Mutual Information Guided Diffusion for Zero-shot Cross-modality Medical Image Translation.

Cross-modality data translation has attracted great interest in medical image computing. Deep generative models show performance improvement in addressing related challenges. Nevertheless, as a fundamental challenge in image translation, the problem of zero-shot learning cross-modality image translation with fidelity remains unanswered. To bridge this gap, we propose a novel unsupervised zero-shot learning method called Mutual Information guided Diffusion Model, which learns to translate an unseen source image to the target modality by leveraging the inherent statistical consistency of Mutual Information between different modalities. To overcome the prohibitive high dimensional Mutual Information calculation, we propose a differentiable local-wise mutual information layer for conditioning the iterative denoising process. The Local-wise-Mutual-Information-Layer captures identical cross-modality features in the statistical domain, offering diffusion guidance without relying on direct mappings between the source and target domains. This advantage allows our method to adapt to changing source domains without the need for retraining, making it highly practical when sufficient labeled source domain data is not available. We demonstrate the superior performance of MIDiffusion in zero-shot cross-modality translation tasks through empirical comparisons with other generative models, including adversarial-based and diffusion-based models. Finally, we showcase the real-world application of MIDiffusion in 3D zero-shot learning-based cross-modality image segmentation tasks.

Structural characteristics of ß-glucans from various sources and their influences on the short- and long-term starch retrogradation in wheat flour.

Beta-glucans possess the ability of retarding starch retrogradation. However, ß-glucans from different sources might show various influences on retrogradation process and the structure-function relationships of ß-glucans related to the feature still remains unclear. In the study, the ß-glucans from oat (OG), highland barley (HBG), and yeast (YG) were selected. Each ß-glucans formed aggregate as observed by atomic force microscopy. OG and HBG with a lower Mw aggregated more obviously and exhibited higher intrinsic and apparent viscosity. The two ß-glucans showed more restraining effect on the short-term starch retrogradation in the sol-like test system (RVA) and the long-term starch retrogradation in the gel-like test system (DSC). However, YG with a higher Mw exerted a greater retarding effect on the short-term starch retrogradation in gel-like test systems (Mixolab and rheology). LF-NMR indicated that OG and HBG increased the population of less-bound water by wrapping around the starch. In summary, the structural characteristics of ß-glucan (Mw and aggregation state) and experiment condition (solid content) jointly influenced starch retrogradation, because a lower Mw and higher aggregation capacity ß-glucan interacted more readily with starch and inhibited more starch re-association due to the higher diffusion rate in the sol-like system.

Frailty phenotype as mediator between systemic inflammation and osteoporosis and fracture risks: A prospective study.

BACKGROUND: Systemic inflammation and frailty have been implicated in osteoporosis (OP) and fracture risks; however, existing evidence remains limited and inconclusive. This study aimed to assess the associations of systemic inflammation and frailty phenotype with incident OP and fracture and to evaluate the mediating role of frailty phenotype. METHODS: The present study analysed data from the UK Biobank, a comprehensive and representative dataset encompassing over 500 000 individuals from the general population. Baseline peripheral blood cell counts were employed to calculate the systemic inflammation markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII). Frailty phenotype was assessed using five criteria, defined as frail (≥3 items met), pre-frail (1-2 items met) and non-frail (0 items met). OP and fracture events were confirmed through participants' health-related records. Multivariable linear and Cox regression models were utilized, along with mediation analysis. RESULTS: Increased systemic inflammation was associated with increased risks of OP and fracture. The corresponding hazard ratios and 95% confidence intervals (CIs) for OP risk per standard deviation increase in the log-transformed NLR, PLR and SII were 1.113 (1.093-1.132), 1.098 (1.079-1.118) and 1.092 (1.073-1.111), and for fracture risk, they were 1.066 (1.051-1.082), 1.059 (1.044-1.075) and 1.073 (1.058-1.089), respectively. Compared with the non-frail individuals, the pre-frail and frail ones showed an elevated OP risk by 21.2% (95% CI: 16.5-26.2%) and 111.0% (95% CI: 98.1-124.8%), respectively, and an elevated fracture risk by 6.1% (95% CI: 2.8-9.5%) and 38.2% (95% CI: 30.7-46.2%), respectively. The systemic inflammation level demonstrated a positive association with frailty, with ß (95% CI) of 0.034 (0.031-0.037), 0.026 (0.023-0.029) and 0.008 (0.005-0.011) in response to per standard deviation increment in log-transformed SII, NLR and PLR, respectively. The frailty phenotype mediated the association between systemic inflammation and OP/fracture risk. Subgroup and sensitivity analyses confirmed the robustness of these findings. CONCLUSIONS: Systemic inflammation and frailty phenotype are independently linked to increased risks of OP and fracture. The frailty phenotype partially mediates the association between systemic inflammation and osteoporotic traits. These results highlight the significance of interventions targeting systemic inflammation and frailty in OP and fracture prevention and management.

