Transcription-wide mapping of dihydrouridine reveals that mRNA dihydrouridylation is required for meiotic chromosome segregation.

The epitranscriptome has emerged as a new fundamental layer of control of gene expression. Nevertheless, the determination of the transcriptome-wide occupancy and function of RNA modifications remains challenging. Here we have developed Rho-seq, an integrated pipeline detecting a range of modifications through differential modification-dependent rhodamine labeling. Using Rho-seq, we confirm that the reduction of uridine to dihydrouridine (D) by the Dus reductase enzymes targets tRNAs in E. coli and fission yeast. We find that the D modification is also present on fission yeast mRNAs, particularly those encoding cytoskeleton-related proteins, which is supported by large-scale proteome analyses and ribosome profiling. We show that the α-tubulin encoding mRNA nda2 undergoes Dus3-dependent dihydrouridylation, which affects its translation. The absence of the modification on nda2 mRNA strongly impacts meiotic chromosome segregation, resulting in low gamete viability. Applying Rho-seq to human cells revealed that tubulin mRNA dihydrouridylation is evolutionarily conserved.

Two sequential gene expression programs bridged by cell division support long-distance collective cell migration.

The precise assembly of tissues and organs relies on spatiotemporal regulation of gene expression to coordinate the collective behavior of cells. In Drosophila embryos, the midgut musculature is formed through collective migration of caudal visceral mesoderm (CVM) cells, but how gene expression changes as cells migrate is not well understood. Here, we have focused on ten genes expressed in the CVM and the cis-regulatory sequences controlling their expression. Although some genes are continuously expressed, others are expressed only early or late during migration. Late expression relates to cell cycle progression, as driving string/Cdc25 causes earlier division of CVM cells and accelerates the transition to late gene expression. In particular, we found that the cell cycle effector transcription factor E2F1 is a required input for the late gene CG5080. Furthermore, whereas late genes are broadly expressed in all CVM cells, early gene transcripts are polarized to the anterior or posterior ends of the migrating collective. We show this polarization requires transcription factors Snail, Zfh1 and Dorsocross. Collectively, these results identify two sequential gene expression programs bridged by cell division that support long-distance directional migration of CVM cells.

KinomeMETA: a web platform for kinome-wide polypharmacology profiling with meta-learning.

Kinase-targeted inhibitors hold promise for new therapeutic options, with multi-target inhibitors offering the potential for broader efficacy while minimizing polypharmacology risks. However, comprehensive experimental profiling of kinome-wide activity is expensive, and existing computational approaches often lack scalability or accuracy for understudied kinases. We introduce KinomeMETA, an artificial intelligence (AI)-powered web platform that significantly expands the predictive range with scalability for predicting the polypharmacological effects of small molecules across the kinome. By leveraging a novel meta-learning algorithm, KinomeMETA efficiently utilizes sparse activity data, enabling rapid generalization to new kinase tasks even with limited information. This significantly expands the repertoire of accurately predictable kinases to 661 wild-type and clinically-relevant mutant kinases, far exceeding existing methods. Additionally, KinomeMETA empowers users to customize models with their proprietary data for specific research needs. Case studies demonstrate its ability to discover new active compounds by quickly adapting to small dataset. Overall, KinomeMETA offers enhanced kinome virtual profiling capabilities and is positioned as a powerful tool for developing new kinase inhibitors and advancing kinase research. The KinomeMETA server is freely accessible without registration at https://kinomemeta.alphama.com.cn/.

Telo boxes within the AGAMOUS second intron recruit histone 3 lysine 27 methylation to increase petal number in rose (Rosa chinensis) in response to low temperatures.

