Universality in RNA and DNA deformations induced by salt, temperature change, stretching force, and protein binding.

Nucleic acid deformations play important roles in many biological processes. The physical understanding of nucleic acid deformation by environmental stimuli is limited due to the challenge in the precise measurement of RNA and DNA deformations and the complexity of interactions in RNA and DNA. Magnetic tweezers experiments provide an excellent opportunity to precisely measure DNA and RNA twist changes induced by environmental stimuli. In this work, we applied magnetic tweezers to measure double-stranded RNA twist changes induced by salt and temperature changes. We observed RNA unwinds when lowering salt concentration, or increasing temperature. Our molecular dynamics simulations revealed the mechanism: lowering salt concentration or increasing temperature enlarges RNA major groove width, which causes twist decrease through twist-groove coupling. Combining these results with previous results, we found some universality in RNA and DNA deformations induced by three different stimuli: salt change, temperature, and stretching force. For RNA, these stimuli first modify the major groove width, which is transduced into twist change through twist-groove coupling. For DNA, these stimuli first modify diameter, which is transduced into twist change through twist-diameter coupling. Twist-groove coupling and twist-diameter coupling appear to be utilized by protein binding to reduce DNA and RNA deformation energy cost upon protein binding.

HSP90ß prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53.

Cataract is a leading ocular disease causing global blindness. The mechanism of cataractogenesis has not been well defined. Here, we demonstrate that the heat shock protein 90ß (HSP90ß) plays a fundamental role in suppressing cataractogenesis. HSP90ß is the most dominant HSP in normal lens, and its constitutive high level of expression is largely derived from regulation by Sp1 family transcription factors. More importantly, HSP90ß is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90ß silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90ß can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90ß silencing causes upregulation of CHMP4B and another client protein, the tumor suppressor p53. CHMP4B upregulation or overexpression induces excessive division of lens epithelial cells without proper differentiation. As a result, these cells were triggered to undergo apoptosis due to activation of the p53/Bak-Bim pathway, leading to cataractogenesis and microphthalmia. Silence of both HSP90ß and CHMP4B restored normal phenotype of zebrafish eye. Together, our results reveal that HSP90ß is a critical inhibitor of cataractogenesis through negative regulation of CHMP4B and the p53-Bak/Bim pathway.

Dzip1 is dynamically expressed in the vertebrate germline and regulates the development of Xenopus primordial germ cells.

Primordial germ cells (PGCs) are the precursors of sperms and oocytes. Proper development of PGCs is crucial for the survival of the species. In many organisms, factors responsible for PGC development are synthesized during early oogenesis and assembled into the germ plasm. During early embryonic development, germ plasm is inherited by a few cells, leading to the formation of PGCs. While germline development has been extensively studied, how components of the germ plasm regulate PGC development is not fully understood. Here, we report that Dzip1 is dynamically expressed in vertebrate germline and is a novel component of the germ plasm in Xenopus and zebrafish. Knockdown of Dzip1 impairs PGC development in Xenopus embryos. At the molecular level, Dzip1 physically interacts with Dazl, an evolutionarily conserved RNA-binding protein that plays a multifaced role during germline development. We further showed that the sequence between amino acid residues 282 and 550 of Dzip1 is responsible for binding to Dazl. Disruption of the binding between Dzip1 and Dazl leads to defective PGC development. Taken together, our results presented here demonstrate that Dzip1 is dynamically expressed in the vertebrate germline and plays a novel function during Xenopus PGC development.

LRG1 loss effectively restrains glomerular TGF-ß signaling to attenuate diabetic kidney disease.