Early-life tobacco smoke elevating later-life osteoporosis risk: Mediated by telomere length and interplayed with genetic predisposition.

INTRODUCTION: The growing prevalence of osteoporosis (OP) in an aging global population presents a significant public health concern. Tobacco smoke negatively affects bone turnover, leading to reduced bone mass and heightened OP and fracture risk. However, the impact of early-life tobacco smoke exposure on later-life OP risk remains unclear. OBJECTIVES: This study was to explore the effects of early-life tobacco smoke exposure on incident OP risk in later life. The mediating role of telomere length (TL) and the interaction with genetic predisposition were also studied. METHODS: Data on in utero tobacco smoke exposure (IUTSE) status and age of tobacco use initiation from the UK Biobank were used to estimate early-life tobacco smoke exposure. Incident OP cases were identified according to health-related records. Linear, Cox, and Laplace regression models were mainly used for data analysis. RESULTS: Individuals with IUTSE showed a higher OP risk [hazard ratio (HR): 1.06, 95 % confidence interval (CI): 1.01, 1.11] and experienced earlier OP onset by 0.30 years [50th percentile difference = -0.30, 95 % CI: -0.51, -0.09] compared to those without. Participants initiating tobacco smoke in childhood, adolescence, and adulthood had 1.41 times (95 % CI: 1.23, 1.61), 1.17 times (95 % CI:1.10, 1.24), and 1.14 times (95 % CI: 1.07, 1.20) the risk of OP, respectively, compared to never smokers. They also experienced earlier OP onset by 2.16, 0.95, and 0.71 years, sequentially. The TL significantly mediated the early-life tobacco exposure and OP association. Significant joint and interactive effects were detected between early-life tobacco smoke exposure and genetic elements. CONCLUSIONS: Our findings implicate that early-life tobacco smoke exposure elevates the later-life OP risk, mediated by telomere length and interplayed with genetic predisposition. These findings highlight the importance of early-life intervention against tobacco smoke exposure and ageing status for precise OP prevention, especially in individuals with a high genetic risk.

Reuleaux triangle core fiber with triple rotational symmetry.

A Reuleaux triangle core fiber (RTF) with triple rotational symmetry is proposed and fabricated. Then the RTF is twisted to form the chiral fiber grating, which converts the core mode into a vortex mode containing 3rd-order orbital angular momentum (OAM). Based on the Fourier expansion of the core boundary, the straight-sided and arc-sided triangular core profiles were analyzed, revealing the mechanism of high-efficiency OAM3 generation. The experimental results show a 3rd-order vortex mode with a high conversion efficiency and purity, and the polarization-independent characteristics endowed by the core shape are also confirmed. The proposed RTF provides a new, to the best of our knowledge, way for higher-order vortex beam generation, which can be used in optical fiber communication systems with OAM multiplexing.

Pathogen-induced methylglyoxal negatively regulates rice bacterial blight resistance by inhibiting OsCDR1 protease activity.

Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial blight (BB), a globally devastating disease of rice (Oryza sativa) that is responsible for significant crop loss. Sugars and sugar metabolites are important for pathogen infection, providing energy and regulating events associated with defense responses; however, the mechanisms by which they regulate such events in BB are unclear. As an inevitable sugar metabolite, methylglyoxal (MG) is involved in plant growth and responses to various abiotic stresses, but the underlying mechanisms remain enigmatic. Whether and how MG functions in plant biotic stress responses is almost completely unknown. Here, we report that the Xoo strain PXO99 induces OsWRKY62.1 to repress transcription of OsGLY II genes by directly binding to their promoters, resulting in overaccumulation of MG. MG negatively regulates rice resistance against PXO99: osglyII2 mutants with higher MG levels are more susceptible to the pathogen, whereas OsGLYII2-overexpressing plants with lower MG content show greater resistance than the wild type. Overexpression of OsGLYII2 to prevent excessive MG accumulation confers broad-spectrum resistance against the biotrophic bacterial pathogens Xoo and Xanthomonas oryzae pv. oryzicola and the necrotrophic fungal pathogen Rhizoctonia solani, which causes rice sheath blight. Further evidence shows that MG reduces rice resistance against PXO99 through CONSTITUTIVE DISEASE RESISTANCE 1 (OsCDR1). MG modifies the Arg97 residue of OsCDR1 to inhibit its aspartic protease activity, which is essential for OsCDR1-enhanced immunity. Taken together, these findings illustrate how Xoo promotes infection by hijacking a sugar metabolite in the host plant.

Human Disturbance Increases Health Risks to Golden Snub-Nosed Monkeys and the Transfer Risk of Pathogenic Antibiotic-Resistant Bacteria from Golden Snub-Nosed Monkeys to Humans.

From the perspective of interactions in the human-animal-ecosystem, the study and control of pathogenic bacteria that can cause disease in animals and humans is the core content of "One Health". In order to test the effect of human disturbance (HD) on the health risk of pathogenic antibiotic-resistant bacteria (PARBs) to wild animals and transfer risk of the PARBs from wild animals to humans, golden snub-nosed monkeys (Rhinopithecus roxellana) were used as sentinel animals. Metagenomic analysis was used to analyze the characteristics of PARBs in the gut microbiota of golden snub-nosed monkeys. Then, the total contribution of antibiotic resistance genes (ARGs) and virulence factors (VFs) of the PARBs were used to assess the health risk of PARBs to golden snub-nosed monkeys, and the antimicrobial drug resistance and bacterial infectious disease of PARBs were determined to assess the transfer risk of PARBs from golden snub-nosed monkeys to humans. There were 18 and 5 kinds of PARBs in the gut microbiota of golden snub-nosed monkeys under HD (HD group) and wild habitat environments (W group), respectively. The total health risks of PARBs to the W group and the HD group were -28.5 × 10-3 and 125.8 × 10-3, respectively. There were 12 and 16 kinds of KEGG pathways of human diseases in the PARBs of the W group and the HD group, respectively, and the gene numbers of KEGG pathways in the HD group were higher than those in the W group. HD increased the pathogenicity of PARBs to golden snub-nosed monkeys, and the PARBs in golden snub-nosed monkeys exhibited resistance to lincosamide, aminoglycoside, and streptogramin antibiotics. If these PARBs transfer from golden snub-nosed monkeys to humans, then humans may acquire symptoms of pathogens including Tubercle bacillus, Staphylococcus, Streptococcus, Yersinia, Pertussis, and Vibrio cholera.

Role of lifestyle factors in mediating the effect of educational attainment on bone mineral density: a Mendelian randomization study.

