Three-Step Depletion Strategy of Glutathione: Tunable Metal-Organic-Framework-Engineered Nanozymes for Driving Oxidative/Nitrative Stress to Maximize Ferroptosis Therapy.

Ferroptosis is a novel type of nonapoptotic programmed cell death involving the accumulation of lipid peroxidation (LPO) to a lethal threshold. Herein, we propose tunable zeolitic imidazolate framework (ZIFs)-engineered biodegradable nanozymes for ferroptosis mediated by both reactive oxygen species (ROS) and nitrogen species (RNS). l-Arginine is utilized as an exogenous nitric oxide donor and loaded into hollow ZIFs@MnO2 artificial nanozymes, which are formed by etching ZIFs with potassium permanganate and simultaneously generating a MnO2 shell in situ. The constructed nanozymes with multienzyme-like activities including peroxidase, oxidase, and catalase can release satisfactory ROS and RNS through a cascade reaction, consequently promoting the accumulation of LPO. Furthermore, it can improve the efficiency of ferroptosis through a three-step strategy of glutathione (GSH) depletion; that is, the outer MnO2 layer consumes GSH under slightly acidic conditions and RNS downregulates SLC7A11 and glutathione reductase, thus directly inhibiting GSH biosynthesis and indirectly preventing GSH regeneration.

A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes.

AIMS/HYPOTHESIS: Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment. METHODS: We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes. RESULTS: The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster 4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1+ monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1+ monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1+ monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1+ monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1+ group compared with the SIGLEC-1- or saline control group. CONCLUSIONS/INTERPRETATION: Our study identified a novel group of SIGLEC-1+ monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes. DATA AVAILABILITY: RNA-seq data have been deposited in the GSA human database ( https://ngdc.cncb.ac.cn/gsa-human/ ) under accession number HRA003649.

Characterization of the genome and cell invasive phenotype of Vibrio diabolicus Cg5 isolated from mass mortality of Pacific oyster, Crassostrea gigas.

Vibrio is an important group of aquatic animal pathogens, which has been identified as the main pathogenic factor causing mass summer mortality of Crassostrea gigas in northern China. This study aims to investigate the potential pathogenic mechanisms of Vibrio Cg5 isolate in C. gigas. We sequenced and annotated the genome of Vibrio Cg5 to analyze potential virulence factors. The gentamicin protection assays were performed with C. gigas primary cells to reveal the cell-invasive behavior of Cg5. The genome analysis showed that Cg5 was a strain of human disease-associated pathogen with multiple antibiotic resistance, and four virulence factors associated with intracellular survival were present in the genome. The gentamicin protection assays showed that Cg5 could potentially invade the cells of C. gigas, indicating that Cg5 could be a facultative intracellular pathogen of C. gigas. These results provide insights into the pathogenic mechanism of V. diabolicus, an emerging pathogenic Vibrio on aquatic animals, which would be valuable in preventing and controlling diseases in oysters.

Whole-genome DNA methylation profiling revealed epigenetic regulation of NF-κB signaling pathway involved in response to Vibrio alginolyticus infection in the Pacific oyster, Crassostrea gigas.

DNA methylation, an essential epigenetic alteration, is tightly linked to a variety of biological processes, such as immune response. To identify the epigenetic regulatory mechanism in Pacific oyster (Crassostrea gigas), whole-genome bisulfite sequencing (WGBS) was conducted on C. gigas at 0 h, 6 h, and 48 h after infection with Vibrio alginolyticus. At 6 h and 48 h, a total of 11,502 and 14,196 differentially methylated regions (DMRs) were identified (p<0.05, FDR<0.001) compared to 0 h, respectively. Gene ontology (GO) analysis showed that differentially methylated genes (DMGs) were significantly enriched in various biological pathways including immunity, cytoskeleton, epigenetic modification, and metabolic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that transcription machinery (ko03021) is one of the most important pathways. Integrated transcriptome and methylome analyses allowed the identification of 167 and 379 DMG-related DEGs at 6 h and 48 h, respectively. These genes were significantly enriched in immune-related pathways, including nuclear factor kappa B (NF-κB) signaling pathway (ko04064) and tumor necrosis factor (TNF) signaling pathway (ko04668). Interestingly, it's observed that the NF-κB pathway could be activated jointly by TNF Receptor Associated Factor 2 (TRAF2) and Baculoviral IAP Repeat Containing 3 (BIRC3, the homolog of human BIRC2) which were regulated by DNA methylation in response to the challenge posed by V. alginolyticus infection. Through this study, we provided insightful information about the epigenetic regulation of immunity-related genes in the C. gigas, which will be valuable for the understanding of the innate immune system modulation and defense mechanism against bacterial infection in invertebrates.

