The Eukaryotic CO2-Concentrating Organelle Is Liquid-like and Exhibits Dynamic Reorganization.

Approximately 30%-40% of global CO2 fixation occurs inside a non-membrane-bound organelle called the pyrenoid, which is found within the chloroplasts of most eukaryotic algae. The pyrenoid matrix is densely packed with the CO2-fixing enzyme Rubisco and is thought to be a crystalline or amorphous solid. Here, we show that the pyrenoid matrix of the unicellular alga Chlamydomonas reinhardtii is not crystalline but behaves as a liquid that dissolves and condenses during cell division. Furthermore, we show that new pyrenoids are formed both by fission and de novo assembly. Our modeling predicts the existence of a "magic number" effect associated with special, highly stable heterocomplexes that influences phase separation in liquid-like organelles. This view of the pyrenoid matrix as a phase-separated compartment provides a paradigm for understanding its structure, biogenesis, and regulation. More broadly, our findings expand our understanding of the principles that govern the architecture and inheritance of liquid-like organelles.

Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion.

22q11.2 microdeletions result in specific cognitive deficits and schizophrenia. Analysis of Df(16)A(+/-) mice, which model this microdeletion, revealed abnormalities in the formation of neuronal dendrites and spines, as well as altered brain microRNAs. Here, we show a drastic reduction of miR-185, which resides within the 22q11.2 locus, to levels more than expected by a hemizygous deletion, and we demonstrate that this reduction alters dendritic and spine development. miR-185 represses, through an evolutionarily conserved target site, a previously unknown inhibitor of these processes that resides in the Golgi apparatus and shows higher prenatal brain expression. Sustained derepression of this inhibitor after birth represents the most robust transcriptional disturbance in the brains of Df(16)A(+/-) mice and results in structural alterations in the hippocampus. Reduction of miR-185 also has milder age- and region-specific effects on the expression of some Golgi-related genes. Our findings illuminate the contribution of microRNAs in psychiatric disorders and cognitive dysfunction.

The kiwifruit amyloplast proteome (kfALP): a resource to better understand the mechanisms underlying amyloplast biogenesis and differentiation.

The biogenesis and differentiation (B&D) of amyloplasts contributes to fruit flavor and color. Here, remodeling of starch granules, thylakoids and plastoglobules was observed during development and ripening in two kiwifruit (Actinidia spp.) cultivars - yellow-fleshed 'Hort16A' and green-fleshed 'Hayward'. A protocol was developed to purify starch-containing plastids with a high degree of intactness, and amyloplast B&D was studied using label-free-based quantitative proteomic analyses in both cultivars. Over 3000 amyloplast-localized proteins were identified, of which >98% were quantified and defined as the kfALP (kiwifruit amyloplast proteome). The kfALP data were validated by Tandem-Mass-Tag (TMT) labeled proteomics in 'Hort16A'. Analysis of the proteomic data across development and ripening revealed: 1) a conserved increase in the abundance of proteins participating in starch synthesis/degradation during both amyloplast B&D; 2) up-regulation of proteins for chlorophyll degradation and of plastoglobule-localized proteins associated with chloroplast breakdown and plastoglobule formation during amyloplast differentiation; 3) constitutive expression of proteins involved in ATP supply and protein import during amyloplast B&D. Interestingly, two different pathways of amyloplast B&D were observed in the two cultivars. In 'Hayward', significant increases in abundance of photosynthetic- and tetrapyrrole metabolism-related proteins were observed, but the opposite trend was observed in 'Hort16A'. In conclusion, analysis of the kfALP provides new insights into the potential mechanisms underlying amyloplast B&D with relevance to key fruit quality traits in contrasting kiwifruit cultivars.

Kinase fusion positive intra-osseous spindle cell tumors: A series of eight cases with review of the literature.