We performed two-step multivariable Mendelian randomization analysis to explore the mediating role of lifestyle factors in educational attainment (EA) and bone mineral density (BMD). Summary statistics from genome-wide association studies of European lineages were used. Coffee intake and processed-meat intake mediated the association between EA and BMD. PURPOSE: This study aimed to explore the causal relationship between educational attainment (EA) and bone mineral density (BMD), as well as the potential mediating roles of lifestyle factors in the expected EA-BMD relationship. By identifying modifiable lifestyle factors, we hope to provide relevant information to prevent osteoporosis or low BMD in the less educated population. METHODS: Using summary statistics from genome-wide association studies (GWAS) of major European lineages, one- and two-sample Mendelian randomization (MR) analyses were performed to estimate the association between EA (in the social sciences genetic association consortium (SSGAC) involving 766,345 individuals and in the UK Biobank (UKB) involving 293,723 individuals) and BMD (in the Genetic Factors for Osteoporosis Consortium involving 426,824 individuals selected from the UKB). The EA variable in both consortia were expressed by years of schooling completed. Two-step multivariable MR was used to assess the mediating roles of eight lifestyle-related factors (moderate-to-vigorous physical activity, watching television, computer using, smoking initiation, coffee intake, alcohol intake frequency, tea intake, and processed-meat intake) in the EA and BMD association, and the corresponding mediating proportion was calculated. Meta-analysis was used to present a pooled estimate. RESULTS: A total of 317 and 73 independent single-nucleotide polymorphisms (SNPs) of GWAS significance (P < 5.0 × 10-8) were selected as instrumental variables (IVs) for EA in the SSGAC and UKB, respectively. A total of 513 SNPs were selected as IVs for the BMD. The results of one- and two-sample MR revealed that the genetically predicted BMD increased by 0.094 and 0.047 g/cm2, respectively, in response to each SD increment of genetically predicted schooling years. Among the eight candidate mediators, coffee intake and processed-meat intake were potential mediators revealed by the two-step multivariable MR analysis, mediating 26.87% and 23.92% of EA's effect on BMD, respectively. Meta-analysis showed consistent findings. Results of sensitivity analysis indicated the robustness of our findings. CONCLUSION: We elucidated the causal protective effect of EA on BMD and the mediating roles of coffee intake and processed-meat intake. Intervening with these factors can potentially reduce the burden of bone density loss or osteoporotic fractures among the less educated population.

Atomistic Construction of Silicon Nitride Ceramic Fiber Molecular Model and Investigation of Its Mechanical Properties Based on Molecular Dynamics Simulations.

Molecular simulations are currently receiving significant attention for their ability to offer a microscopic perspective that explains macroscopic phenomena. An essential aspect is the accurate characterization of molecular structural parameters and the development of realistic numerical models. This study investigates the surface morphology and elemental distribution of silicon nitride fibers through TEM and EDS, and SEM and EDS analyses. Utilizing a customized molecular dynamics approach, molecular models of amorphous and multi-interface silicon nitride fibers with complex structures were constructed. Tensile simulations were conducted to explore correlations between performance and molecular structural composition. The results demonstrate successful construction of molecular models with amorphous, amorphous-crystalline interface, and mixed crystalline structures. Mechanical property characterization reveal the following findings: (1) The nonuniform and irregular amorphous structure causes stress concentration and crack formation under applied stress. Increased density enhances material strength but leads to higher crack sensitivity. (2) Incorporating a crystalline reinforcement phase without interfacial crosslinking increases free volume and relative tensile strength, improving toughness and reducing crack susceptibility. (3) Crosslinked interfaces effectively enhance load transfer in transitional regions, strengthening the material's tensile strength, while increased density simultaneously reduces crack propagation.

The regulation of chromatin configuration at AGAMOUS locus by LFR-SYD-containing complex is critical for reproductive organ development in Arabidopsis.

Switch defective/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes are evolutionarily conserved, multi-subunit machinery that play vital roles in the regulation of gene expression by controlling nucleosome positioning and occupancy. However, little is known about the subunit composition of SPLAYED (SYD)-containing SWI/SNF complexes in plants. Here, we show that the Arabidopsis thaliana Leaf and Flower Related (LFR) is a subunit of SYD-containing SWI/SNF complexes. LFR interacts directly with multiple SWI/SNF subunits, including the catalytic ATPase subunit SYD, in vitro and in vivo. Phenotypic analyses of lfr-2 mutant flowers revealed that LFR is important for proper filament and pistil development, resembling the function of SYD. Transcriptome profiling revealed that LFR and SYD shared a subset of co-regulated genes. We further demonstrate that the LFR and SYD interdependently activate the transcription of AGAMOUS (AG), a C-class floral organ identity gene, by regulating the occupation of nucleosome, chromatin loop, histone modification, and Pol II enrichment on the AG locus. Furthermore, the chromosome conformation capture (3C) assay revealed that the gene loop at AG locus is negatively correlated with the AG expression level, and LFR-SYD was functional to demolish the AG chromatin loop to promote its transcription. Collectively, these results provide insight into the molecular mechanism of the Arabidopsis SYD-SWI/SNF complex in the control of higher chromatin conformation of the floral identity gene essential to plant reproductive organ development.