TU-LESS procedure for acute abdomen in late pregnancy: a retrospective study.

BACKGROUND: Acute abdominal conditions during pregnancy are significant risks to maternal and fetal health, necessitating timely diagnosis and intervention. The choice of surgical approach is a major concern for obstetricians. OBJECTIVE: To evaluate the safety and efficacy of the TU-LESS procedure for acute abdomen in late pregnancy. METHODS: We retrospectively analyzed 12 patients who underwent TU-LESS for acute abdominal conditions in the third trimester from 2020 to 2023. We reviewed medical records for clinical characteristics, surgical interventions, postoperative complications, and pregnancy outcomes. RESULTS: The study included patients with a median age of 27 (range 20-35) and a BMI of 24.33 kg/m2 (range 21.34-31.96). The median gestational age at surgery was 30 weeks (range, 28 + 3-32 + 4 weeks), with surgeries lasting an average of 60 min (range, 30-163 min). Blood loss was 2-20 mL, and the median hospital stay post-surgery was 6 days (range, 2-16 days). There were no significant complications. The median time to delivery after TU-LESS was 56 days (range, 26-66 days), resulting in 8 full-term deliveries, 2 preterm cesareans, and 2 preterm vaginal deliveries. All newborns were healthy, with no fetal losses or neonatal deaths. CONCLUSION: TU-LESS, performed by experienced obstetricians and gynecologists with proper preoperative preparation, is safe and effective for managing acute abdomen in late pregnancy, without the need to delay surgery due to gestational age.

Multi-omic insights into the formation and evolution of a novel shell microstructure in oysters.

BACKGROUND: Molluscan shell, composed of a diverse range of architectures and microstructures, is a classic model system to study the relationships between molecular evolution and biomineralized structure formation. The shells of oysters differ from those of other molluscs by possessing a novel microstructure, chalky calcite, which facilitates adaptation to the sessile lifestyle. However, the genetic basis and evolutionary origin of this adaptive innovation remain largely unexplored. RESULTS: We report the first whole-genome assembly and shell proteomes of the Iwagaki oyster Crassostrea nippona. Multi-omic integrative analyses revealed that independently expanded and co-opted tyrosinase, peroxidase, TIMP genes may contribute to the chalky layer formation in oysters. Comparisons with other molluscan shell proteomes imply that von Willebrand factor type A and chitin-binding domains are basic members of molluscan biomineralization toolkit. Genome-wide identification and analyses of these two domains in 19 metazoans enabled us to propose that the well-known Pif may share a common origin in the last common ancestor of Bilateria. Furthermore, Pif and LamG3 genes acquire new genetic function for shell mineralization in bivalves and the chalky calcite formation in oysters likely through a combination of gene duplication and domain reorganization. CONCLUSIONS: The spatial expression of SMP genes in the mantle and molecular evolution of Pif are potentially involved in regulation of the chalky calcite deposition, thereby shaping the high plasticity of the oyster shell to adapt to a sessile lifestyle. This study further highlights neo-functionalization as a crucial mechanism for the diversification of shell mineralization and microstructures in molluscs, which may be applied more widely for studies on the evolution of metazoan biomineralization.

Reference genomes of channel catfish and blue catfish reveal multiple pericentric chromosome inversions.