Transforming growth factor (TGF)-ß signaling is a well-established pathogenic mediator of diabetic kidney disease (DKD). However, owing to its pleiotropic actions, its systemic blockade is not therapeutically optimal. The expression of TGF-ß signaling regulators can substantially influence TGF-ß's effects in a cell- or context-specific manner. Among these, leucine-rich α2-glycoprotein 1 (LRG1) is significantly increased in glomerular endothelial cells (GECs) in DKD. As LRG1 is a secreted molecule that can exert autocrine and paracrine effects, we examined the effects of LRG1 loss in kidney cells in diabetic OVE26 mice by single-cell transcriptomic analysis. Gene expression analysis confirmed a predominant expression of Lrg1 in GECs, which further increased in diabetic kidneys. Loss of Lrg1 led to the reversal of angiogenic and TGF-ß-induced gene expression in GECs, which were associated with DKD attenuation. Notably, Lrg1 loss also mitigated the increased TGF-ß-mediated gene expression in both podocytes and mesangial cells in diabetic mice, indicating that GEC-derived LRG1 potentiates TGF-ß signaling in glomerular cells in an autocrine and paracrine manner. Indeed, a significant reduction in phospho-Smad proteins was observed in the glomerular cells of OVE26 mice with LRG1 loss. These results indicate that specific antagonisms of LRG1 may be an effective approach to curb the hyperactive glomerular TGF-ß signaling to attenuate DKD.

Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury.

Retinoic acid receptor responder protein-1 (RARRES1) is a podocyte-enriched transmembrane protein whose increased expression correlates with human glomerular disease progression. RARRES1 promotes podocytopenia and glomerulosclerosis via p53-mediated podocyte apoptosis. Importantly, the cytopathic actions of RARRES1 are entirely dependent on its proteolytic cleavage into a soluble protein (sRARRES1) and subsequent podocyte uptake by endocytosis, as a cleavage mutant RARRES1 exerted no effects in vitro or in vivo. As RARRES1 expression is upregulated in human glomerular diseases, here we investigated the functional consequence of podocyte-specific overexpression of RARRES1 in mice in the experimental focal segmental glomerulosclerosis and diabetic kidney disease. We also examined the effects of long-term RARRES1 overexpression on slowly developing aging-induced kidney injury. As anticipated, the induction of podocyte overexpression of RARRES1 (Pod-RARRES1WT) significantly worsened glomerular injuries and worsened kidney function in all three models, while overexpression of RARRES1 cleavage mutant (Pod-RARRES1MT) did not. Remarkably, direct uptake of sRARRES1 was also seen in proximal tubules of injured Pod-RARRES1WT mice and associated with exacerbated tubular injuries, vacuolation, and lipid accumulation. Single-cell RNA sequence analysis of mouse kidneys demonstrated RARRES1 led to a marked deregulation of lipid metabolism in proximal tubule subsets. We further identified matrix metalloproteinase 23 (MMP23) as a highly podocyte-specific metalloproteinase and responsible for RARRES1 cleavage in disease settings, as adeno-associated virus 9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo. Thus, our study delineates a previously unrecognized mechanism by which a podocyte-derived protein directly facilitates podocyte and tubular injury in glomerular diseases and suggests that podocyte-specific functions of RARRES1 and MMP23 may be targeted to ameliorate glomerular disease progression in vivo.

Fully dense generative adversarial network for removing artifacts caused by microwave dielectric effect in thermoacoustic imaging.

Microwave-induced thermoacoustic (TA) imaging (MTAI) combines pulsed microwave excitation and ultrasound detection to provide high contrast and spatial resolution images through dielectric contrast, which holds great promise for clinical applications. However, artifacts caused by microwave dielectric effect will seriously affect the accuracy of MTAI images that will hinder the clinical translation of MTAI. In this work, we propose a deep learning-based method fully dense generative adversarial network (FD-GAN) for removing artifacts caused by microwave dielectric effect in MTAI. FD-GAN adds the fully dense block to the generative adversarial network (GAN) based on the mutual confrontation between generator and discriminator, which enables it to learn both local and global features related to the removal of artifacts and generate high-quality images. The practical feasibility was tested in simulated, experimental data. The results demonstrate that FD-GAN can effectively remove the artifacts caused by the microwave dielectric effect, and shows superiority in denoising, background suppression, and improvement of image distortion. Our approach is expected to significantly improve the accuracy and quality of MTAI images, thereby enhancing the diagnostic accuracy of this innovative imaging technique.

