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Abstract This prospective, nonrandomized, open-label phase 2 trial (Chinese Clinical Trial Registry, ChiCTR2200061906) aimed to evaluate the effectiveness of adding the PD-1 antibody tislelizumab to perioperative chemotherapy in patients with locally advanced gastroesophageal junction adenocarcinoma (GEJA). This study enrolled patients with GEJA clinically staged as cT3-4aNanyM0 or cT1-2N+M0 from October 2022 to June 2023. Eligible patients were administered three preoperative and five postoperative 3-week cycles of treatment with PD-1 antibody tislelizumab plus SOX (S-1 and oxaliplatin) regimen. The primary endpoint was major pathological response (MPR) rate. Thirty-two patients were enrolled. The median age was 60 years (range: 28–74 years), and 53.1% (17/32) patients were Siewert III type. All patients received at least one cycle of assigned preoperative treatment, and 93.8% (30/32) patients completed three cycles of assigned preoperative tislelizumab and SOX. The R0 resection rate was 96.9% (31/32). MPR, pathological complete response (pCR) of primary tumors and ypT0N0 rates were 50.0% (16/32, 95% CI: 31.9–68.1%), 28.1% (9/32, 95% CI: 13.7–46.7%) and 25.0% (8/32, 95% CI: 11.5–43.4%), respectively. The surgical morbidity rate was 15.6% (5/32), and no 30-day mortality was observed. In the preoperative and postoperative treatment periods, the rate of treatment-related grade 3–4 adverse events was 31.2% (10/32). At the date of 7th Jan 2025, 8 (25.0%) patients occurred recurrence. Therefore, perioperative tislelizumab plus chemotherapy demonstrated significantly improved pathological regression and might be a promising option for patients with locally advanced resectable GEJA.

Abstract Amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies.

Abstract Background HD is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the HTT. Silencing the expression of mutated proteins is a therapeutic direction to rescue HD patients, and recent advances in gene editing technology such as CRISPR/CasRx have opened up new avenues for therapeutic intervention. Methods The CRISPR/CasRx system was employed to target human HTT exon 1, resulting in an efficient knockdown of HTT mRNA. This therapeutic effect was substantiated in various models: HEK 293 T cell, the HD 140Q-KI mouse, and the HD-KI pig model. The efficiency of the knockdown was analyzed through Western blot and RT-qPCR. Additionally, neuropathological changes were examined using Western blot, immunostaining, and RNA sequencing. The impact on motor abilities was assessed via behavioral experiments, providing a comprehensive evaluation of the treatment's effectiveness. Results CRISPR/CasRx system can significantly reduce HTT mRNA levels across various models, including HEK 293 T cells, HD 140Q-KI mice at various disease stages, and HD-KI pigs, and resulted in decreased expression of mHTT. Utilizing the CRISPR/CasRx system to knock down HTT RNA has shown to ameliorate gliosis in HD 140Q-KI mice and delay neurodegeneration in HD pigs. Conclusions These findings highlight the effectiveness of the RNA-targeting CRISPR/CasRx as a potential therapeutic strategy for HD. Furthermore, the success of this approach provides valuable insights and novel avenues for the treatment of other genetic disorders caused by gene mutations.

Abstract Heliocidaris crassispina is a tropical sea urchin that holds both ecological and economic value and serves as an ideal experimental animal. This study first employed a combination of PacBio HiFi and Hi-C sequencing data to present a high-quality, chromosome-level assembly of H. crassispina genome. This assembled genome spanned 709.77 Mb, with a contig N50 length of 4.98 Mb and a scaffold N50 length of 33.23 Mb. The assembly was anchored on 21 pseudo-chromosomes, covering 98.32% of the genome. A total of 18,665 protein-coding genes were identified, and BUSCO analysis revealed a completeness score of 97.1%. Additionally, non-coding RNAs (ncRNAs) were annotated, including miRNAs, rRNAs, tRNAs and snRNAs, providing a more complete functional understanding of the genome. The high-quality reference genome will enrich the current echinoderm genomic resources and provide a solid foundation for future studies on H. crassispina, including resource surveys, genomic breeding, and marine ranch management.

Abstract Due to its complex application environment, hydraulic pile hammers are difficult to model and accurately grasp their motion laws in automation control. Therefore, to address the high-precision prediction problem of the motion law of hydraulic pile hammer systems under complex working conditions, a knowledge embedding surrogate model based on a dual neural network is designed, which can be divided into two parts: feature extraction network and prediction network. On this basis, the model introduces physics knowledge embedding technology, adds inequality constraints based on physical laws to the loss function, and introduces transfer learning algorithms to maintain high accuracy of the model under limited data conditions. The results showed that the PSM (γ = 0.5) model designed in the study had a median of -0.001 and a variance of 0.038 under undisturbed conditions, demonstrating high prediction stability. Under perturbation conditions, the median of the PSM (γ = 1.5) model was -0.003, with a variance of 0.031, indicating the highest prediction accuracy. From this, the research model has good prediction accuracy under complex working conditions, which can lay a technical foundation for predicting the motion law of hydraulic pile hammers and automatic control.

