Multi-omics integration reveals the oncogenic role of eccDNAs in diffuse large B-cell lymphoma through STING signalling.

BACKGROUND: Extrachromosomal circular DNAs (eccDNAs), a type of double-stranded DNAs (dsDNAs) that facilitate the activation of the DNA sensing machinery, have been implicated in the progression and prognosis of various diseases. While the roles of eccDNAs remain contentious, their significance in diffuse large B-cell lymphoma (DLBCL) has not been reported. METHODS: Circular DNA sequencing (circle-seq) was used to demonstrate the expression profile of eccDNAs in DLBCL, and atomic force microscopy to validate the presence of eccDNAs. CCK-8 and scRNA-seq techniques were employed to uncover the activation of eccDNA in the STING pathway, leading to enhanced cell proliferation. Chemotherapeutic drugs were used to test the hypothesis that DNA damage induces the production of eccDNA, thereby activating the STING pathway independent of cGAS. GEO databases were used for verification of the prognosis of the eccDNA-related genes, and animal models were used to investigate the synergistic effects of DNA damage therapy in combination with STING inhibitors on anti-tumour responses. RESULTS: EccDNAs were widely expressed in DLBCL and associated with the prognosis of patients. Elevated abundance of eccDNAs promoted the progression of DLBCL. Chemotherapeutic drugs-induced DNA damage triggered the generation of eccDNAs, resulting in the activation of the STING signalling in a cGAS-independent manner. Moreover, inhibition of STING exerted a synergistic anti-tumour effect with cisplatin. CONCLUSIONS: EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. This finding offers a rational therapeutic strategy combining chemotherapy with targeting STING. HIGHLIGHTS: EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. The combined treatment of chemotherapeutic drugs with STING inhibitor significantly delayed the tumor progression, providing new insights into the therapeutic strategy for patients with DLBCL, particularly the relapsed and/or refractory (R/R) ones.

An unusual winter bloom of dinoflagellates with notable damage to kelp cultivation around Shandong peninsula, China.

In the coastal waters around Shandong peninsula, an unprecedented winter bloom of dinoflagellates Gonyaulax polygramma and Akashiwo sanguinea occurred in 2021 from late November to early December. The bloom affected a wide area of coastal waters extending from west to east along the northern Shandong peninsula and had a devastating blow to the kelp cultivation industry. Based on the remote-sensing data, the initiation of the bloom was traced back to the region adjacent to the mouth of the Yellow River in Laizhou Bay, where enhanced freshwater discharge from the Yellow River was recorded from September to November. It's proposed that the increased precipitation in the Yellow River basin associated with northward extension of the precipitation band in China could be an important reason for this winter bloom. This unusual winter bloom around Shandong peninsula highlights the potential risks of harmful algal blooms and their impacts on coastal ecosystems under the background of climate change.

Dynamics and scale variations of blooms of Phaeocystis globosa "giant colony" ecotype and key environmental factors in the Beibu Gulf, China.

The Beibu Gulf has experienced blooms of Phaeocystis globosa "giant colony" ecotype (PGGCE), with noticeable variations in bloom scale across years. However, driving environmental factors and their roles remain poorly understood. In this study, we quantified dynamics of PGGCE cells in 2016-2017 and 2018-2019, and analyzed their correlations with environment factors. The results revealed that PGGCE blooms primarily occurred in Guangxi coast and western waters of Leizhou Peninsula during winter months, exhibiting distinct developmental processes. Bloom intensity, duration, and distribution differed significantly between two bloom events. In 2016-2017, peak PGGCE density exceeded 2.0 × 105 cells L-1 nearly double that of 2018-2019. Furthermore, bloom sustained five months during 2016-2017, compared to three months during 2018-2019. Prolonged period of low temperatures and elevated nitrate concentrations favored PGGCE growth and colony formation, resulting in a larger scale bloom during winter 2016 as opposed to winter 2018.

Influence of acidic metabolic environment on differentiation of stem cell-derived cardiomyocytes.