Immune cell patterns before and after neoadjuvant immune checkpoint blockade combined with chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant immune checkpoint blockade (ICB) combined with chemoradiotherapy offers high pathologic complete response (pCR) rate for patients with locally advanced esophageal squamous cell carcinomas (ESCC). But the dynamic tumor immune microenvironment modulated by such neoadjuvant therapy remains unclear. PATIENTS AND METHODS: A total of 41 patients with locally advanced ESCC were recruited. All patients received neoadjuvant toripalimab combined with concurrent chemoradiotherapy. Matched pre- and post-treatment tissues were obtained for fluorescent multiplex immunohistochemistry (mIHC) and IHC analyses. The densities and spatial distributions of immune cells were determined by HALO modules. The differences of immune cell patterns before and after neoadjuvant treatment were investigated. RESULTS: In the pre-treatment tissues, more stromal CD3 + FoxP3 + Tregs and CD86+/CD163 + macrophages were observed in patients with residual tumor existed in the resected lymph nodes (pN1), compared with patients with pCR. The majority of macrophages were distributed in close proximity to tumor nest in pN1 patients. In the post-treatment tissues, pCR patients had less CD86 + cell infiltration, whereas higher CD86 + cell density was significantly associated with higher tumor regression grades (TRG) in non-pCR patients. When comparing the paired pre- and post-treatment samples, heterogeneous therapy-associated immune cell patterns were found. Upon to the treatment, CD3 + T lymphocytes were slightly increased in pCR patients, but markedly decreased in non-pCR patients. In contrast, a noticeable increase and a less obvious decrease of CD86 + cell infiltration were respectively depicted in non-pCR and pCR patients. Furthermore, opposite trends of the treatment-induced alterations of CD8 + and CD15 + cell infiltrations were observed between pN0 and pN1 patients. CONCLUSIONS: Collectively, our data demonstrate a comprehensive picture of tumor immune landscape before and after neoadjuvant ICB combined with chemoradiotherapy in ESCC. The infiltration of CD86 + macrophage may serve as an unfavorable indicator for neoadjuvant toripalimab combined with chemoradiotherapy.

Monolayer 1T-Ag6S2 with Excellent Thermoelectric Properties.

We obtained a new material called monolayer 1T-Ag6S2 by replacing metal atoms in 1T phase transition-metal dichalcogenide sulfides (TMDs) with octahedral Ag6 clusters. Subsequently, the thermoelectric transport properties of monolayer 1T-Ag6S2 were systematically investigated using first-principles calculations and the generalized gradient approximation (GGA-PBE) exchange correlation functional. The findings demonstrate that monolayer 1T-Ag6S2 displays characteristics of a wide-bandgap semiconductor, with a bandgap of 2.48 eV. Notably, the incorporation of Ag6 clusters disrupts the structural symmetry, effectively enhancing the electronic structure and phonon properties of the material. Due to the flat valence band near the Fermi level, the extended relaxation time of the hole results in a greater effective mass compared to the electron, leading to a significant increase in the Seebeck coefficient. Under optimal doping conditions, the power factor of monolayer 1T-Ag6S2 can achieve 14.9 mW/mK2 at 500 K. The intricate crystal structure induces phonon path bending, reduces the overall frequency of phonon vibrations (<10 THz), and causes hybridization of low-frequency optical and acoustic branches, resulting in remarkably low lattice thermal conductivity (0.20 and 0.17 W/mK along the x and y axes at 500 K, respectively). The monolayer 1T-Ag6S2 demonstrates a remarkably high figure of merit ZT of 3.14 (3.15) on the x (y) axis at 500 K, significantly higher than those of conventional TMD materials. Such excellent thermoelectric properties suggest that monolayer 1T-Ag6S2 is a promising thermoelectric (TE) material. Our work reveals the deep mechanism of cluster substitution to optimize the thermoelectric properties of materials and provides a useful reference for subsequent research.

Terrirubrum flagellatum gen. nov., sp. nov. of Terrirubraceae fam. nov. and Lichenibacterium dinghuense sp. nov. from forest soil and proposal of Rhodoblastaceae fam. nov.