Abstract Background Long noncoding RNAs (lncRNAs) play a critical role in gastric cancer (GC) progression and metastasis. However, research comprehensively exploring tissue-derived lncRNAs for predicting peritoneal recurrence in patients with GC remains limited. This study aims to investigate the transcriptional landscape of lncRNAs in GC with peritoneal metastasis (PM) and to develop an integrated lncRNA-based score to predict peritoneal recurrence in patients with GC after radical gastrectomy. Methods We analyzed the transcriptome profile of lncRNAs in paired peritoneal, primary gastric tumor, and normal tissue specimens from 12 patients with GC in the Sun Yat-sen University Cancer Center (SYSUCC) discovery cohort. Key lncRNAs were identified via interactive analysis with the TCGA database and SYSUCC validation cohort. A score model was constructed using the LASSO regression model and nomogram COX regression and evaluated using receiver operating characteristic curves. The role of lncRNAs in the PM of GC was then examined through wound healing, Transwell, 3D multicellular tumor spheroid invasion, and peritoneal cavity xenograft tumorigenicity assays in mice. Result Five essential lncRNAs were screened and incorporated into the PM risk score to predict peritoneal recurrence-free survival (pRFS). We developed a comprehensive, integrated nomogram score, including the PM risk score, pT, pN, and tumor size, which could effectively predict the 5-year pRFS with an Area under the curve of 0.79 (95% CI: 0.71-0.88). Subsequently, we demonstrated that one of these lncRNAs, CASC15, promoted the invasion and migration of GC cells in vitro and facilitated the PM of GC cells in vivo, initially verifying that lncRNAs contribute to the PM of GC. Mechanistic analysis demonstrated that CASC15 promoted EMT and metastasis by activating the JNK and p38 pathways. Conclusion A lncRNA-based integrated score was constructed in this study to predict peritoneal recurrence in patients clinically.

Abstract In this study, a chromosome-level genome of the tropical sea cucumber Stichopus monotuberculatus was generated by a combination of Nanopore long-read, Illumina short-read, and Hi-C sequencing technologies. The final assembly was 810.54 Mb in length, with contig N50 and scaffold N50 values of 10.15 Mb and 35.36 Mb, respectively. This assembly comprised 23 pseudo-chromosomes, covering 99.82% of the genome. Completeness analysis using BUSCO indicated that 97.8% of the metazoan conserved genes were presented in their entirety. A total of 29,596 protein-coding genes were predicted, with functional annotations available for 94.43% of these genes. The high-quality genome assembly produced in this study may provide an essential foundation for future researches on resource conservation and genetic breeding of S. monotuberculatus.

In this study, we present the complete mitochondrial genome of Rhinogobius shennongensis, sequenced using the Illumina HiSeq platform. The result is a circular mitogenome of 16,500 base pairs (bp) with a pronounced A + T nucleotide bias. Phylogenetic analysis was conducted using both Bayesian inference (BI) and maximum-likelihood (ML) methods, utilizing the complete mitochondrial genomes of R. shennongensis and 19 additional Rhinogobius species. The analysis indicated a close mitochondrial relationship between R. maculagenys and R. shennongensis. This research not only enriches genetic resources but also supports phylogenetic studies within the genus Rhinogobius. To further clarify evolutionary dynamics, additional mitochondrial genome sequencing of other Rhinogobius species is essential.

Abstract Sea cucumbers are predominant deposit feeders in benthic ecosystems, providing protective benefits to coral reefs by reducing disease prevalence. However, how they receive sufficient nutrition from seabed sediments remains poorly understood. Here, we investigate Holothuria leucospilota, an ecologically significant tropical sea cucumber, to elucidate digestive mechanisms underlying marine deposit-feeding. Genomic analysis reveals intriguing evolutionary adaptation characterized by an expansion of digestive carbohydrase genes and a contraction of digestive protease genes, suggesting specialization in digesting microalgae. Developmentally, two pivotal dietary shifts, namely, from endogenous nutrition to planktonic feeding, and from planktonic feeding to deposit feeding, induce changes in digestive tract enzyme profiles, with adults mainly expressing carbohydrases and lipases. A nuanced symbiotic relationship exists between gut microbiota and the host, namely, specific resident bacteria supply crucial enzymes for food digestion, while other bacteria are digested and provide assimilable nutrients. Our study further identifies Holothuroidea lineage-specific lysozymes that are restrictedly expressed in the intestines to support bacterial digestion. Overall, this work advances our knowledge of the evolutionary innovations in the sea cucumber digestive system which enable them to efficiently utilize nutrients from seabed sediments and promote food recycling within marine ecosystems.