Mesenchymal spindle cell tumors with kinase fusions, often presenting in superficial or deep soft tissue locations, may rarely occur in bone. Herein, we describe the clinicopathologic and molecular data of eight bone tumors characterized by various kinase fusions from our files and incorporate the findings with the previously reported seven cases, mainly as single case reports. In the current series all but one of the patients were young children or teenagers, with an age range from newborn to 59 years (mean 19 years). Most tumors (n = 5) presented in the head and neck area (skull base, mastoid, maxilla, and mandible), and remaining three in the tibia, pelvic bone, and chest wall. The fusions included NTRK1 (n = 3), RET (n = 2), NTRK3 (n = 2), and BRAF (n = 1). In the combined series (n = 15), most tumors (73%) occurred in children and young adults (<30 years) and showed a predilection for jaw and skull bones (40%), followed by long and small tubular bones (33%). The fusions spanned a large spectrum of kinase genes, including in descending order NTRK3 (n = 6), NTRK1 (n = 4), RET (n = 2), BRAF (n = 2), and RAF1 (n = 1). All fusions confirmed by targeted RNA sequencing were in-frame and retained the kinase domain within the fusion oncoprotein. Similar to the soft tissue counterparts, most NTRK3-positive bone tumors in this series showed high-grade morphology (5/6), whereas the majority of NTRK1 tumors were low-grade (3/4). Notably, all four tumors presenting in the elderly were high-grade spindle cell sarcomas, with adult fibrosarcoma (FS)-like, malignant peripheral nerve sheath tumor (MPNST)-like and MPNST phenotypes. Overall, 10 tumors had high-grade morphology, ranging from infantile and adult-types FS, MPNST-like, and MPNST, whereas five showed benign/low-grade histology (MPNST-like and myxoma-like). Immunohistochemically (IHC), S100 and CD34 positivity was noted in 57% and 50%, respectively, while co-expression of S100 and CD34 in 43% of cases. One-third of tumors (4 high grade and the myxoma-like) were negative for both S100 and CD34. IHC for Pan-TRK was positive in all eight NTRK-fusion positive tumors tested and negative in two tumors with other kinase fusions. Clinical follow-up was too limited to allow general conclusions.

Towards artificial intelligence to multi-omics characterization of tumor heterogeneity in esophageal cancer.

Esophageal cancer is a unique and complex heterogeneous malignancy, with substantial tumor heterogeneity: at the cellular levels, tumors are composed of tumor and stromal cellular components; at the genetic levels, they comprise genetically distinct tumor clones; at the phenotypic levels, cells in distinct microenvironmental niches acquire diverse phenotypic features. This heterogeneity affects almost every process of esophageal cancer progression from onset to metastases and recurrence, etc. Intertumoral and intratumoral heterogeneity are major obstacles in the treatment of esophageal cancer, but also offer the potential to manipulate the heterogeneity themselves as a new therapeutic strategy. The high-dimensional, multi-faceted characterization of genomics, epigenomics, transcriptomics, proteomics, metabonomics, etc. of esophageal cancer has opened novel horizons for dissecting tumor heterogeneity. Artificial intelligence especially machine learning and deep learning algorithms, are able to make decisive interpretations of data from multi-omics layers. To date, artificial intelligence has emerged as a promising computational tool for analyzing and dissecting esophageal patient-specific multi-omics data. This review provides a comprehensive review of tumor heterogeneity from a multi-omics perspective. Especially, we discuss the novel techniques single-cell sequencing and spatial transcriptomics, which have revolutionized our understanding of the cell compositions of esophageal cancer and allowed us to determine novel cell types. We focus on the latest advances in artificial intelligence in integrating multi-omics data of esophageal cancer. Artificial intelligence-based multi-omics data integration computational tools exert a key role in tumor heterogeneity assessment, which will potentially boost the development of precision oncology in esophageal cancer.

Sequence characteristics, genetic diversity and phylogenetic analysis of the Cucurbita ficifolia (Cucurbitaceae) chloroplasts genome.

BACKGROUND: Curcubita ficifolia Bouché (Cucurbitaceae) has high value as a food crop and medicinal plant, and also has horticultural value as rootstock for other melon species. China is home to many different cultivars, but the genetic diversity of these resources and the evolutionary relationships among them, as well as the differences between C. ficifolia and other Cucurbita species, remain unclear. RESULTS: We investigated the chloroplast (cp) genomes of 160 C. ficifolia individuals from 31 populations in Yunnan, a major C. ficifolia production area in China. We found that the cp genome of C. ficifolia is ~151 kb and contains 128 genes, of which 86 are protein coding genes, 34 encode tRNA, and eight encode rRNAs. We also identified 64 SSRs, mainly AT repeats. The cp genome was found to contain a total of 204 SNP and 57 indels, and a total of 21 haplotypes were found in the 160 study individuals. The reverse repeat (IR) region of C. ficifolia contained a few differences compared with this region in the six other Cucurbita species. Sequence difference analysis demonstrated that most of the variable regions were concentrated in the single copy (SC) region. Moreover, the sequences of the coding regions were found to be more similar among species than those of the non-coding regions. The phylogenies reconstructed from the cp genomes of 61 representative species of Cucurbitaceae reflected the currently accepted classification, in which C. ficifolia is sister to the other Cucurbita species, however, different interspecific relationships were found between Cucurbita species. CONCLUSIONS: These results will be valuable in the classification of C. ficifolia genetic resources and will contribute to our understanding of evolutionary relationships within the genus Cucurbita.