Two Gram-negative, aerobic, rod-shaped bacterial strains, 7MK25T and 6Y81T, were isolated from forest soil of Dinghushan Biosphere Reserve, Guangdong Province, PR China. Based on the results of 16S rRNA gene sequence analysis, strain 7MK25T showed the highest similarity (93.6 %) to Methyloferula stellata AR4T, followed by Bosea thiooxidans DSM 9653T (93.3 %). Strain 6Y81T had the highest similarity of 97.9 % to Lichenibacterium minor RmlP026T, followed by Lichenibacterium ramalinae RmlP001T (97.2 %). Phylogenomic analysis using the UBCG and PhyloPhlAn methods consistently showed that strain 7MK25T formed a sister clade to Boseaceae, while strain 6Y81T formed an independent clade within the genus Lichenibacterium, both in the order Hyphomicrobiales. The digital DNA-DNA hybridization and average nucleotide identity values between strains 7MK25T, 6Y81T and their close relatives were in the ranges of 19.1-29.9 % and 72.5-85.5 %, respectively. The major fatty acids of 7MK25T were summed feature 8 (C18 : 1 ω7c/C18 : 1 ω6c), C19 : 0 cyclo ω8c, C16 : 0 and C17 : 0 cyclo, while those of 6Y81T were summed feature 8 (C18 : 1 ω7c/C18 : 1 ω6c), C16 : 0 and C16 : 0 3-OH. Strains 7MK25T and 6Y81T took diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylcholine as their dominant polar lipids, and Q-10 as their major respiratory quinone. On the basis of phenotypic and phylogenetic data, strain 7MK25T is proposed to represent a novel species of a novel genus with name Terrirubrum flagellatum gen. nov., sp. nov., within a novel family Terrirubraceae fam. nov., with 7MK25T (=KCTC 62738T=GDMCC 1.1452T) as its type strain. Strain 6Y81T represents a novel species in the genus Lichenibacterium, for which the name Lichenibacterium dinghuense sp. nov. (type strain 6Y81T=KACC 21 727T=GDMCC 1.2176T) is proposed. Rhodoblastaceae fam. nov. with Rhodoblastus as the type genus is also proposed to solve the non-monophylectic problem of the family Roseiarcaceae.

Photoredox radical cyclization reaction of o-vinylaryl isocyanides with acyl chlorides to access 2,4-disubstituted quinolines.

We herein report an efficient photoredox radical cyclization reaction of o-vinylaryl isocyanides with acyl chlorides to access a wide range of 2,4-disubstituted quinolines. Preliminary mechanism experiment results suggested that this reaction was initiated by an acyl radical generated from acyl chlorides through a single-electron-transfer (SET) process. This transformation showed good substrate suitability and functional group compatibility at room temperature.

Electro-oxidative three-component cascade coupling of isocyanides with elemental sulfur and amines for the synthesis of 2-aminobenzothiazoles.

2-Aminobenzothiazoles are commonly encountered in various functional compounds. Herein, we disclose an electro-oxidative three-component reaction for the effective synthesis of 2-aminobenzothiazoles under mild conditions, utilizing non-toxic and abundant elemental sulfur as the sulfur source. Both aliphatic amines and aryl amines demonstrate good compatibility at room temperature, highlighting the broad functional group tolerance of this approach. Additionally, elemental selenium demonstrated reactivities comparable to those of elemental sulfur.

Highly Efficient Stable Luminescent Radical-Based X-ray Scintillator.

Stable luminescent radicals are open-shell emitters with unique doublet emission characteristics. This feature makes stable luminescent radicals exhibit widespread application prospects in constructing optical, electrical, and magnetic materials. In this work, a stable luminescent radical-based X-ray scintillator of AuPP-1.0 was prepared, which exhibited a high X-ray excited luminescence (XEL) efficiency as well as excellent stability. A mechanism study showed that the heavy atom of Au in AuPP-1.0 endowed it with effective absorption of X-rays, and the doublet emission characteristics of AuPP-1.0 significantly increased its exciton utilization rate in the radioluminescence process. Moreover, AuPP-1.0 has good processability to fabricate a flexible screen for high-quality X-ray imaging, whose resolution can reach 20 LP mm-1. This work demonstrates that the doublet emission is beneficial for improving the exciton utilization rate of radioluminescence, providing a brand-new strategy for the construction of high-performance X-ray scintillators.

Bipolar Molecular Torque Wrench Modulates the Stacking of Two-Dimensional Metal-Organic Framework Nanosheets.