BACKGROUND: Channel catfish and blue catfish are the most important aquacultured species in the USA. The species do not readily intermate naturally but F1 hybrids can be produced through artificial spawning. F1 hybrids produced by mating channel catfish female with blue catfish male exhibit heterosis and provide an ideal system to study reproductive isolation and hybrid vigor. The purpose of the study was to generate high-quality chromosome level reference genome sequences and to determine their genomic similarities and differences. RESULTS: We present high-quality reference genome sequences for both channel catfish and blue catfish, containing only 67 and 139 total gaps, respectively. We also report three pericentric chromosome inversions between the two genomes, as evidenced by long reads across the inversion junctions from distinct individuals, genetic linkage mapping, and PCR amplicons across the inversion junctions. Recombination rates within the inversional segments, detected as double crossovers, are extremely low among backcross progenies (progenies of channel catfish female × F1 hybrid male), suggesting that the pericentric inversions interrupt postzygotic recombination or survival of recombinants. Identification of channel catfish- and blue catfish-specific genes, along with expansions of immunoglobulin genes and centromeric Xba elements, provides insights into genomic hallmarks of these species. CONCLUSIONS: We generated high-quality reference genome sequences for both blue catfish and channel catfish and identified major chromosomal inversions on chromosomes 6, 11, and 24. These perimetric inversions were validated by additional sequencing analysis, genetic linkage mapping, and PCR analysis across the inversion junctions. The reference genome sequences, as well as the contrasted chromosomal architecture should provide guidance for the interspecific breeding programs.

Development of Nanopore sequencing-based full-length transcriptome database toward functional genome annotation of the Pacific oyster, Crassostrea gigas.

The Pacific oyster (Crassostrea gigas) is a widely cultivated shellfish in the world, while its transcriptome diversity remains less unexplored due to the limitation of short reads. In this study, we used Oxford Nanopore sequencing to develop the full-length transcriptome database of C. gigas. We identified 77,920 full-length transcripts from 21,523 genes, and uncovered 9668 alternative splicing events and 87,468 alternative polyadenylation sites. Notably, a total of 16,721 novel transcripts were annotated in this work. Furthermore, integrative analysis of 25 publicly available RNA-seq datasets revealed the transcriptome diversity involved in post-transcriptional regulation in C. gigas. We further developed a Drupal based webserver, Cgtdb, which can be used for transcriptome visualization, sequence alignment, and functional genome annotation analyses. This work provides valuable resources and a useful tool for integrative analysis of various transcriptome datasets in C. gigas, which will serve as an essential reference for functional annotation of the oyster genome.

A chromosome-level genome assembly of Ostrea denselamellosa provides initial insights into its evolution.

The oyster Ostrea denselamellosa is a live-bearing species with a sharp decline in the natural population. Despite recent breakthroughs in long-read sequencing, high quality genomic data are very limited in O. denselamellosa. Here, we carried out the first whole genome sequencing at the chromosome-level in O. denselamellosa. Our studies yielded a 636 Mb assembly with scaffold N50 around 71.80 Mb. 608.3 Mb (95.6% of the assembly) were anchored to 10 chromosomes. A total of 26,412 protein-coding genes were predicted, of which 22,636 (85.7%) were functionally annotated. By comparative genomics, we found that long interspersed nuclear element (LINE) and short interspersed nuclear element (SINE) made up a larger proportion in O. denselamellosa genome than in other oysters'. Moreover, gene family analysis showed some initial insight into its evolution. This high-quality genome of O. denselamellosa provides a valuable genomic resource for studies of evolution, adaption and conservation in oysters.

Integrated analysis of mRNAs and lncRNAs reveals candidate marker genes and potential hub lncRNAs associated with growth regulation of the Pacific Oyster, Crassostrea gigas.