Development and validation of a novel TNM staging N-classification of oral cavity squamous cell carcinoma.

BACKGROUND: For oral cavity squamous cell carcinoma (OSCC), extent of extranodal extension (ENE) (minor, ≤2 mm; major, >2 mm) is differentially prognostic, whereas limitations exist with the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N-classification (TNM-8-N). METHODS: Resected OSCC patients at four centers were included and extent of ENE was recorded. Thresholds for optimal overall survival (OS) discrimination of lymph node (LN) features were established. After dividing into training and validation sets, two new N-classifications were created using 1) recursive partitioning analysis (RPA), and 2) adjusted hazard ratios (aHRs) and were ranked against TNM-8-N and two published proposals. RESULTS: A total of 1460 patients were included (pN0: 696; pN+: 764). Of the pN+ cases, 135 (18%) had bilateral/contralateral LNs; 126 (17%) and 244 (32%) had minor and major ENE, and two (0.3%) had LN(s) >6 cm without ENE (N3a). LN number (1 and >1 vs. 0: aHRs, 1.92 [95% confidence interval (CI), 1.44-2.55] and 3.21 [95% CI, 2.44-4.22]), size (>3 vs. ≤3 cm: aHR, 1.88 [95% CI, 1.44-2.45]), and ENE extent (major vs. minor: aHR, 1.40 [95% CI, 1.05-1.87]) were associated with OS, whereas presence of contralateral LNs was not (aHR, 1.05 [95% CI, 0.81-1.36]). The aHR proposal provided optimal performance with these changes to TNM-8-N: 1) stratification of ENE extent, 2) elimination of N2c and 6-cm threshold, and 3) stratification of N2b by 3 cm threshold. CONCLUSION: A new N-classification improved staging performance compared to TNM-8-N, by stratifying by ENE extent, eliminating the old N2c category and the 6 cm threshold, and by stratifying multiple nodes by size.

Genetic Control of Alternative Splicing and its Distinct Role in Colorectal Cancer Mechanisms.

BACKGROUND & AIMS: Dysregulation of alternative splicing is implicated in many human diseases, and understanding the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of cancers. We aimed to provide a comprehensive functional dissection of splicing quantitative trait loci (sQTLs) in cancer and focus on elucidating its distinct role in colorectal cancer (CRC) mechanisms. METHODS: We performed a comprehensive sQTL analysis to identify genetic variants that control messenger RNA splicing across 33 cancer types from The Cancer Genome Atlas and independently validated in our 154 CRC tissues. Then, large-scale, multicenter, multi-ethnic case-control studies (34,585 cases and 76,023 controls) were conducted to examine the association of these sQTLs with CRC risk. A series of biological experiments in vitro and in vivo were performed to investigate the potential mechanisms of the candidate sQTLs and target genes. RESULTS: The molecular characterization of sQTL revealed its distinct role in cancer susceptibility. Tumor-specific sQTL further showed better response to cancer development. In addition, functionally informed polygenic risk score highlighted the potentiality of sQTLs in the CRC prediction. Complemented by large-scale population studies, we identified that the risk allele (T) of a multi-ancestry-associated sQTL rs61746794 significantly increased the risk of CRC in Chinese (odds ratio, 1.20; 95% CI, 1.12-1.29; P = 8.82 × 10-7) and European (odds ratio, 1.11; 95% CI, 1.07-1.16; P = 1.13 × 10-7) populations. rs61746794-T facilitated PRMT7 exon 16 splicing mediated by the RNA-binding protein PRPF8, thus increasing the level of canonical PRMT7 isoform (PRMT7-V2). Overexpression of PRMT7-V2 significantly enhanced the growth of CRC cells and xenograft tumors compared with PRMT7-V1. Mechanistically, PRMT7-V2 functions as an epigenetic writer that catalyzes the arginine methylation of H4R3 and H3R2, subsequently regulating diverse biological processes, including YAP, AKT, and KRAS pathway. A selective PRMT7 inhibitor, SGC3027, exhibited antitumor effects on human CRC cells. CONCLUSIONS: Our study provides an informative sQTLs resource and insights into the regulatory mechanisms linking splicing variants to cancer risk and serving as biomarkers and therapeutic targets.