The precise modulation of nanosheet stacking modes introduces unforeseen properties and creates momentous applications but remains a challenge. Herein, we proposed a strategy using bipolar molecules as torque wrenches to control the stacking modes of 2-D Zr-1,3,5-(4-carboxylphenyl)-benzene metal-organic framework (2-D Zr-BTB MOF) nanosheets. The bipolar phenyl-alkanes, phenylmethane (P-C1) and phenyl ethane (P-C2), predominantly instigated the rotational stacking of Zr-BTB-P-C1 and Zr-BTB-P-C2, displaying a wide angular distribution. This included Zr-BTB-P-C1 orientations at 0, 12, 18, and 24° and Zr-BTB-P-C2 orientations at 0, 6, 12, 15, 24, and 30°. With reduced polarity, phenyl propane (P-C3) and phenyl pentane (P-C5) introduced steric hindrance and facilitated alkyl hydrophobic interactions with the nanosheets, primarily resulting in the modulation of eclipsed stacking for Zr-BTB-P-C3 (64.8%) and Zr-BTB-P-C5 (93.3%) nanosheets. The precise angle distributions of four Zr-BTB-P species were in agreement with theoretical calculations. The alkyl induction mechanism was confirmed by the sequential guest replacement and 2-D 13C-1H heteronuclear correlation (HETCOR). In addition, at the single-particle level, we first observed that rotational stacked pores exhibited similar desorption rates for xylene isomers, while eclipsed stacked pores showed significant discrepancy for xylenes. Moreover, the eclipsed nanosheets as stationary phases exhibited high resolution, selectivity, repeatability, and durability for isomer separation. The universality was proven by another series of bipolar acetate-alkanes. This bipolar molecular torque wrench strategy provides an opportunity to precisely control the stacking modes of porous nanosheets.

Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development.

Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several in vitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the in vivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a novel inducible tubular epithelial cell-specific Vpr transgenic mouse model to show that Vpr expression leads to progressive tubulointerstitial damage, interstitial inflammation and fibrosis, and tubular cyst development. Importantly, Vpr-expressing tubular epithelial cells displayed significant hypertrophy, aberrant cell division, and atrophy; all reminiscent of tubular injuries observed in human HIV-associated nephropathy (HIVAN). Single-cell RNA sequencing analysis revealed the Vpr-mediated transcriptomic responses in specific tubular subsets and highlighted the potential multifaceted role of p53 in the regulation of cell metabolism, proliferation, and death pathways in Vpr-expressing tubular epithelial cells. Thus, our study demonstrates that HIV Vpr expression in tubular cells is sufficient to induce HIVAN-like tubulointerstitial damage and fibrosis, independent of glomerulosclerosis and proteinuria. Additionally, as this new mouse model develops progressive CKD with diffuse fibrosis and kidney failure, it can serve as a useful tool to examine the mechanisms of kidney disease progression and fibrosis in vivo.

Signal-On Mass Spectrometric Biosensing of Multiplex Matrix Metalloproteinases with a Phospholipid-Structured Mass-Encoded Microplate.

The detection of matrix metalloproteinases (MMPs) is of great importance for diagnosis and staging of cancer. This work proposed a signal-on mass spectrometric biosensing strategy with a phospholipid-structured mass-encoded microplate for assessment of multiplex MMP activities. The designed substrate and internal standard peptides were subsequently labeled with the reagents of isobaric tags for relative and absolute quantification (iTRAQ), and DSPE-PEG(2000)maleimide was embedded on the surface of a 96-well glass bottom plate to fabricate the phospholipid-structured mass-encoded microplate, which offered a simulated environment of the extracellular space for enzyme reactions between MMPs and the substrates. The strategy achieved multiplex MMP activity assays by dropping the sample in the well for enzyme cleavages, followed by adding trypsin to release the coding regions for ultrahigh performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) analysis. The peak area ratios of released coding regions and their respective internal standard (IS) peptides exhibited satisfied linear ranges of 0.05-50, 0.1-250, and 0.1-100 ng mL-1 with the detection limits of 0.017, 0.046, and 0.032 ng mL-1 for MMP-2, MMP-7, and MMP-3, respectively. The proposed strategy demonstrated good practicability in inhibition analysis and detections of multiplex MMP activities in serum samples. It is of great potential for clinical applications and can be expanded for multiplex enzyme assays.

Aberrant degree centrality profiles during rumination in major depressive disorder.