BACKGROUND: The Pacific oyster, Crassostrea gigas, is an economically important shellfish around the world. Great efforts have been made to improve its growth rate through genetic breeding. However, the candidate marker genes, pathways, and potential lncRNAs involved in oyster growth regulation remain largely unknown. To identify genes, lncRNAs, and pathways involved in growth regulation, C. gigas spat was cultured at a low temperature (15 ℃) to yield a growth-inhibited model, which was used to conduct comparative transcriptome analysis with spat cultured at normal temperature (25 ℃). RESULTS: In total, 8627 differentially expressed genes (DEGs) and 1072 differentially expressed lncRNAs (DELs) were identified between the normal-growth oysters (cultured at 25 ℃, hereinafter referred to as NG) and slow-growth oysters (cultured at 15 ℃, hereinafter referred to as SG). Functional enrichment analysis showed that these DEGs were mostly enriched in the AMPK signaling pathway, MAPK signaling pathway, insulin signaling pathway, autophagy, apoptosis, calcium signaling pathway, and endocytosis process. LncRNAs analysis identified 265 cis-acting pairs and 618 trans-acting pairs that might participate in oyster growth regulation. The expression levels of LNC_001270, LNC_003322, LNC_011563, LNC_006260, and LNC_012905 were inducible to the culture temperature and food abundance. These lncRNAs were located at the antisense, upstream, or downstream of the SREBP1/p62, CDC42, CaM, FAS, and PIK3CA genes, respectively. Furthermore, the expression of the trans-acting lncRNAs, including XR_9000022.2, LNC_008019, LNC_015817, LNC_000838, LNC_00839, LNC_011859, LNC_007294, LNC_006429, XR_002198885.1, and XR_902224.2 was also significantly associated with the expression of genes enriched in AMPK signaling pathway, insulin signaling pathway, autophagy, apoptosis, calcium signaling pathway, and endocytosis process. CONCLUSIONS: In this study, we identified the critical growth-related genes and lncRNAs that could be utilized as candidate markers to illustrate the molecular mechanisms underlying the growth regulation of Pacific oysters.

"Electron Transport Chain Interference" Strategy of Amplified Mild-Photothermal Therapy and Defect-Engineered Multi-Enzymatic Activities for Synergistic Tumor-Personalized Suppression.

Arming activatable mild-photothermal therapy (PTT) with the property of relieving tumor thermotolerance holds great promise for overcoming traditional mild PTT limitations such as thermoresistance, insufficient therapeutic effect, and off-target heating. Herein, a mitochondria-targeting, defect-engineered AFCT nanozyme with enhanced multi-enzymatic activity was elaborately designed as a tumor microenvironment (TME)-activatable phototheranostic agent to achieve remarkable anti-tumor therapy via "electron transport chain (ETC) interference and synergistic adjuvant therapy". Density functional theory calculations revealed that the synergistic effect among multi-enzyme active centers endows the AFCT nanozymes with excellent catalytic activity. In TME, open sources of H2O2 can be achieved by superoxide dismutase-mimicking AFCT nanozymes. In response to the dual stimuli of H2O2 and mild acidity, the peroxidase-mimicking activity of AFCT nanozymes not only catalyzes the accumulation of H2O2 to generate ·OH but also converts the loaded 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) into its oxidized form with strong near-infrared absorption, specifically unlocking its photothermal and photoacoustic imaging properties. Intriguingly, the undesired thermoresistance of tumor cells can be greatly alleviated owing to the reduced expression of heat shock proteins enabled by NADH POD-mimicking AFCT-mediated NADH depletion and consequent restriction of ATP supply. Meanwhile, the accumulated ·OH can facilitate both apoptosis and ferroptosis in tumor cells, resulting in synergistic therapeutic outcomes in combination with TME-activated mild PTT.

Biomineralized RuO2 Nanozyme with Multi-Enzyme Activity for Ultrasound-Triggered Peroxynitrite-Boosted Ferroptosis.

Ferroptosis, as a non-apoptotic cell death pathway, has attracted increasing attention for cancer therapy. However, the clinical application of ferroptosis-participated modalities is severely limited by the low efficiency owing to the intrinsic intracellular regulation pathways. Herein, chlorin e6 (Ce6) and N-acetyl-l-cysteine-conjugated bovine serum albumin-ruthenium dioxide is elaborately designed and constructed for ultrasound-triggered peroxynitrite-mediated ferroptosis. Upon ultrasound stimulation, the sonosensitizers of Ce6 and RuO2 exhibit highly efficient singlet oxygen (1 O2 ) generation capacity, which is sequentially amplified by superoxide dismutase and catalase-mimicking activity of RuO2 with hypoxia relief. Meanwhile, the S-nitrosothiol group in BCNR breaks off to release nitric oxide (NO) on-demand, which then reacts with 1 O2 forming highly cytotoxic peroxynitrite (ONOO- ) spontaneously. Importantly, BCNR nanozyme with glutathione peroxidase-mimicking activity can consume glutathione (GSH), along with the generated ONOO- downregulates glutathione reductase, avoiding GSH regeneration. The two-parallel approach ensures complete depletion of GSH within the tumor, resulting in the boosted ferroptosis sensitization of cancer cells. Thus, this work presents a superior paradigm for designing peroxynitrite-boosted ferroptosis sensitization cancer therapeutic.