The petals of rose (Rosa sp.) flowers determine the ornamental and industrial worth of this species. The number of petals in roses was previously shown to be subject to fluctuations in ambient temperature. However, the mechanisms by which rose detects and responds to temperature changes are not entirely understood. In this study, we identified short interstitial telomere motifs (telo boxes) in the second intron of AGAMOUS (RcAG) from China rose (Rosa chinensis) that play an essential role in precise temperature perception. The second intron of RcAG harbors two telo boxes that recruit telomere repeat binding factors (RcTRBs), which interact with CURLY LEAF (RcCLF) to compose a repressor complex. We show that this complex suppresses RcAG expression when plants are subjected to low temperatures via depositing H3K27me3 marks (trimethylation of lysine 27 on histone H3) over the RcAG gene body. This regulatory mechanism explains the low-temperature-dependent decrease in RcAG transcript levels, leading to the production of more petals under these conditions. Our results underscore an interesting intron-mediated regulatory mechanism governing RcAG expression, enabling rose plants to perceive temperature cues and establish petal numbers.

KinomeMETA: meta-learning enhanced kinome-wide polypharmacology profiling.

Kinase inhibitors are crucial in cancer treatment, but drug resistance and side effects hinder the development of effective drugs. To address these challenges, it is essential to analyze the polypharmacology of kinase inhibitor and identify compound with high selectivity profile. This study presents KinomeMETA, a framework for profiling the activity of small molecule kinase inhibitors across a panel of 661 kinases. By training a meta-learner based on a graph neural network and fine-tuning it to create kinase-specific learners, KinomeMETA outperforms benchmark multi-task models and other kinase profiling models. It provides higher accuracy for understudied kinases with limited known data and broader coverage of kinase types, including important mutant kinases. Case studies on the discovery of new scaffold inhibitors for membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase and selective inhibitors for fibroblast growth factor receptors demonstrate the role of KinomeMETA in virtual screening and kinome-wide activity profiling. Overall, KinomeMETA has the potential to accelerate kinase drug discovery by more effectively exploring the kinase polypharmacology landscape.

The functional connectivity between right insula and anterior cingulate cortex underlying the association between future self-continuity and delay discounting.

Delay discounting refers to the tendency of individuals to devalue future rewards as the delay in their receipt increases over time. Previous studies have indicated that future self-continuity correlates with delay discounting rates. However, the neural basis underlying the relationship between future self-continuity and delay discounting is not clear. To address this question, we used voxel-based morphometry and resting-state functional connectivity analyses to investigate the neural basis underlying the association between future self-continuity and delay discounting. Behavioral result showed that future self-continuity was positively associated with delay discounting. Voxel-based morphometry analysis result indicated that gray matter volume in the right dorsal anterior insula was positively correlated with future self-continuity. Resting-state functional connectivity analysis found that functional connectivity between the right dorsal anterior insula and anterior cingulate cortex was positively associated with future self-continuity. Mediation analysis showed that the right dorsal anterior insula-right anterior cingulate cortex functional connectivity partially mediated the relationship between future self-continuity and delay discounting. These results suggested that right dorsal anterior insula-right anterior cingulate cortex functional connectivity could be the neural basis underlying the association between future self-continuity and delay discounting. In summary, the study provided novel insights into how future self-continuity affected delay discounting and offers new explanations from a neural perspective.

Mixed lineage kinase 3 and CD70 cooperation sensitize trastuzumab-resistant HER2+ breast cancer by ceramide-loaded nanoparticles.

Trastuzumab is the first-line therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but often patients develop acquired resistance. Although other agents are in clinical use to treat trastuzumab-resistant (TR) breast cancer; still, the patients develop recurrent metastatic disease. One of the primary mechanisms of acquired resistance is the shedding/loss of the HER2 extracellular domain, where trastuzumab binds. We envisioned any new agent acting downstream of the HER2 should overcome trastuzumab resistance. The mixed lineage kinase 3 (MLK3) activation by trastuzumab is necessary for promoting cell death in HER2+ breast cancer. We designed nanoparticles loaded with MLK3 agonist ceramide (PPP-CNP) and tested their efficacy in sensitizing TR cell lines, patient-derived organoids, and patient-derived xenograft (PDX). The PPP-CNP activated MLK3, its downstream JNK kinase activity, and down-regulated AKT pathway signaling in TR cell lines and PDX. The activation of MLK3 and down-regulation of AKT signaling by PPP-CNP induced cell death and inhibited cellular proliferation in TR cells and PDX. The apoptosis in TR cells was dependent on increased CD70 protein expression and caspase-9 and caspase-3 activities by PPP-CNP. The PPP-CNP treatment alike increased the expression of CD70, CD27, cleaved caspase-9, and caspase-3 with a concurrent tumor burden reduction of TR PDX. Moreover, the expressions of CD70 and ceramide levels were lower in TR than sensitive HER2+ human breast tumors. Our in vitro and preclinical animal models suggest that activating the MLK3-CD70 axis by the PPP-CNP could sensitize/overcome trastuzumab resistance in HER2+ breast cancer.