Rumination is closely linked to the onset and maintenance of major depressive disorder (MDD). Prior neuroimaging studies have identified the association between self-reported rumination trait and the functional coupling among a network of brain regions using resting-state functional magnetic resonance imaging (MRI). However, little is known about the underlying neural circuitry mechanism during active rumination in MDD. Degree centrality (DC) is a simple metric to denote network integration, which is critical for higher-order psychological processes such as rumination. During an MRI scan, individuals with MDD (N = 45) and healthy controls (HC, N = 46) completed a rumination state task. We examined the interaction effect between the group (MDD vs. HC) and condition (rumination vs. distraction) on vertex-wise DC. We further characterized the identified brain region's functional involvement with Neurosynth and BrainMap. Network-wise seed-based functional connectivity (FC) analysis was also conducted for the identified region of interest. Finally, exploratory correlation analysis was conducted between the identified region of interest's network FCs and self-reported in-scanner affect levels. We found that a left superior frontal gyrus (SFG) region, generally overlapped with the frontal eye field, showed a significant interaction effect. Further analysis revealed its involvement with executive functions. FCs between this region, the frontoparietal, and the dorsal attention network (DAN) also showed significant interaction effects. Furthermore, its FC to DAN during distraction showed a marginally significant negative association with in-scanner affect level at the baseline. Our results implicated an essential role of the left SFG in the rumination's underlying neural circuitry mechanism in MDD and provided novel evidence for the conceptualization of rumination in terms of impaired executive control.

Positional Isomers of Covalent Organic Frameworks for Indoor Humidity Regulation.

Humidity is one of the most important indicators affecting human health. Here, a pair of covalent organic frameworks (COFs) of positional isomers (p-COF and o-COF) for indoor humidity regulation is reported. Although p-COF and o-COF have the same sql topology and pore size, they exhibit different water adsorption behaviors due to the subtle differences in water adsorption sites. Particularly, o-COF exhibits a steep adsorption isotherm in the range of 45-65% RH with a hysteresis loop, which is perfectly suitable for indoor humidity regulation. In the laboratory experiment, when the humidity of the external environment is 20-75% RH, o-COF can control the humidity of the room in the range of 45-60% RH. o-COF has shown great potential as a dual humidification/dehumidification adsorbent for indoor humidity regulation.

Metamaterial absorber optimization method based on an artificial neural network surrogate.

Finding the optimal design parameters for the target EM response of a metamaterial absorber is still a challenging task even if the layout of the absorber has been determined. To effectively address this issue, we introduce the idea of surrogate-based optimization into the area of metamaterial absorber design. This paper proposes a surrogate based optimization method combining artificial neural network (ANN) and trust region algorithm for metamaterial absorbers. Each optimization iteration utilizes the optimal solution from the previous iteration and the sample points surrounding it as the training dataset to build an effective ANN surrogate model. To improve the convergence of the optimization method for metamaterial absorbers based on ANN surrogate model, we incorporate a trust region algorithm. The proposed method employs a simple forward neural network architecture and requires less training data, leading to a quick convergence towards the target solution after only a few iterations. Compared to the three commonly used alternative methods, the proposed method can optimize geometric and material parameters more efficiently in the same time. The validity of the proposed method is demonstrated by two examples of electromagnetic optimizations of metamaterial absorbers.

Patlak-Ki derived from ultra-high sensitivity dynamic total body [18F]FDG PET/CT correlates with the response to induction immuno-chemotherapy in locally advanced non-small cell lung cancer patients.