Parallel evolution in Crassostrea oysters along the latitudinal gradient is associated with variation in multiple genes involved in adipogenesis.

Parallel diversification provides a proper framework for studying the role of natural selection in evolution. Yet, empirical studies from ecological 'non-model' species of invertebrates are limited at the whole genome level. Here, we presented a chromosome-scale genome assembly for Crassostrea angulata and investigated the parallel genomic evolution in oysters. Specifically, we used population genomics approaches to compare two southern-northern oyster species pairs (C. angulata-C. gigas and southern-northern C. ariakensis) along the coast of China. The estimated divergence time of C. angulata and C. gigas is earlier than that of southern and northern C. ariakensis, which aligns with the overall elevated genome-wide divergence. However, the southern-northern C. ariakensis FST profile represented more extremely divergent "islands". Combined with recent reciprocal hybridization studies, we proposed that they are currently at an early stage of speciation. These two southern-northern oyster species pairs exhibited significant repeatability in patterns of genome-wide differentiation, especially in genomic regions with extremely high and low divergence. This suggested that divergent and purifying selection has contributed to the genomic parallelism between southern and northern latitudes. Top differentiated genomic regions shared in these two oyster species pairs contained candidate genes enriched for functions in energy metabolism, especially adipogenesis, which are closely related to reproductive behaviours. These genes might be good candidates for further investigation in vivo. In conclusion, our results suggest that similar divergent selection and shared genomic features could predictably transform standing genetic variation within one species pair into differences in another.

Contribution of m5C RNA Modification-Related Genes to Prognosis and Immunotherapy Prediction in Patients with Ovarian Cancer.

Background: 5-Methylcytosine (m5C) RNA modification is closely implicated in the occurrence of a variety of cancers. Here, we established a novel prognostic signature for ovarian cancer (OC) patients based on m5C RNA modification-related genes and explored the correlation between these genes with the tumor immune microenvironment. Methods: Methylated-RNA immunoprecipitation sequencing helped us to identify candidate genes related to m5C RNA modification at first. Based on TCGA database, we screened the differentially expressed candidate genes related to the prognosis and constructed a prognostic model using LASSO Cox regression analyses. Notably, the accuracy of the model was evaluated by Kaplan-Meier analysis and receiver operator characteristic curves. Independent prognostic risk factors were investigated by Cox proportional hazard model. Furthermore, we also analyzed the biological functions and pathways involved in the signature. Finally, the immune response of the model was visualized in great detail. Results: Totally, 2,493 candidate genes proved to be involved in m5C modification of RNA for OC. We developed a signature with prognostic value consisting of six m5C RNA modification-related genes. Specially, samples have been split into two cohorts with low- and high-risk scores according to the model, in which the low-risk OC patients exhibited dramatically better overall survival time than those with high-risk scores. Besides, not only was this model a prognostic factor independent of other clinical characteristics but it predicted the intensity of the immune response in OC. Significantly, the accuracy and availability of the signature were verified by ICGC database. Conclusions: Our study bridged the gap between m5C RNA modification and the prognosis of OC and was expected to provide an effective breakthrough for immunotherapy in OC patients.

The gold-ringed octopus (Amphioctopus fangsiao) genome and cerebral single-nucleus transcriptomes provide insights into the evolution of karyotype and neural novelties.