Stem cell-based myocardial regeneration is a frontier topic in the treatment of myocardial infarction. Manipulating the metabolic microenvironment of stem cells can influence their differentiation into cardiomyocytes, which have promising clinical applications. pH is an important indicator of the metabolic environment during cardiomyocyte development. And lactate, as one of the main acidic metabolites, is a major regulator of the acidic metabolic environment during early cardiomyocyte development. Here, we summarize the progress of research into the influence of pH value and lactate on cardiomyocyte survival and differentiation, as well as related mechanisms.

Improving fine-mapping by modeling infinitesimal effects.

Fine-mapping aims to identify causal genetic variants for phenotypes. Bayesian fine-mapping algorithms (for example, SuSiE, FINEMAP, ABF and COJO-ABF) are widely used, but assessing posterior probability calibration remains challenging in real data, where model misspecification probably exists, and true causal variants are unknown. We introduce replication failure rate (RFR), a metric to assess fine-mapping consistency by downsampling. SuSiE, FINEMAP and COJO-ABF show high RFR, indicating potential overconfidence in their output. Simulations reveal that nonsparse genetic architecture can lead to miscalibration, while imputation noise, nonuniform distribution of causal variants and quality control filters have minimal impact. Here we present SuSiE-inf and FINEMAP-inf, fine-mapping methods modeling infinitesimal effects alongside fewer larger causal effects. Our methods show improved calibration, RFR and functional enrichment, competitive recall and computational efficiency. Notably, using our methods' posterior effect sizes substantially increases polygenic risk score accuracy over SuSiE and FINEMAP. Our work improves causal variant identification for complex traits, a fundamental goal of human genetics.

Advances in Online Detection Technology for Laser Additive Manufacturing: A Review.

In additive manufacturing (AM), the mechanical properties of manufactured parts are often insufficient due to complex defects and residual stresses, limiting their use in high-value or mission-critical applications. Therefore, the research and application of nondestructive testing (NDT) technologies to identify defects in AM are becoming increasingly urgent. This article reviews the recent progress in online detection technologies in AM, a special introduction to the high-speed synchrotron X-ray technology for real-time in situ observation, and analysis of defect formation processes in the past 5 years, and also discusses the latest research efforts involving process monitoring and feedback control algorithms. The formation mechanism of different defects and the influence of process parameters on defect formation, important parameters such as defect spatial resolution, detection speed, and scope of application of common NDT methods, and the defect types, advantages, and disadvantages associated with current online detection methods for monitoring three-dimensional printing processes are summarized. In response to the development requirements of AM technology, the most promising trends in online detection are also prospected. This review aims to serve as a reference and guidance for the work to identify/select the most suitable measurement methods and corresponding control strategy for online detection.

Biomechanical effects of a mandibular advancement device on the periodontal ligament: Based on different bone models.

Obstructive sleep apnea syndrome (OSAS) is recurrent apnoea caused by upper airway obstruction during sleep. In severe cases, OSAS might lead to sudden death. Currently, the mandibular advancement device (MAD) is the preferred product for the treatment of mild to moderate OSAS because of its compliance, portability and low cost. However, many clinical studies have suggested that long-term use of MAD might cause occlusal changes, periodontitis, muscle soreness, and joint damage. In view of the difficulties in the measurement of relevant mechanical factors in vivo, the present work aimed to quantitatively analyze biomechanical mechanisms that might lead to these side effects through computer numerical simulations and a nonhomogeneous alveolar bone model was established to approximate the actual bony features of the jaw in the simulations model. First, a 3D digital model of the teeth, periodontal ligament(PDL), and alveolar bone was created on the basis of computed tomography images and assembled with a 3D model of the MAD. A nonhomogeneous alveolar bone model was created based on computed tomographic images, and the stresses acting on the PDL were computed using the finite element method. The results showed that the nonhomogeneous model could more realistically reflect the mechanical properties of the alveolar bone and obtain the true stresses compared with the homogeneous model, which underestimated the adverse effects of PDL therapy. The numerical simulations in this paper can help doctors make more accurate judgements about MAD treatment from an oral health protection perspective.

Marked shifts of harmful algal blooms in the Bohai Sea linked with combined impacts of environmental changes.