Alternate routes to mnm5s2U synthesis in Gram-positive bacteria.

The wobble bases of tRNAs that decode split codons are often heavily modified. In bacteria, tRNAGlu, Gln, Asp contains a variety of xnm5s2U derivatives. The synthesis pathway for these modifications is complex and fully elucidated only in a handful of organisms, including the Gram-negative Escherichia coli K12 model. Despite the ubiquitous presence of mnm5s2U modification, genomic analysis shows the absence of mnmC orthologous genes, suggesting the occurrence of alternate biosynthetic schemes for the conversion of cmnm5s2U to mnm5s2U. Using a combination of comparative genomics and genetic studies, a member of the YtqA subgroup of the radical Sam superfamily was found to be involved in the synthesis of mnm5s2U in both Bacillus subtilis and Streptococcus mutans. This protein, renamed MnmL, is encoded in an operon with the recently discovered MnmM methylase involved in the methylation of the pathway intermediate nm5s2U into mnm5s2U in B. subtilis. Analysis of tRNA modifications of both S. mutans and Streptococcus pneumoniae shows that growth conditions and genetic backgrounds influence the ratios of pathway intermediates owing to regulatory loops that are not yet understood. The MnmLM pathway is widespread along the bacterial tree, with some phyla, such as Bacilli, relying exclusively on these two enzymes. Although mechanistic details of these newly discovered components are not fully resolved, the occurrence of fusion proteins, alternate arrangements of biosynthetic components, and loss of biosynthetic branches provide examples of biosynthetic diversity to retain a conserved tRNA modification in Nature.IMPORTANCEThe xnm5s2U modifications found in several tRNAs at the wobble base position are widespread in bacteria where they have an important role in decoding efficiency and accuracy. This work identifies a novel enzyme (MnmL) that is a member of a subgroup of the very versatile radical SAM superfamily and is involved in the synthesis of mnm5s2U in several Gram-positive bacteria, including human pathogens. This is another novel example of a non-orthologous displacement in the field of tRNA modification synthesis, showing how different solutions evolve to retain U34 tRNA modifications.

RcOST1L phosphorylates RcPIF4 for proteasomal degradation to promote flowering in rose.

Flowering is a vital agronomic trait that determines the economic value of most ornamental plants. The flowering time of rose (Rosa spp.) is photoperiod insensitive and is thought to be tightly controlled by light intensity, although the detailed molecular mechanism remains unclear. Here, we showed that rose plants flower later under low-light (LL) intensity than under high-light (HL) intensity, which is mainly related to the stability of PHYTOCHROME-INTERACTING FACTORs (RcPIFs) mediated by OPEN STOMATA 1-Like (RcOST1L) under different light intensity regimes. We determined that HL conditions trigger the rapid phosphorylation of RcPIFs before their degradation. A yeast two-hybrid screen identified the kinase RcOST1L as interacting with RcPIF4. Moreover, RcOST1L positively regulated rose flowering and directly phosphorylated RcPIF4 on serine 198 to promote its degradation under HL conditions. Additionally, phytochrome B (RcphyB) enhanced RcOST1L-mediated phosphorylation of RcPIF4 via interacting with the active phyB-binding motif. RcphyB was activated upon HL and recruited RcOST1L to facilitate its nuclear accumulation, in turn leading to decreased stability of RcPIF4 and flowering acceleration. Our findings illustrate how RcPIF abundance safeguards proper rose flowering under different light intensities, thus uncovering the essential role of RcOST1L in the RcphyB-RcPIF4 module in flowering.

Enhancing endometrial receptivity: the roles of human chorionic gonadotropin in autophagy and apoptosis regulation in endometrial stromal cells.