BACKGROUND: Coleoid cephalopods have distinctive neural and morphological characteristics compared to other invertebrates. Early studies reported massive genomic rearrangements occurred before the split of octopus and squid lineages (Proc Natl Acad Sci U S A 116:3030-5, 2019), which might be related to the neural innovations of their brain, yet the details remain elusive. Here we combine genomic and single-nucleus transcriptome analyses to investigate the octopod chromosome evolution and cerebral characteristics. RESULTS: We present a chromosome-level genome assembly of a gold-ringed octopus, Amphioctopus fangsiao, and a single-nucleus transcriptome of its supra-esophageal brain. Chromosome-level synteny analyses estimate that the chromosomes of the ancestral octopods experienced multiple chromosome fission/fusion and loss/gain events by comparing with the nautilus genome as outgroup, and that a conserved genome organization was detected during the evolutionary process from the last common octopod ancestor to their descendants. Besides, protocadherin, GPCR, and C2H2 ZNF genes are thought to be highly related to the neural innovations in cephalopods (Nature 524:220-4, 2015), and the chromosome analyses pinpointed several collinear modes of these genes on the octopod chromosomes, such as the collinearity between PCDH and C2H2 ZNF, as well as between GPCR and C2H2 ZNF. Phylogenetic analyses show that the expansion of the octopod protocadherin genes is driven by a tandem-duplication mechanism on one single chromosome, including two separate expansions at 65 million years ago (Ma) and 8-14 Ma, respectively. Furthermore, we identify eight cell types (i.e., cholinergic and glutamatergic neurons) in the supra-esophageal brain of A. fangsiao, and the single-cell expression analyses reveal the co-expression of protocadherin and GPCR in specific neural cells, which may contribute to the neural development and signal transductions in the octopod brain. CONCLUSIONS: The octopod genome analyses reveal the dynamic evolutionary history of octopod chromosomes and neural-related gene families. The single-nucleus transcriptomes of the supra-esophageal brain indicate their cellular heterogeneities and functional interactions with other tissues (i.e., gill), which provides a foundation for further octopod cerebral studies.

Tailoring Silica-Based Nanoscintillators for Peroxynitrite-Potentiated Nitrosative Stress in Postoperative Radiotherapy of Colon Cancer.

The development of a manageable reactive nitrogen species-potentiated nitrosative stress induction system for cancer therapy has remained elusive. Herein, tailored silica-based nanoscintillators were reported for low-dosage X-ray boosting for the in situ formation of highly cytotoxic peroxynitrite (ONOO-). Significantly, cellular nitrosative stress revolving around the intracellular protein tyrosine nitration through ONOO- pathways was explored. High-energy X-rays were directly deposited on silica-based nanoscintillators, forming the concept of an open source and a reduced expenditure-aggravated DNA damage strategy. Moreover, the resultant ONOO-, along with the released nitric oxide, not only can act as "oxygen suppliers" to combat tumor hypoxia but also can induce mitochondrial damage to initiate caspase-mediated apoptosis, further improving the therapeutic efficacy of radiotherapy. Thus, the design of advanced nanoscintillators with specific enhanced nitrosative stress offers promising potential for postoperative radiotherapy of colon cancer.

Near Infrared-Triggered Theranostic Nanoplatform with Controlled Release of HSP90 Inhibitor for Synergistic Mild Photothermal and Enhanced Nanocatalytic Therapy with Hypoxia Relief.

Mild photothermal therapy (PTT, <45 °C) can prevent tumor metastasis and heat damage to normal tissue, compared with traditional PTT (>50 °C). However, its therapeutic efficacy is limited owing to the hypoxic tumor environment and tumor thermoresistance owing to the overproduction of heat shock proteins (HSPs). Herein, a near-infrared (NIR)-triggered theranostic nanoplatform (GA-PB@MONs@LA) is designed for synergistic mild PTT and enhanced Fenton nanocatalytic therapy against hypoxic tumors. The nanoplatform is fabricated by the confined formation of Prussian blue (PB) nanoparticles in mesoporous organosilica nanoparticles (MONs), followed by the loading of gambogic acid (GA), an HSP90 inhibitor, and coating with thermo-sensitive lauric acid (LA). Upon NIR irradiation, the photothermal effect (44 °C) of PB not only induces apoptosis of tumor cells but also triggers the on-demand release of GA, inhibiting the production of HSP90. Moreover, the delivered heat simultaneously enhances the catalase-like and Fenton activity of PB@MONs@LA in an acidic tumor microenvironment, relieving the tumor hypoxia and promoting the generation of highly toxic •OH. In addition, the nanoplatform enables magnetic resonance/photoacoustic dual-modal imaging. Thus, this study describes a distinctive paradigm for the development of NIR-triggered theranostic nanoplatforms for enhanced cancer therapy.