The Bohai Sea, a semi-enclosed inland sea in China and an important mariculture region, has experienced extensive harmful algal blooms (HABs) and their negative impacts for several decades. To investigate the changes of HABs and their potential drivers over time and space, a dataset of 230 HAB events (1952-2017), along with corresponding environmental data (1990-2017) was compiled. The frequency of HAB events in the Bohai Sea has increased over time but plateaued in the last decade, and our analysis showed that history of HABs in the Bohai Sea could be categorized into three periods based on their frequency, scale, and HAB-forming species. The seasonal window of HAB events has started earlier and lasted longer, and the main hotspot has moved from Bohai Bay to coastal waters of Qinhuangdao over time. There were marked shifts in the representative HAB-forming microalgae, from dinoflagellates in the first period (before 2000) to haptophytes in the second period (2000-2009), and pelagophytes in the third period (2009 onwards). These community changes are accompanied by a trend toward diversification of HAB-forming microalgae, decrease in cell-size, and increase in negative impacts. Statistical analyses indicate that long-term changes in HABs in the Bohai Sea are linked with the combined effects of climate change, eutrophication and mariculture development. The results of the present study require to refine future monitoring programs, develop adaptive management strategies and predictive models for HABs in the Bohai Sea.

A dynamic-static combination model based on radiomics features for prostate cancer using multiparametric MRI.

Objective. To propose a new dynamic multiparametric magnetic resonance imaging (mpMRI) radiomics method for the detection of prostate cancer (PCa), and establish a combined model using dynamic and static radiomics features based on this method.Approach. A total of 166 patients (82 PCa patients and 84 non-PCa patients) were enrolled in the study, and 31 872 mpMRI images were performed in a radiomics workflow. The whole prostate segmentation and traditional static radiomics features extraction were performed on intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI,bvalue of 10, 50, 100, 150, 200, 400, 600, 800, 1000, 1500 s mm-2respectively), apparent diffusion coefficient (ADC), and T2-weighted imaging (T2WI) sequences respectively. Through the building of eachb-value DWI model and the analysis of the static key radiomics features, three types of dynamic features called standard discrete (SD), parameter (P) and relative change rate (RCR) were constructed. And the b-value parameters used to construct dynamic features were divided into three groups ('Df_', 'Db_' and 'Da_'): the front part (10-200 s mm-2), the back part (400-1500 s mm-2), and all (10-1500 s mm-2) of theb-values set, respectively. Afterwards, the dynamic mpMRI model and combined model construction were constructed, and the PCa discrimination performance of each model was evaluated.Main results.The models based on dynamic features showed good potential for PCa identification. Where, the results of Db_SD, Da_P and Db_P models were encouraging (test cohort AUCs: 90.78%, 87.60%, 86.3%), which was better than the commonly used ADC model (AUC of ADC was 75.48%). Among the combined models, the models using static features of T2WI and dynamic features performed the best. The AUC of Db_SD + T2WI, Db_P + T2WI and Db_RCR + T2WI model was 92.90%, 91.29% and 81.46%.Significance.The dynamic-static combination model based on dynamic mpMRI radiomics method has a good effect on the identification of PCa. This method has broad application prospects in PCa individual diagnosis management.

Experimental Investigation on the Mechanical Performance of Steel-ECC Composite Girders with Corrugated Webs under Negative Moment.

In order to improve the cracking performance in the negative moment region of composite continuous girder bridges with corrugated webs, engineered cementitious composite (ECC) is used instead of conventional normal concrete (NC). Web and concrete types are used as the main research parameters in experiments. The test results indicate that steel-ECC specimens have a higher flexural load capacity and stiffness than steel-NC specimens. The cracks of steel-ECC specimens are characterised by small width and dense distribution. Nonlinear finite element models are established and verified by experimental results. The simulated load-displacement curves are similar to the experimental ones, and the models have a high degree of accuracy. The ECC slab strength, thickness and width are used as parameters for the investigation to analyse the effect of the ECC slab on the flexural bearing capacity of composite girders. Compared with the results of calculations according to the code, the bearing capacity obtained from the parametric analysis is higher. It suggests that the contribution of the ECC slab needs to be considered when calculating the bearing capacity of the steel-ECC composite girder with corrugated webs.

TRACY-WIDOM AT EACH EDGE OF REAL COVARIANCE AND MANOVA ESTIMATORS.