PURPOSE: This study aimed to investigate the predictive value of metabolic features in response to induction immuno-chemotherapy in patients with locally advanced non-small cell cancer (LA-NSCLC), using ultra-high sensitivity dynamic total body [18F]FDG PET/CT. METHODS: The study analyzed LA-NSCLC patients who received two cycles of induction immuno-chemotherapy and underwent a 60-min dynamic total body [18F]FDG PET/CT scan before treatment. The primary tumors (PTs) were manually delineated, and their metabolic features, including the Patlak-Ki, Patlak-Intercept, maximum SUV (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were evaluated. The overall response rate (ORR) to induction immuno-chemotherapy was evaluated according to RECIST 1.1 criteria. The Patlak-Ki of PTs was calculated from the 20-60 min frames using the Patlak graphical analysis. The best feature was selected using Laplacian feature importance scores, and an unsupervised K-Means method was applied to cluster patients. ROC curve was used to examine the effect of selected metabolic feature in predicting tumor response to treatment. The targeted next generation sequencing on 1021 genes was conducted. The expressions of CD68, CD86, CD163, CD206, CD33, CD34, Ki67 and VEGFA were assayed through immunohistochemistry. The independent samples t test and the Mann-Whitney U test were applied in the intergroup comparison. Statistical significance was considered at P < 0.05. RESULTS: Thirty-seven LA-NSCLC patients were analyzed between September 2020 and November 2021. All patients received two cycles of induction chemotherapy combined with Nivolumab/ Camrelizumab. The Laplacian scores showed that the Patlak-Ki of PTs had the highest importance for patient clustering, and the unsupervised K-Means derived decision boundary of Patlak-Ki was 2.779 ml/min/100 g. Patients were categorized into two groups based on their Patlak-Ki values: high FDG Patlak-Ki (H-FDG-Ki, Patlak-Ki > 2.779 ml/min/100 g) group (n = 23) and low FDG Patlak-Ki (L-FDG-Ki, Patlak-Ki ≤ 2.779 ml/min/100 g) group (n = 14). The ORR to induction immuno-chemotherapy was 67.6% (25/37) in the whole cohort, with 87% (20/23) in H-FDG-Ki group and 35.7% (5/14) in L-FDG-Ki group (P = 0.001). The sensitivity and specificity of Patlak-Ki in predicting the treatment response were 80% and 75%, respectively [AUC = 0.775 (95%CI 0.605-0.945)]. The expression of CD3+/CD8+ T cells and CD86+/CD163+/CD206+ macrophages were higher in the H-FDG-Ki group, while Ki67, CD33+ myeloid cells, CD34+ micro-vessel density (MVD) and tumor mutation burden (TMB) were comparable between the two groups. CONCLUSIONS: The total body [18F]FDG PET/CT scanner performed a dynamic acquisition of the entire body and clustered LA-NSCLC patients into H-FDG-Ki and L-FDG-Ki groups based on the Patlak-Ki. Patients with H-FDG-Ki demonstrated better response to induction immuno-chemotherapy and higher levels of immune cell infiltration in the PTs compared to those with L-FDG-Ki. Further studies with a larger patient cohort are required to validate these findings.

Elabela, a Novel Peptide, Exerts Neuroprotective Effects Against Ischemic Stroke Through the APJ/miR-124-3p/CTDSP1/AKT Pathway.

Elabela (ELA), which is the second endogenous peptide ligand of the apelin receptor (APJ) to be discovered, has been widely studied for potential use as a therapeutic peptide. However, its role in ischemic stroke (IS), which is a leading cause of disability and death worldwide and has limited therapeutic options, is uncertain. The aim of the present study was to investigate the beneficial effects of ELA on neuron survival after ischemia and the underlying molecular mechanisms. Primary cortical neurons were isolated from the cerebral cortex of pregnant C57BL/6J mice. Flow cytometry and immunofluorescence showed that ELA inhibited oxygen-glucose deprivation (OGD) -induced apoptosis and axonal damage in vitro. Additionally, analysis of the Gene Expression Omnibus database revealed that the expression of microRNA-124-3p (miR-124-3p) was decreased in blood samples from patients with IS, while the expression of C-terminal domain small phosphatase 1 (CTDSP1) was increased. These results indicated that miR-124-3p and CTDSP1 were related to ischemic stroke, and there might be a negative regulatory relationship between them. Then, we found that ELA significantly elevated miR-124-3p expression, suppressed CTDSP1 expression, and increased p-AKT expression by binding to the APJ receptor under OGD in vitro. A dual-luciferase reporter assay confirmed that CTDSP1 was a direct target of miR-124-3p. Furthermore, adenovirus-mediated overexpression of CTDSP1 exacerbated neuronal apoptosis and axonal damage and suppressed AKT phosphorylation, while treatment with ELA or miR-124-3p mimics reversed these effects. In conclusion, these results indicated that ELA could alleviate neuronal apoptosis and axonal damage by upregulating miR-124-3p and activating the CTDSP1/AKT signaling pathway. This study, for the first time, verified the protective effect of ELA against neuronal injury after ischemia and revealed the underlying mechanisms. We demonstrated the potential for the use of ELA as a therapeutic agent in the treatment of ischemic stroke.