Inadequate endometrial receptivity often results in embryo implantation failure and miscarriage. Human chorionic gonadotropin (hCG) is a key signaling molecule secreted during early embryonic development, which regulates embryonic maternal interface signaling and promotes embryo implantation. This study aimed to examine the impact of hCG on endometrial receptivity and its underlying mechanisms. An exploratory study was designed, and endometrial samples were obtained from women diagnosed with simple tubal infertility or male factor infertile (n = 12) and recurrent implantation failure (RIF, n = 10). Using reverse transcription-quantitative PCR and western blotting, luteinizing hormone (LH)/hCG receptor (LHCGR) levels and autophagy were detected in the endometrial tissues. Subsequently, primary endometrial stromal cells (ESCs) were isolated from these control groups and treated with hCG to examine the presence of LHCGR and markers of endometrial receptivity (HOXA10, ITGB3, FOXO1, LIF, and L-selectin ligand) and autophagy-related factors (Beclin1, LC3, and P62). The findings revealed that the expressions of receptivity factors, LHCGR, and LC3 were reduced in the endometrial tissues of women with RIF compared with the control group, whereas the expression of P62 was elevated. The administration of hCG to ESCs specifically activated LHCGR, stimulating an increase in the endometrial production of HOXA10, ITGB3, FOXO1, LIF and L-selectin ligands. Furthermore, when ESCs were exposed to 0.1 IU/mL hCG for 72 h, the autophagy factors Beclin1 and LC3 increased within the cells and P62 decreased. Moreover, the apoptotic factor Bax increased and Bcl-2 declined. However, when small interfering RNA was used to knock down LHCGR, hCG was less capable of controlling endometrial receptivity and autophagy molecules in ESCs. In addition, hCG stimulation enhanced the phosphorylation of ERK1/2 and mTOR proteins. These results suggest that women with RIF exhibit lower levels of LHCGR and compromised autophagy function in their endometrial tissues. Thus, hCG/LHCGR could potentially improve endometrial receptivity by modulating autophagy and apoptosis.

Association between different obesity patterns and the risk of NAFLD detected by transient elastography: a cross-sectional study.

BACKGROUND: Obesity has become a major global public health challenge. Studies examining the associations between different obesity patterns and the risk of nonalcoholic fatty liver disease (NAFLD) are limited. This study aimed to investigate the relationships between different obesity patterns and the risk of NAFLD in a large male population in the US. METHODS: Data from the 2017 to March 2020 National Health and Nutrition Examination Survey (NHANES) were utilized. Liver steatosis and fibrosis were assessed with FibroScan using the controlled attenuation parameter (CAP) and liver stiffness measurements (LSM). Steatosis was identified with a CAP value of 248 dB/m or higher. Abdominal obesity was defined by a waist circumference (WC) of 102 cm or more for males and 88 cm or more for females. Overweight was defined as a body mass index (BMI) of 24.0 kg/m2 and above. General obesity was identified with a BMI of 28.0 kg/m2 or higher. Obesity status was categorized into four types: overweight, general obesity, abdominal obesity, and combined obesity. Multivariate logistic regression, adjusting for potential confounders, was used to examine the link between obesity patterns and NAFLD risk. Subgroup analysis further explored these associations. RESULTS: A total of 5,858 adults were included. After multivariable adjustment, compared to the normal weight group, the odds ratios (ORs) [95% confidence interval (CI)] for NAFLD in individuals with overweight, general obesity, abdominal obesity, and combined obesity were 6.90 [3.74-12.70], 2.84 [2.38-3.39], 3.02 [2.02-4.51], and 9.53 [7.79-11.64], respectively. Subgroup analysis showed the effect of different obesity patterns on NAFLD risk was stable among individuals with different clinical conditions. In the fully adjusted multivariate logistic regression model, WC was positively associated with NAFLD risk (OR: 1.48; 95% CI: 1.42-1.53; P < 0.001). WC also demonstrated strong discriminatory ability for NAFLD in Receiver Operating Characteristic (ROC) analysis, achieving an Area Under the Curve (AUC) of 0.802. CONCLUSIONS: Different patterns of obesity are risk factors for NAFLD. An increase in WC significantly increased NAFLD risk. More attention should be paid to preventing different patterns of obesity among adults.