Abundance of Modifications in Mature miRNAs Revealed by LC-MS/MS Method Coupled with a Two-Step Hybridization Purification Strategy.

Accurate detection of endogenous miRNA modifications, such as N6-methyladenosine (m6A), 7-methylguanosine (m7G), and 5-methylcytidine (m5C), poses significant challenges, resulting in considerable uncertainty regarding their presence in mature miRNAs. In this study, we demonstrate for the first time that liquid chromatography coupled with a tandem mass spectrometry (LC-MS/MS) nucleoside analysis method is a practical tool for quantitatively analyzing human miRNA modifications. The newly designed liquid-solid two-step hybridization (LSTH) strategy enhances specificity for miRNA purification, while LC-MS/MS offers robust capability in recognizing modifications and sufficient sensitivity with detection limits ranging from attomoles to low femtomoles. Therefore, it provides a more reliable approach compared to existing techniques for revealing modifications in endogenous miRNAs. With this approach, we characterized m6A, m7G, and m5C modifications in miR-21-5p, Let-7a/e-5p, and miR-10a-5p isolated from cultured cells and observed unexpectedly low abundance (<1% at each site) of these modifications.

The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity.

Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S-Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase (MTAP) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m6A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non-small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti-tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m6A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.

Efficient Exciton Dissociation on Ceria Chelated Cerium-Based MOF Isogenous S-Scheme Photocatalyst for Acetaldehyde Purification.

Long-term exposure to low concentration indoor VOCs of acetaldehyde (CH3CHO) is harmful to human health. Thus, a novel isogenous heterojunction CeO2/Ce-MOF photocatalyst is synthesized via a one-step hydrothermal method for the effective elimination of CH3CHO in this work. This CeO2/Ce-MOF photocatalyst performs well in CH3CHO removal and achieves an apparent quantum efficiency of 7.15% at 420 nm, which presents ≈6.7 and 3.4 times superior to those generated by CeO2 and Ce-MOF, respectively. The enhanced efficiency is due to two main aspects including i) an effective photocarrier separation ability and the prolonged reaction lifetime of excitons play crucial roles and ii) the formation of an internal electric field (IEF) is sufficient to overcome the considerable exciton binding energy, and increases the exciton dissociation efficiency by up to 50.4%. Moreover, the reasonable pathways and mechanisms of CH3CHO degradation are determined by in situ DRIFTS analysis and simulated DFT calculations. Those results demonstrated that S-scheme heterojunction successfully increases the efficiency of harmful volatile organic compounds elimination, and it offers essential guidance for designing rare earth-based MOF photocatalysts.

Revealing the Charge Storage Mechanism in Porous Carbon to Achieve Efficient K Ion Storage.

Constructing a porous structure is considered an appealing strategy to improve the electrochemical properties of carbon anodes for potassium-ion batteries (PIBs). Nevertheless, the correlation between electrochemical K-storage performance and pore structure has not been well elucidated, which hinders the development of high-performance carbon anodes. Herein, various porous carbons are synthesized with porosity structures ranging from micropores to micro/mesopores and mesopores, and systematic investigations are conducted to establish a relationship between pore characteristics and K-storage performance. It is found that micropores fail to afford accessible active sites for K ion storage, whereas mesopores can provide abundant surface adsorption sites, and the enlarged interlayer spacing facilitates the intercalation process, thus resulting in significantly improved K-storage performances. Consequently, PCa electrode with a prominent mesoporous structure achieves the highest reversible capacity of 421.7 mAh g-1 and an excellent rate capability of 191.8 mAh g-1 at 5 C. Furthermore, the assembled potassium-ion hybrid capacitor realizes an impressive energy density of 151.7 Wh kg-1 at a power density of 398 W kg-1. The proposed work not only deepens the understanding of potassium storage in carbon materials with distinctive porosities but also paves a path toward developing high-performance anodes for PIBs with customized energy storage capabilities.