We study the sample covariance matrix for real-valued data with general population covariance, as well as MANOVA-type covariance estimators in variance components models under null hypotheses of global sphericity. In the limit as matrix dimensions increase proportionally, the asymptotic spectra of such estimators may have multiple disjoint intervals of support, possibly intersecting the negative half line. We show that the distribution of the extremal eigenvalue at each regular edge of the support has a GOE Tracy-Widom limit. Our proof extends a comparison argument of Ji Oon Lee and Kevin Schnelli, replacing a continuous Green function flow by a discrete Lindeberg swapping scheme.

Intense blooms of Phaeocystis globosa in the South China Sea are caused by a unique "giant-colony" ecotype.

The haptophyte Phaeocystis globosa, an important causative agent of harmful algal blooms globally, exhibits varying morphological and physiological features and high genetic diversity, yet the relationship among these has never been elucidated. In this study, colony sizes and pigment profiles of 19 P. globosa isolates from the Pacific and Atlantic Oceans were determined. Genetic divergence of these strains was analyzed using the chloroplast rbcS-rpl27 intergenic spacer, a novel high-resolution molecular marker. Strains could be divided into four genetic clades based on these sequences, or two groups based on colony size and the identity of diagnostic pigments (19'-hexanoyloxyfucoxanthin, hex-fuco, and 19'-butanoyloxyfucoxanthin, but-fuco). Three strains from the South China Sea (SCS), all belonging to the same genetic clade, have unique biological features in forming giant colonies and possessing but-fuco as their diagnostic pigment. Based on these findings, we propose that these SCS strains should be a unique "giant-colony" ecotype of P. globosa. During the period 2016-2021, more than 1000 rbcS-rpl27 sequences were obtained from 16 P. globosa colony samples and 18 phytoplankton samples containing solitary P. globosa cells in the SCS. Phylogenetic analysis indicated that >95% of the sequences from P. globosa colonies in the SCS were comprised of the "giant-colony" ecotype, whereas the genetic diversity of solitary cells was much higher. Results demonstrated that intense blooms of P. globosa featuring giant colonies in the SCS were mainly caused by this giant-colony P. globosa ecotype.

First record of a Takayama bloom in Haizhou Bay in response to dissolved organic nitrogen and phosphorus.

Since 1990s, harmful algal blooms (HABs) of Kareniaceae, primarily caused by species of Karenia and Karlodinium and rarely by Takayama species, have been substantially increasing in frequency and duration in the coastal waters of China. In this study, we recorded a bloom of high abundance of T. acrotrocha in the Haizhou Bay, the Yellow Sea in September 2020, which is the first record of a Takayama bloom in the temperate coastal waters of China. We found that high concentrations of DON and DOP accelerated the proliferation of T. acrotrocha in the Haizhou Bay. Intensive mariculture, and terrestrial nitrogen and phosphorus input may be responsible for the eutrophication in the Haizhou Bay featuring high concentrations of DON and DOP, and high DIN/DIP ratios. The results suggested that, under ocean warming, the HABs of Kareniaceae are becoming increasingly dominant in eutrophic temperate coasts with intensive mariculture activities.

Acoustic Bioprinting of Patient-Derived Organoids for Predicting Cancer Therapy Responses.

Cancer models, which are biologically representative of patient tumors, can predict the treatment responses and help determine the most appropriate cancer treatment for individual patients. Here, a point-of-care testing system called acoustically bioprinted patient-derived microtissues (PDMs) that can model cancer invasion and predict treatment response in individual patients with colorectal cancer (CRC), is reported. The PDMs are composed of patient-derived colorectal tumors and healthy organoids which can be precisely arranged by acoustic bioprinting approach for recapulating primary tissue's architecture. Particularly, these tumor organoids can be efficiently generated and can apprehend histological, genomic, and phenotypical characteristics of primary tumors. Consequently, these PDMs allow physiologically relevant in vitro drug (5-fluorouracil) screens, thus predicting the paired patient's responses to chemotherapy. A correlation between organoid invasion speed and normalized spreading speed of the paired patients is further established. It provides a quantitative indicator to help doctors make better decisions on ultimate anus-preserving operation for extremely low CRC patients. Thus, by combing acoustic bioprinting and organoid cultures, this method may open an avenue to establish complex 3D tissue models for precision and personalized medicine.

Green Tides in the Yellow Sea Promoted the Proliferation of Pelagophyte Aureococcus anophagefferens.