Clinical effect of external ventricular drainage under intracranial pressure monitoring in the treatment of aneurysmal subarachnoid hemorrhage patients and investigation of the mechanism of miR-146a-5p/STC1 axis in inhibiting early brain injury in aneurys.

Aneurismal subarachnoid hemorrhage (aSAH) is a common disease in the neural system, with high death rate. Our study aimed to explore the clinical effect of external ventricular drainage under intracranial pressure monitoring in the treatment of patients with aSAH and investigate the role along with mechanism of miR-146a-5p in aSAH. Ninety-six aSAH patients were allocated into control group (CG) and study group (SG). The CG was released by lumbar puncture. The SG underwent external ventricular drainage based on intracranial pressure monitoring. The prognosis, daily living ability, neurological function, S100ß and NSE (neuron-specific enolase) levels and incidence of complications were monitored. Besides, a rat model of SAH was built to assess the neurobehavioral function, blood-brain barrier permeability, brain water content, neuronal apoptosis as well as inflammation. SAH cell model stimulated by oxyhemoglobin, and cell apoptosis as well as inflammation were measured. Luciferase reporter assay was implemented to explore the interaction between miR-146a-5p and STC1. Results showed higher GOS and BI scores but lower NIHSS scores, S100ß and NSE levels and complication rates in SG compared with CG. Additionally, miR-146a-5p presented down-regulation in brain tissues of SAH rat model, and overexpressed miR-146a-5p reduced brain injury along with neuroinflammation in SAH rat model. Oxyhemoglobin-induced nerve cell apoptosis along with inflammation after SAH, and overexpressed miR-146a-5p repressed oxyhemoglobin-induced nerve cell apoptosis along with inflammation. STC1 is the target mRNA of miR-146a-5p, and overexpressed miR-146a-5p represses oxyhemoglobin-induced nerve cell apoptosis along with inflammation via regulating STC1 expression. In conclusion, external ventricular drainage under intracranial pressure monitoring could promote prognosis, promote daily living ability, improve neurological function, reduce S100ß protein and NSE levels, and reduce the incidence of complications in patients with aSAH. Meanwhile, miR-146a-5p inhibited early brain injury and neuroinflammation in aSAH via regulating STC1 expression.

Novel lignans from Syringa pinnatifolia and protective effect against H2O2-induced oxidative injury through regulating the expression of Nrf2/HO-1 in H9c2 cells.

Phytochemical analysis of the peeled stems of Syringa pinnatifolia Hemsl. led to the discovery of 13 undescribed lignans, namely helanols A and B (1 and 2) and alashanenols W-G1 (3-13), as well as four known analogues, of which helanols A and B were lignans with novel skeleton of α-ß' linkage. The structures were unambiguously established by extensive spectroscopic analyses, NMR calculations, ECD calculations, and single crystal X-ray crystallography. Five lignans (1, 2, 5, 11 and 13) exhibited a moderate protective effect against H2O2-induced oxidative injuries in H9c2 cells with the protective rates of 11.3-20.6 % at the concentration of 0.3-20 µM, while the positive control quercetin showed protective rates of 58.7 % at 10 µM. Further mechanism investigation suggested that 1 and 2 exerted the protective effect by regulating the expression of Nrf2/HO-1.

A new direction in periodontitis treatment: biomaterial-mediated macrophage immunotherapy.

Periodontitis is a chronic inflammation caused by a bacterial infection and is intimately associated with an overactive immune response. Biomaterials are being utilized more frequently in periodontal therapy due to their designability and unique drug delivery system. However, local and systemic immune response reactions driven by the implantation of biomaterials could result in inflammation, tissue damage, and fibrosis, which could end up with the failure of the implantation. Therefore, immunological adjustment of biomaterials through precise design can reduce the host reaction while eliminating the periodontal tissue's long-term chronic inflammation response. It is important to note that macrophages are an active immune system component that can participate in the progression of periodontal disease through intricate polarization mechanisms. And modulating macrophage polarization by designing biomaterials has emerged as a new periodontal therapy technique. In this review, we discuss the role of macrophages in periodontitis and typical strategies for polarizing macrophages with biomaterials. Subsequently, we discuss the challenges and potential opportunities of using biomaterials to manipulate periodontal macrophages to facilitate periodontal regeneration.