Encapsulating Bi Nanoparticles in Reduced Graphene Oxide with Strong Interfacial Bonding toward Advanced Potassium Storage.

Bismuth (Bi) is regarded as a promising anode material for potassium ion batteries (PIBs) due to its high theoretical capacity, but the huge volume expansion during potassiation and intrinsic low conductivity cause poor cycle stability and rate capability. Herein, a unique Bi nanoparticles/reduced graphene oxide (rGO) composite is fabricated by anchoring the Bi nanoparticles over the rGO substrate through a ball-milling and thermal reduction process. As depicted by the in-depth XPS analysis, strong interfacial Bi-C bonding can be formed between Bi and rGO, which is beneficial for alleviating the huge volume expansion of Bi during potassiation, restraining the aggregation of Bi nanoparticles and promoting the interfacial charge transfer. Theoretical calculation reveals the positive effect of rGO to enhance the potassium adsorption capability and interfacial electron transfer as well as reduce the diffusion energy barrier in the Bi/rGO composite. Thereby, the Bi/rGO composite exhibits excellent potassium storage performances in terms of high capacity (384.8 mAh g-1 at 50 mA g-1 ), excellent cycling stability (197.7 mAh g-1 after 1000 cycles at 500 mA g-1 with no capacity decay) and superior rate capability (55.6 mAh g-1 at 2 A g-1 ), demonstrating its great potential as an anode material for PIBs.

Element Diffusion Induced Carrier Transport Enhancement in High-Performance CZTSSe Self-Powered Photodetector.

Cu2ZnSn(S,Se)4 (CZTSSe) has attracted great interest in thin-film solar cells due to its excellent photoelectric performance in past decades, and recently is gradually expanding to the field of photodetectors. Here, the CZTSSe self-powered photodetector is prepared by using traditional photovoltaic device structure. Under zero bias, it exhibits the excellent performance with a maximum responsivity of 0.77 A W-1, a high detectivity of 8.78 × 1012 Jones, and a wide linear dynamic range of 103 dB. Very fast response speed with the rise/decay times of 0.576/1.792 µs, and ultra-high switching ratio of 3.54 × 105 are obtained. Comprehensive electrical and microstructure characterizations confirm that element diffusion among ITO, CdS, and CZTSSe layers not only optimizes band alignment of CdS/CZTSSe, but also suppresses the formation of interface defects. Such a suppression of interface defects and spike-like band alignment significantly inhibit carrier nonradiative recombination at interface and promote carrier transport capability. The low trap density in CZTSSe and low back contact barrier of CZTSSe/Mo could be responsible for the very fast response time of photodetector. This work definitely provides guidance for designing a high performance self-powered photodetector with high photoresponse, high switching ratio, fast response speed, and broad linear dynamic range.

Visible Light-Activated Ultralong-Lived Triplet Excitons of Carbon Dots for White-Light Manipulated Anti-Counterfeiting.

Room temperature phosphorescence (RTP) has emerged as an interesting but rare phenomenon with multiple potential applications in anti-counterfeiting, optoelectronic devices, and biosensing. Nevertheless, the pursuit of ultralong lifetimes of RTP under visible light excitation presents a significant challenge. Here, new phosphorescent materials that can be excited by visible light with record-long lifetimes are demonstrated, realized through embedding nitrogen doped carbon dots (N-CDs) into a poly(vinyl alcohol) (PVA) film. The RTP lifetime of the N-CDs@PVA film is remarkably extended to 2.1 s excited by 420 nm, representing the highest recorded value for visible light-excited phosphorescent materials. Theoretical and experimental studies reveal that the robust hydrogen bonding interactions can effectively reduce the non-radiative decay rate and radiative transition rate of triplet excitons, thus dramatically prolong the phosphorescence lifetime. Notably, the RTP emission of N-CDs@PVA film can also be activated by easily accessible low-power white-light-emitting diode. More significantly, the practical applications of the N-CDs@PVA film in state-of-the-art anti-counterfeiting security and optical information storage domains are further demonstrated. This research offers exciting opportunities for utilizing visible light-activated ultralong-lived RTP systems in a wide range of promising applications.

Accelerating Charge Kinetics in Photocatalytic CO2 Reduction by Modulating the Cobalt Coordination in Heterostructures of Cadmium Sulfide/Metal-Organic Layer.