Abstract Background The activation of endoplasmic reticulum (ER) stress is an early pathological hallmark of Alzheimer’s disease (AD) brain, but how ER stress contributes to the onset and development of AD remains poorly characterized. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor and an ER stress inducible protein. Previous studies reported that MANF is increased in the brains of both pre-symptomatic and symptomatic AD patients, but the consequence of the early rise in MANF protein is unknown. Methods We examined the expression of MANF in the brain of AD mouse models at different pathological stages. Through behavioral, electrophysiological, and neuropathological analyses, we assessed the level of synaptic dysfunctions in the MANF transgenic mouse model which overexpresses MANF in the brain and in wild type (WT) mice with MANF overexpression in the hippocampus. Using proteomic and transcriptomic screening, we identified and validated the molecular mechanism underlying the effects of MANF on synaptic function. Results We found that increased expression of MANF correlates with synapse loss in the hippocampus of AD mice. The ectopic expression of MANF in mice via transgenic or viral approaches causes synapse loss and defects in learning and memory. We also identified that MANF interacts with ELAV like RNA-binding protein 2 (ELAVL2) and affects its binding to RNA transcripts that are involved in synaptic functions. Increasing or decreasing MANF expression in the hippocampus of AD mice exacerbates or ameliorates the behavioral deficits and synaptic pathology, respectively. Conclusions Our study established MANF as a mechanistic link between ER stress and synapse loss in AD and hinted at MANF as a therapeutic target in AD treatment.

PirB is the main virulence factor of acute hepatopancreatic necrosis disease (AHPND) which induced the sloughing of hepatopancreatic cells and shrimp death. In addition, Litopenaeus vannamei aminopeptidase N (Lv-APN) is reported to be a functional receptor that mediates the pathogenicity by VpAHPND. This study aims to screen the PirB binding peptide to rescue the survival rate under VpAHPND infection. Here, the PirB toxin-binding peptides were selected using the random phage peptide library kit, and their biological function was verified by injecting them under VpAHPND challenge. The receptor candidates for PirB were genome-wide identified and selected based on gene expression profiles, and the biological function of Lv-APN1 was confirmed through RNAi. Docking analysis of Peptide-Lv-APN1 and PirB-Lv-APN1 was conducted using the MDockPeP server, with comparative analysis implied. As a result, a total of 11 PirB binding peptides were screened, among which P2 was found to effectively improve the shrimp survival rate under VpAHPND challenge. And knocked down of Lv-APN1, candidate receptor for PirB toxin, rescued mortality under VpAHPND challenge. Furthermore, docking analysis revealed that the interface of Lv-APN1 to rPirB was consistent with the P2 to rPirB, suggesting that P2 is likely to bind to PirB to block its binding to Lv-APN1 to reduce the mortality. In conclusion, both the injection of P2 and inference of Lv-APN1 can rescue the mortality of shrimp under VpAHPND challenge, and docking analysis revealed P2 is likely to bind to rPirB, blocking its binding to Lv-APN1 and reducing VpAHPND infection.

Semi-clathrate hydrates, with high latent heat, tunability, and excellent stability, show promise as phase change cold storage materials. To meet the varying phase change temperature requirements for different applications, this study investigated the dissociation behavior of hydrates formed from two tetrabutylammonium (TBA+) salt mixtures—FBS (TBAF, TBAB, TBAHSO4) and FCS (TBAF, TBAC, TBAHSO4)—at varying concentrations and ratios using differential scanning calorimetry. The results revealed that tuning the ratios of these mixtures enabled single-peak phase change regulation, ranging from 3.8 °C to 15.1 °C and 26 °C to 28.1 °C. The mixed tetrabutylammonium salt solutions exhibited a synergistic effect, enhancing phase change enthalpy beyond pure solutions, with peak values of 225.77 kJ/kg (FBS 0.7-0.3-0) and 239.48 kJ/kg (FCS 0.5-0.5-0). Further analysis indicated that reducing the molar mass of the mixed anions increased both phase change temperature and enthalpy, with FCS exhibiting a more pronounced improvement. For single-peak phase changes, maximum enthalpies of 225.77 kJ/kg (FBS) and 226.48 kJ/kg (FCS) were observed when the mixed anion molar masses were 25.69 and 20.96 kg/kmol, respectively. These finding highlight the potential of mixed tetrabutylammonium slat hydrates for applications, including high-energy density cold storage, multi-temperature range preservation, and advanced air conditioning systems.