Enhancing immune responses of ESC-based TAA cancer vaccines with a novel OMV delivery system.

Embryonic stem cell (ESC)-derived epitopes can act as therapeutic tumor vaccines against different types of tumors Jin (Adv Healthc Mater 2023). However, these epitopes have poor immunogenicity and stimulate insufficient CD8+ T cell responses, which motivated us to develop a new method to deliver and enhance their effectiveness. Bacterial outer membrane vesicles (OMVs) can serve as immunoadjuvants and act as a delivery vector for tumor antigens. In the current study, we engineered a new OMV platform for the co-delivery of ESC-derived tumor antigens and immune checkpoint inhibitors (PD-L1 antibody). An engineered Staphylococcal Protein A (SpA) was created to non-specifically bind to anti-PD-L1 antibody. SpyCatcher (SpC) and SpA were fused into the cell outer membrane protein OmpA to capture SpyTag-attached peptides and PD-L1 antibody, respectively. The modified OMV was able to efficiently conjugate with ESC-derived TAAs and PD-L1 antibody (SpC-OMVs + SpT-peptides + anti-PD-L1), increasing the residence time of TAAs in the body. The results showed that the combination therapy of ESC-based TAAs and PD-L1 antibody delivered by OMV had significant inhibitory effects in mouse tumor model. Specifically, it was effective in reducing tumor growth by enhancing IFN-γ-CD8+ T cell responses and increasing the number of CD8+ memory cells and antigen-specific T cells. Overall, the new OMV delivery system is a versatile platform that can enhance the immune responses of ESC-based TAA cancer vaccines.

Association of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and gallstones among US adults aged ≤ 50 years: a cross-sectional study from NHANES 2017-2020.

BACKGROUND: The chronic digestive condition gallstones is quite common around the world, the development of which is closely related to oxidative stress, inflammatory response and abnormalities of lipid metabolism. In the last few years, as a novel biomarker of lipid metabolism, the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) has garnered significant interest. However, its relationship with gallstones has not been studied yet. METHODS: 3,772 people, all under 50, were included in this study, and their full data came from the National Health and Nutrition Examination Survey (NHANES) database for the years 2017-2020. Information on gallstones was obtained through self-reported questionnaires. Smoothed curve fitting multifactorial logistic regression was utilized to evaluate the connection of NHHR with gallstone formation incidence. Subsequently, subgroup analysis and interaction tests were applied. Finally, to create a prediction model, logistic regression and feature screening by last absolute shrinkage and selection operator (LASSO) were used. The resulting model was displayed using a nomogram. RESULTS: In multivariate logistic regression that accounted for all factors, there was a 77% increase in the likelihood of gallstones for every unit rise in lnNHHR (OR 1.77 [CI 1.11-2.83]). Following NHHR stratification, the Q4 NHHR level was substantially more linked to the risk of gallstones than the Q1 level (OR 1.86 [CI 1.04-3.32]). This correlation was stronger in women, people under 35, smokers, abstainers from alcohol, non-Hispanic White people, those with excessively high cholesterol, people with COPD, and people without diabetes. After feature screening, a predictive model and visualized nomogram for gallstones were constructed with an AUC of 0.785 (CI 0.745-0.819), which was assessed by DCA to be clinically important. CONCLUSION: In the group of people ≤ 50 years of age, elevated NHHR levels were substantially linked to a higher incidence of gallstones. This correlation was stronger in several specific groups such as females, under 35 years of age, smokers, and so on. Predictive models constructed using the NHHR have potential clinical value in assessing gallstone formation.

The genetic and immune features of salivary gland secretory carcinoma with high-grade transformation.