Harmful algal blooms formed by fast-growing, ephemeral macroalgae have expanded worldwide, yet there is limited knowledge of their potential ecological consequences. Here, we select intense green tides formed by Ulva prolifera in the Yellow Sea, China, to examine the ecological consequences of these blooms. Using 28-isofucosterol in the surface sediment as a biomarker of green algae, we identified the settlement region of massive floating green algae in the area southeast of the Shandong Peninsula in the southern Yellow Sea. The responses of the phytoplankton assemblage from the deep chlorophyll-a maximum layer were then resolved using high-throughput sequencing. We found striking changes in the phytoplankton community in the settlement region after an intensive green tide in 2016, characterized by a remarkable increase in the abundance of the pelagophyte Aureococcus anophagefferens, the causative species of ecosystem disruptive brown tides. Our study strongly suggests that the occurrence of massive macroalgal blooms may promote blooms of specific groups of microalgae through alteration of the marine environment.

Modeling cancer metastasis using acoustically bio-printed patient-derived 3D tumor microtissues.

Cancer metastasis causes most cancer-related deaths, and modeling cancer invasion holds potential in drug discovery and companion diagnostics. Although 2D cocultures have been developed to study cancer invasion, it is challenging to recreate the 3D cancer invasion of an individual cancer patient. Here, we report an acoustic bioprinting technology that can precisely construct tumor microtissues for modeling cancer invasion in 3D. By using acoustic droplet technology, we can precisely encapsulate cancer associated fibroblasts (CAFs) derived from a colorectal cancer patient into gel droplets and print them into a 3D CAF microtissue. After depositing a tumor organoid derived from the same patient, our 3D bio-printed microtissue can be used to model cancer cell migration and invasion from the tumor organoid to the 3D CAF microtissue. We further used 3D bio-printed microtissues to investigate cancer invasion dynamics as well as their treatment response using time-lapse imaging. Thus, our acoustic 3D bioprinting technology can be widely used for establishing various microtissues for modeling cancer invasion and other diseases, highlighting its potential in personalized treatment.

A pilot study on prophylactic tube enterostomy for the prevention of anastomotic leakage in patients with high-risk intestinal anastomosis.

BACKGROUND: Anastomotic leakages (ALs) are one of the most serious complications following gastrointestinal anastomosis. Currently, very few operative measures are available for the prevention of ALs. This pilot study aimed to evaluate the safety and efficacy of tube enterostomy (T-E) for the prevention of ALs in patients with high-risk intestinal anastomosis. METHODS: In this retrospective study, demographic data and postoperative outcomes were compared among patients who received T-E and two historical cohorts: one group that underwent primary anastomosis without T-E (non-T-E group) and another that underwent conventional stoma construction without anastomosis (stoma group). The operative procedures were selected according to a scoring system that quantitatively evaluated risk of Als (Zhongnan score). RESULTS: From March 2017 to March 2020, a total of 45 consecutive patients were enrolled in the T-E group. Among these patients, 53.3% (24/45) were diagnosed with Crohn's disease (CD), and 66.7% (30/45) of them underwent emergency surgery. After propensity score matching, the demographic data were comparable among the three groups. One case of AL (2.2%) occurred in the T-E group, while four cases of ALs (8.9%, 4/45) were found in the non-T-E group (p = 0.13). Tube feeding was provided to 33.3% (15/45) of the T-E patients. Major tube-related complications included one tube dislocation (2.2%) and 3 (6.7%) minor leakages after tube withdrawal (treated conservatively). One death occurred in the stoma group. In the subgroup analysis of CD patients, lower rates of ALs and abdominal abscesses were observed in the T-E group than in the non-T-E and stoma subgroups, but the differences were not significant. CONCLUSIONS: T-E seems to be a safe and feasible operative method for the protection of high-risk intestinal anastomosis, can be reversed and can provide enteral feeding with acceptable tube-related complications. Further studies are needed to validate the role of T-E.

Pigment Characterization of the Giant-Colony-Forming Haptophyte Phaeocystis globosa in the Beibu Gulf Reveals Blooms of Different Origins.