Abstract Here we review scanning tunneling microscopy research on the surface determination for various types of kagome materials, including 11-type (CoSn, FeSn, FeGe), 32-type (Fe3Sn2), 13-type (Mn3Sn), 135-type (AV3Sb5, A = K, Rb, Cs), 166-type (TbMn6Sn6, YMn6Sn6 and ScV6Sn6), and 322-type (Co3Sn2S2 and Ni3In2Se2). We first demonstrate that the measured step height between different surfaces typically deviates from the expected value of ±0.4 ∼0.8Å, which is owing to the tunneling convolution effect with electronic states and becomes a serious issue for Co3Sn2S2 where the expected Sn-S interlayer distance is 0.6Å. Hence, we put forward a general methodology for surface determination as atomic step geometry imaging, which is fundamental but also experimentally challenging to locate the step and to image with atomic precision. We discuss how this method can be used to resolve the surface termination puzzle in Co3Sn2S2. This method provides a natural explanation for the existence of adatoms and vacancies, and beyond using unknown impurity states, we propose and use designer layer-selective substitutional chemical markers to confirm the validity of this method. Finally, we apply this method to determine the surface of a new kagome material Ni3In2Se2, as a cousin of Co3Sn2S2, and we image the underlying kagome geometry on the determined Se surface above the kagome layer, which directly visualizes the p-d hybridization physics. We emphasize that this general method does not rely on theory, but the determined surface identity can provide guidelines for first-principles calculations with adjustable parameters on the surface-dependent local density of states and quasi-particle interference patterns.

Abstract The interplay of topology, magnetism, and correlations gives rise to intriguing phases of matter. In this study, through state-of-the-art angle-resolved photoemission spectroscopy, density functional theory, and dynamical mean-field theory calculations, we visualize a fourfold degenerate Dirac nodal line at the boundary of the bulk Brillouin zone in the antiferromagnet YMn2Ge2. We further demonstrate that this gapless, antiferromagnetic Dirac nodal line is enforced by the combination of magnetism, space-time inversion symmetry, and nonsymmorphic lattice symmetry. The corresponding drumhead surface states traverse the whole surface Brillouin zone. YMn2Ge2 thus serves as a platform to exhibit the interplay of multiple degenerate nodal physics and antiferromagnetism. Interestingly, the magnetic nodal line displays a d-orbital dependent renormalization along its trajectory in momentum space, thereby manifesting Hund’s coupling. Our findings offer insights into the effect of electronic correlations on magnetic Dirac nodal lines, leading to an antiferromagnetic Hund nodal line.

Abstract Purpose To evaluate the difference in the diagnostic efficacy of 18F-PSMA-1007 PET/CT and pelvic MRI in primary prostate cancer, as well as the correlation between the two methods and histopathological parameters and serum PSA levels. Methods A total of 41 patients with suspected prostate cancer who underwent 18F-PSMA-1007 PET/CT imaging in our department from 2018 to 2023 were retrospectively collected. All patients underwent 18F-PSMA-1007 PET/CT and MRI scans. The sensitivity, PPV and diagnostic accuracy of MRI and 18F-PSMA-1007 PET/CT in the diagnosis of prostate cancer were calculated after comparing the results of MRI and 18F-PSMA-1007 PET/CT with biopsy. The Spearman test was used to calculate the correlation between 18F-PSMA-1007 PET/CT, MRI parameters, histopathological indicators, and serum PSA levels. Results Compared with histopathological results, the sensitivity, PPV and diagnostic accuracy of 18F-PSMA-1007 PET/CT in the diagnosis of prostate cancer were 95.1%, 100.0% and 95.1%, respectively. The sensitivity, PPV and diagnostic accuracy of MRI in the diagnosis of prostate cancer were 82.9%, 100.0% and 82.9%, respectively. There was a mild to moderately positive correlation between Gleason (Gs) score, Ki-67 index, serum PSA level and 18F-PSMA-1007 PET/CT parameters (p 0.05). Conclusion Compared with MRI, 18F-PSMA-1007 PET/CT has higher sensitivity and diagnostic accuracy in the detection of malignant prostate tumors. In addition, the Ki-67 index and AMACR (P504S) expression were only correlated with 18F-PSMA-1007 PET/CT parameters. Gs score and serum PSA level were correlated with 18F-PSMA-1007 PET/CT and MRI parameters. 18F-PSMA-1007 PET/CT examination can provide certain reference values for the clinical diagnosis, evaluation, and treatment of malignant prostate tumors.