Artificial photocatalytic CO2 reduction (CO2 R) holds great promise to directly store solar energy into chemical bonds. The slow charge and mass transfer kinetics at the triphasic solid-liquid-gas interface calls for the rational design of heterogeneous photocatalysts concertedly boosting interfacial charge transfer, local CO2 concentration, and exposure of active sites. To meet these requirements, in this study heterostructures of CdS/MOL (MOL = metal-organic layer) furnishing different redox Co sites are fabricated for CO2 R photocatalysts. It is found that the coordination environment of Co is key to photocatalytic activity. The best catalyst ensemble comprising ligand-chelated Co2+ with the bipyridine electron mediator demonstrates a high CO yield rate of 1523 µmol h-1 gcat -1 , selectivity of 95.8% and TON of 1462.4, which are ranked among the best seen in literature. Comprehensive photochemical and electroanalytical characterizations attribute the high CO2 R performance to the improved photocarrier separation and charge kinetics originated from the proper energy band alignment and coordination chemistry. This work highlights the construction of 2D heterostructures and modulation of transition metal coordination to expedite the charge kinetics in photocatalytic CO2 reduction.

CircDCAF8 promotes the progression of hepatocellular carcinoma through miR-217/NAP1L1 Axis, and induces angiogenesis and regorafenib resistance via exosome-mediated transfer.

BACKGROUND: Circular RNAs (circRNAs), which are a new type of single-stranded circular RNA, have significant involvement in progression of many diseases, including tumors. Currently, multiple circRNAs have been identified in hepatocellular carcinoma (HCC). Our study aims to investigate the function and mechanism of circDCAF8 in HCC. METHODS: The expression of circDCAF8 (hsa_circ_0014879) in HCC and para-carcinoma tissue samples was determined using quantitative real-time polymerase chain reaction (qRT-PCR). The biological function of circDCAF8 in HCC was confirmed by experiments conducted both in vitro and in vivo. And the relationship between circDCAF8, miR-217 and NAP1L1 was predicted by database and verified using qRT-PCR, RNA-binding protein immunoprecipitation (RIP) and dual-luciferase reporter assays. Exosomes isolated from HCC cells were utilized to assess the connection of exosomal circDCAF8 with HCC angiogenesis and regorafenib resistance. RESULTS: CircDCAF8 is upregulated in HCC tissues and cell lines, and is linked to an unfavourable prognosis for HCC patients. Functionally, circDCAF8 was proved to facilitate proliferation, migration, invasion and Epithelial-Mesenchymal Transformation (EMT) in HCC cells. Animal examinations also validated the tumor-promoting characteristics of circDCAF8 on HCC. Besides, exosomal circDCAF8 promoted angiogenesis in HUVECs. Mechanistically, circDCAF8 interacted with miR-217 and NAP1L1 was a downstream protein of miR-217. CircDCAF8 promoted NAP1L1 expression by sponging miR-217. In addition, exosomes may transfer circDCAF8 from regorafenib-resistant HCC cells to sensitive cells, where it would confer a resistant phenotype. CONCLUSION: CircDCAF8 facilitates HCC proliferation and metastasis via the miR-217/NAP1L1 axis. Meanwhile, circDCAF8 can promote angiogenesis and drive resistance to regorafenib, making it a viable therapeutic target for HCC patients.

The bacterial patterns suggesting the dynamic features of tick-associated microorganisms in hard ticks.

BACKGROUND: Ticks are blood-feeding significant arthropods that can harbour various microorganisms, including pathogens that pose health risks to humans and animals. Tick-symbiont microorganisms are believed to influence tick development, but the intricate interactions between these microbes and the relationships between different tick-borne microorganisms remain largely unexplored. RESULTS: Based on 111 tick pool samples presenting questing and engorged statuses including 752 questing tick and 1083 engorged tick from cattle and goats, which were collected in two types of geographic landscape (semi-desert and alpine meadow). We observed significant variations in the composition of tick-borne microorganisms across different environments and blood-engorgement statuses, with a pronounced divergence in symbionts compared to environmental bacteria. Metabolic predictions revealed over 90 differential pathways for tick-borne microorganisms in distinct environments and more than 80 metabolic variations in response to varying blood engorgement statuses. Interestingly, nine pathways were identified, particularly related to chorismate synthesis and carbohydrate metabolism. Moreover, microbial network relationships within tick-borne microorganism groups were highly distinct across different environments and blood-engorgement statuses. The microbial network relationships of symbionts involve some pathogenic and environmental microorganisms. Regression modelling highlighted positive correlations between the Coxiella symbiont and related pathogens, while some environmental bacteria showed strong negative correlations with Coxiella abundance. We also identified commensal bacteria/pathogens in bacterial cooccurrence patterns. Furthermore, we tested pathogenic microorganisms of each tick sample analysis revealed that 86.36% (1601/1855) of the tick samples carried one or more pathogenic microorganisms, The total carrier rate of bacterial pathogens was 43.77% ((812/1855). Most blood samples carried at least one pathogenic microorganism. The pathogens carried by the ticks have both genus and species diversity, and Rickettsia species are the most abundant pathogens among all pathogens. CONCLUSION: Our findings underscore that the bacterial pattern of ticks is dynamic and unstable, which is influenced by the environment factors and tick developmental characteristics.