HPV16 E6/E7 stabilize PGK1 protein by reducing its poly-ubiquitination in cervical cancer.

This study aimed to explore the expression profile, prognostic value, regulatory effect, and the underlying mechanism of dysregulation of phosphoglycerate kinase 1 (PGK1) in high-risk human papillomavirus (HPV)-positive cervical epithelial squamous cell carcinoma (CESC). Bioinformatic analysis was performed using the CESC subset of The Cancer Genome Atlas (TCGA)-Cervical Cancer (CESC) and normal cervix in The Genotype-Tissue Expression (GTEx) project. HPV-16 positive CaSki and SiHa cells were used as in vitro cell models. Results showed that compared to the normal cervix, CESC tissues had significantly higher expression of PGK1. CESC patients with the higher 50% expression of PGK1 had substantially shorter disease-specific survival (DSS), and progression-free survival (PFS) compared to the cases with the lower 50% expression of PGK1. PGK1 knockdown impaired, but PGK1 overexpression enhanced the proliferation, colony formation, aerobic glycolytic activities (lactate production, intracellular ATP levels, glucose uptake, and extracellular acidification rate), migration, and invasion of CaSki and SiHa cells. HPV-16 E6/E7 knockdown in CaSki and SiHa cells had limited influence on PGK1 transcription but significantly decreased the half-life of PGK1 protein. E6/E7 knockdown mediated PGK1 downregulation could be blocked by adding MG-132. PGK1 poly-ubiquitination was significantly enhanced after E6/E7 knockdown. In conclusion, this study showed that PGK1 expression might serve as a prognostic biomarker in cervical cancer. Its upregulation contributes to enhanced aerobic glycolysis, migration, and invasion of CESC cells. HPV16 E6/E7 stabilizes PGK1 protein by reducing its poly-ubiquitination.

Effects of low salinity on hemolymph osmolality and transcriptome of the Iwagaki oyster, Crassostrea nippona.

Crassostrea nippona is a kind of oysters with great development value as it can be edible in summer for its late reproductive period. Salinity is one of the important limiting abiotic factors to the survival and distribution of this stenohaline species. To better understand the physiological and immunological response of C. nippona to varying environmental salinities, the effects of low salinity on the hemolymph osmolality and gill transcriptome were investigated in this study. The osmolality of hemolymph in vivo and surrounding water were assessed regularly over one week at five test salinities ranging from 5 psµ to 30 psµ. They reached osmotic equilibrium within hours above 15 psµ but remained hyperosmotic at 10 and 5 psµ for the whole sampling period. Through comparative transcriptome analysis, there were less differentially expressed genes (DEGs) in pairwise comparison of S1 (10 psµ) vs S3 (30 psµ) than in S2 (20 psµ) vs S3. KEGG enrichment analysis identified ubiquitin-mediated proteolysis and mitochondrial apoptosis pathway specifically enriched at 10 psµ. This study gained comprehensive insights on the low salinity response of C. nippona at the molecular level, which provide a theoretical basis for understanding the immune mechanism under low salinity stress.

Identification of an Epigenetically Marked Locus within the Sex Determination Region of Channel Catfish.

Channel catfish has an XY sex determination system. However, the X and Y chromosomes harbor an identical gene content of 950 genes each. In this study, we conducted comparative analyses of methylome and transcriptome of genetic males and genetic females before gonadal differentiation to provide insights into the mechanisms of sex determination. Differentially methylated CpG sites (DMCs) were predominantly identified on the sex chromosome, most notably within the sex determination region (SDR), although the overall methylation profiles across the entire genome were similar between genetic males and females. The drastic differences in methylation were located within the SDR at nucleotide position 14.0-20.3 Mb of the sex chromosome, making this region an epigenetically marked locus within the sex determination region. Most of the differentially methylated CpG sites were hypermethylated in females and hypomethylated in males, suggesting potential involvement of methylation modification in sex determination in channel catfish. Along with the differential methylation in the SDR, a number of differentially expressed genes within the SDR were also identified between genetic males and females, making them potential candidate genes for sex determination and differentiation in channel catfish.