OBJECTIVES: To compare the clinicopathological, molecular, and immune features of conventional and high-grade transformation (HGT) secretory carcinoma (SC) in salivary glands. MATERIALS AND METHODS: The clinicopathological data of 88 cases including 74 conventional SCs and 14 SCs with HGT were reviewed. Targeted next-generation sequencing was performed in 11 SCs with HGT and 7 conventional SCs. The level of PD-L1 and CD8+ TILs was determined by immunohistochemistry. RESULTS: Compared with the conventional group, the rates of nodal metastasis, local recurrence, distant metastasis and mortality were significantly higher in the HGT cohort. Mutations of ARID1A/B, KMT2A, HOXD13, NRG1 and ETV6 genes were identified in HGT SCs. A recurrent E307G mutation in GATA6 gene was also observed in two cases. Two deceased HGT patients with distant metastasis harboured NOTCH3 mutations. ETV6-RET translocation was prone to occur in the HGT SCs. Additionally, PD-L1 expression was low, and CD8+ TILs were sparse in most HGT cases. CONCLUSION: Our findings reveal novel gene alterations involved in the progression of HGT in SCs. Most HGT SCs patients cannot benefit from PD-L1 blocking and may be approached with a distinct treatment strategy including the lymph node dissection and application of molecular target drugs in precision oncology.

Minor Humulane and Eremophilane Sesquiterpenoids from Syringa pinnatifolia and Their Protective Effect Against Oxidative Injuries in H9c2 Cells.

As a part of systematic research, an ongoing phytochemical investigation of the sesquiterpenoid-containing fraction led to the isolation of five new sesquiterpenoids from the peeled stems of Syringa pinnatifolia, including two pairs of enantiomeric humulane-type (±)-alashanoids A1 and B1 (1 and 2) and one eremophilane-type alashanoid C1 (3). These structures were elucidated by the analysis of extensive spectroscopic data, including ESI-MS and 1D and 2D NMR, and the absolute configuration was determined by comparing its experimental and calculated electronic circular dichroism and calculated NMR. These isolates exhibited moderate in vitro cardioprotective effects against oxidative injuries in H9c2 cells.

Linewidth Measurement of a Narrow-Linewidth Laser: Principles, Methods, and Systems.

Narrow-linewidth lasers mainly depend on the development of advanced laser linewidth measurement methods for related technological progress as key devices in satellite laser communications, precision measurements, ultra-high-speed optical communications, and other fields. This manuscript provides a theoretical analysis of linewidth characterization methods based on the beat frequency power spectrum and laser phase noise calculations, and elaborates on existing research of measurement technologies. In addition, to address the technical challenges of complex measurement systems that commonly rely on long optical fibers and significant phase noise jitter in the existing research, a short-delay self-heterodyne method based on coherent envelope spectrum demodulation was discussed in depth to reduce the phase jitter caused by 1/f noise. We assessed the performance parameters and testing conditions of different lasers, as well as the corresponding linewidth characterization methods, and analyzed the measurement accuracy and error sources of various methods.

High-Efficiency Frequency Doubling Blue-Laser VECSEL Based on Intracavity Beam Control.

Blue lasers are integral to a variety of applications, including marine communication, underwater resource exploration, cold laser processing, laser medicine, and beyond. Vertical external cavity surface-emitting lasers (VECSELs) have the advantages of high output power and tunable wavelength, and can output blue laser via frequency doubling. In this article, a new type of intracavity beam control external-cavity structure is introduced. The laser beam waist is effectively adjusted by intracavity beam control, and the frequency conversion efficiency is improved. A laser cavity stability analysis model was developed to investigate the impact of laser cavity lens parameters and relative positions on stability. The external resonant cavity of VECSELs utilizes two optical lenses to position the beam waist near the laser output coupling mirror and locates the frequency doubling crystal at a high optical power density position to optimize frequency conversion efficiency. The VECSEL straight external-cavity structure achieves a frequency conversion efficiency of up to 60.2% at 488 nm, yielding a blue laser output exceeding 1.3 W. The full width at half maximum of the 488 nm spectrum measures approximately 0.23 nm. This intracavity beam-controlled direct external-cavity structure effectively mitigates laser mode leakage and shows potential for the development of an efficient and compact blue laser source.