The giant-colony-forming haptophyte Phaeocystis globosa has caused several large-scale blooms in the Beibu Gulf since 2011, but the distribution and dynamics of the blooms remained largely unknown. In this study, colonies of P. globosa, as well as membrane-concentrated phytoplankton samples, were collected during eight cruises in the Beibu Gulf from September 2016 to August 2017. Pigments were analyzed by high-performance liquid chromatography coupled with a diode array detector (HPLC-DAD). The pigment 19'-hexanoyloxyfucoxanthin (hex-fuco), generally considered a diagnostic pigment for Phaeocystis, was not detected in P. globosa colonies in the Beibu Gulf, whereas 19'-butanoyloxyfucoxanthin (but-fuco) was found in all colony samples. Moreover, but-fuco in membrane-concentrated phytoplankton samples exhibited a similar distribution pattern to that of P. globosa colonies, suggesting that but-fuco provided the diagnostic pigment for bloom-forming P. globosa in the Beibu Gulf. Based on the distribution of but-fuco in different water masses in the region prior to the formation of intensive blooms, it is suggested that P. globosa blooms in the Beibu Gulf could originate from two different sources. IMPORTANCE Phaeocystis globosa has formed intensive blooms in the South China Sea and even around the world, causing huge social economic losses and environmental damage. However, little is known about the formation mechanism and dynamics of P. globosa blooms. 19'-Hexanoyloxyfucoxanthin (hex-fuco) is often used as the pigment proxy to estimate Phaeocystis biomass, while this is challenged by the giant-colony-forming P. globosa in the Beibu Gulf, which contains only 19'-butanoyloxyfucoxanthin (but-fuco) but not hex-fuco. Using but-fuco as a diagnostic pigment, we traced two different origins of P. globosa blooms in the Beibu Gulf. This study clarifies the development process of P. globosa blooms in the Beibu Gulf, which provides a basis for the early monitoring and prevention of the blooms.

Experimental study on co-culture of DiI labeled rat bone marrow mesenchymal stem cells and polycaprolactone film in vitro to make a cell patch.

BACKGROUND: In stem cell therapy, due to the lack of an effective carrier, a large number of transplanted stem cells are lost and die. Therefore, finding a suitable carrier has become a further direction of stem cell therapy. OBJECTIVE: In research on the co-culture of polycaprolactone (PCL) with 1,1'-Dioctadecyl-3,3,3',3'- tetramethylindocarbocyanine perchlorate (DiI) labeled bone marrow mesenchymal stem cells (BMSCs), we observe the effect of materials on the growth and proliferation of DiI labeled stem cells, and the effect of DiI labeling on patch preparation, so as to find a kind of biomaterial suitable for the growth and proliferation of BMSCs, and find a suitable cell carrier for stem cell therapy of myocardial infarction and in vivo tracing. METHODS: Clean grade Sprague Dawley rats were selected as experimental objects, BMSCs were isolated and cultured, and the surface markers were identified by flow cytometry. After the BMSCs were cultured for 3 passages, the BMSCs were stained with DiI dye, and the BMSCs DiI and PCL biomaterial film were co-cultured. After 24 hours, the cell growth was observed under fluorescence microscope, and fixed for scanning under electron microscope. The cell proliferation was detected by CCK-8 at 1, 4, 7, 10 days of culture. The measurement data conforming to normal distribution are expressed in the form of mean ± standard deviation (X¯± s). One way ANOVA was used for comparison among groups, LSD analysis was used for pairwise comparison. The difference was statistically significant (P < 0.05). RESULTS: BMSCs were strongly positive for CD90, CD44H, but negative for CD11b/c, CD45. Under fluorescence microscope, BMSCs DiI showed red light, fusiform or polygonal. Under the scanning electron microscope, the cell patch formed by co-culture of PCL film and DiI-BMSCs had a large number of cells on the surface and normal cell state. CCK-8 assay showed that the OD value on the first day was 0.330 ± 0.025; The OD value was 0.620 ± 0.012 on the 4th day, 1.033 ± 0.144 on the 7th day and 1.223 ± 0.133 on the 10th day. There was significant difference among the time points (P < 0.05). CONCLUSIONS: The cell patch made of PCL film and DiI labeled BMSCs can survive and proliferate on the surface, so it can be used as a scaffold material for stem cell therapy in vivo.