCM spray drying, and looked ahead to the prospects of this method, including the introduction of new parameters and imaging techniques, aiming to provide a reference for further research in the field of TCM spray drying.

Adenophorone, An Unprecedented Sesquiterpene from Eupatorium adenophorum: Structural Elucidation, Bioinspired Total Synthesis and Neuroprotective Activity Evaluation.

(-)-Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9 ]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X-ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio- and stereoselective hydrogenation, and subsequent merged MBH-Tsuji-Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)-euptox A (2) in 8 steps from commercially available monoterpene (-)-carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2 O2 -treated SH-SY5Y and PC12 cells.

The exhaustion of lymphocytes is the main factor that decreases the sensitivity of QFT-GIT detection in silicosis.

BACKGROUND: Tuberculosis infection is a major complication of silicosis, but there is no study on whether silicosis can affect the sensitivity of QuantiFERON-TB Gold In-Tube (QFT-GIT) assays. This study will analyze the relationship between silicosis and QFT-GIT, determine the main factor of the QFT-GIT sensitivity decrease in silicosis and explore the methods to increase the sensitivity. METHODS: Silicosis patients with positive tubercle bacillus cultures were collected. The QFT-GIT, flow cytometry and blocking antibodies were used. RESULTS: The sensitivity of QFT-GIT in silicosis patients (58.46%) was significantly decreased and the expression of PD-1 on T cells and CD56+NK cells in pulmonary tuberculosis combined with silicosis were higher than normal tuberculosis patients and silicosis only patients. Further analysis found that the ratio of PD-1+CD4+T and IFN-γwere negatively correlated and blockaded the PD-1 pathway with antibodies can restore the sensitivity of QFT-GIT in silicosis. CONCLUSIONS: This is the first study to analyze the relationship between immune exhaustion and QFT-GIT in silicosis and found that the sensitivity of QFT-GIT was decreased by the expression of PD-1 on lymphocytes. Antibody blocking experiments increased the expression of IFN-γ and provided a new method to improve the sensitivity of QFT in silicosis. The study also found that silicosis can increase PD-1 expression. As PD-1 functions in infectious diseases, it will promote immune exhaustion in silicosis and lead to tuberculosis from latent to active infection. The study provided theoretical evidence for the diagnosis and immunotherapy of silicosis complications, and it has great value in clinical diagnostics and treatment.