Comparison of Short-Term Outcomes After Robotic Versus Laparoscopic Radical Gastrectomy for Advanced Gastric Cancer in Elderly Individuals: A Propensity Score-Matching Study.

BACKGROUND: Robotic gastrectomy (RG) has been widely used to treat gastric cancer. However, whether the short-term outcomes of robotic gastrectomy are superior to those of laparoscopic gastrectomy (LG) for elderly patients with advanced gastric cancer has not been reported. METHODS: The study enrolled of 594 elderly patients with advanced gastric cancer who underwent robotic or laparoscopic radical gastrectomy. The RG cohort was matched 1:3 with the LG cohort using propensity score-matching (PSM). RESULTS: After PSM, 121 patients were included in the robot group and 363 patients in the laparoscopic group. Excluding the docking and undocking times, the operation time of the two groups was similar (P = 0.617). The RG group had less intraoperative blood loss than the LG group (P < 0.001). The time to ambulation and first liquid food intake was significantly shorter in the RG group than in the LG group (P < 0.05). The incidence of postoperative complications did not differ significantly between the two groups (P = 0.14). Significantly more lymph nodes were dissected in the RG group than in the LG group (P = 0.001). Postoperative adjuvant chemotherapy was started earlier in the RG group than in the LG group (P = 0.02). CONCLUSIONS: For elderly patients with advanced gastric cancer, RG is safe and feasible. Compared with LG, RG is associated with less intraoperative blood loss; a faster postoperative recovery time, allowing a greater number of lymph nodes to be dissected; and earlier adjuvant chemotherapy.

Defining the Genomic Landscape of Diffuse Sclerosing Papillary Thyroid Carcinoma: Prognostic Implications of RET Fusions.

BACKGROUND: Diffuse sclerosing papillary thyroid carcinoma (DSPTC) is an aggressive histopathologic subtype of papillary thyroid carcinoma. Correlation between genotype and phenotype has not been comprehensively described. This study aimed to describe the genomic landscape of DSPTC comprehensively using next-generation sequencing (NGS), analyze the prognostic implications of different mutations, and identify potential molecular treatment targets. METHODS: Tumor tissue was available for 41 DSPTC patients treated at Memorial Sloan Kettering Cancer Center between 2004 and 2021. After DNA extraction, NGS was performed using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets platform, which sequences 505 critical cancer genes. Clinicopathologic characteristics were compared using the chi-square test. The Kaplan-Meier method and log-rank statistics were used to compare outcomes. RESULTS: The most common mutation was RET fusion, occurring in 32% (13/41) of the patients. Other oncologic drivers occurred in 68% (28/41) of the patients, including 8 BRAFV600E mutations (20%) and 4 USP8 mutations (10%), which have not been described in thyroid malignancy previously. Patients experienced RET fusion-positive tumors at a younger age than other drivers, with more aggressive histopathologic features and more advanced T stage (p = 0.019). Patients who were RET fusion-positive had a significantly poorer 5-year recurrence-free survival probability than those with other drivers (46% vs 84%; p = 0.003; median follow-up period, 45 months). In multivariable analysis, RET fusion was the only independent risk factor for recurrence (hazard ratio [HR], 7.69; p = 0.017). CONCLUSION: Gene-sequencing should be strongly considered for recurrent DSPTC due to significant prognostic and treatment implications of RET fusion identification. The novel finding of USP8 mutation in DSPTC requires further investigation into its potential as a driver mutation.