Erratum: Inflammation conditional genome editing mediated by the CRISPR-Cas9 system.

[This corrects the article DOI: 10.1016/j.isci.2023.106872.].

Metal mixture and osteoporosis risk: Insights from plasma metabolite profiling.

The pathophysiology of osteoporosis (OP) is influenced by exposure to nonessential harmful metals and insufficient or excessive intake of necessary metals. Investigating multiple plasma metals, metabolites, and OP risk among older adults may reveal novel clues of underlying mechanisms for metal toxicity on bone mass. A total of 294 adults ≥ 55 years from Wuhan communities were included. Plasma concentrations of 23 metals and metabolites were measured via inductively coupled plasma-mass spectrometry and global metabolite detection. To investigate the relationships between plasma metals, OP risk, and OP-related metabolites, three different statistical techniques were used: generalized linear regression model, two-way orthogonal partial least-squares analysis (O2PLS), and weighted quantile sum (WQS). The mean ages were 66.82 and 66.21 years in OP (n = 115) and non-OP (n = 179) groups, respectively. Of all 2999 metabolites detected, 111 differential between-group members were observed. The OP risk decreased by 58.5% (OR=0.415, 95% CI: 0.237, 0.727) per quartile increment in the WQS index indicative of metal mixture exposure. Consistency remained for bone mineral density (BMD) measurements. The O2PLS model identified the top five OP-related metabolites, namely, DG(18:2_22:6), 3-phenoxybenzoic acid, TG(16:1_16:1_22:6), TG(16:0_16:0_20:4), and TG(14:1_18:2_18:3), contributing most to the joint covariation between the metal mixture and metabolites. Significant correlations between each of them and the metal mixture were found using WQS regression. Furthermore, the five metabolites mediated the associations of the metal mixtures, BMD, and OP risk. Our findings shed additional light on the mediation functions of plasma metabolites in the connection between multiple metal co-exposure and OP pathogenesis and offer new insights into the probable mechanisms underpinning the bone effects of the metal mixture.

Mediating role of host metabolites in strontium's effect on osteoporosis among older individuals: Findings from Wuhan, China.

Strontium is receiving widespread attention due to its remarkable biological qualities in preventing bone resorption and fostering osteogenesis. However, the chemical processes behind strontium's dual activities on bone cells are not yet fully understood. This study used the metabolomic technique to identify and examine potential biomarkers between strontium exposure and osteoporosis (OP) risk. A total of 806 participants were recruited for the detection of plasma strontium content via inductively coupled plasma-mass spectrometry. Plasma metabolites were profiled in 254 participants through an untargeted metabolomics technique. Generalized linear models were primarily used to analyze associations among plasma strontium, metabolites, and OP. The mediating effects of metabolites on the strontium-OP association were further investigated. A total of 31 differential metabolites were observed, 10 of which were upregulated and 21 were downregulated in the OP group compared with the non-OP group. Five metabolites (3-phenoxybenzoic acid, Cer (t18:0/16:1), HexCer(t16:1/12:1(2OH)), HexCer(t14:2/18:1(2OH)), and TG(16:0-18:1-24:4)) were selected as potential mediators based on their significant association with OP risk and with femoral neck and lumbar spine bone mineral density (BMD). Moreover, all except TG(16:0-18:1-24:4) were involved in the OP discrimination model with excellent power combined with several traditional variables. 3-Phenoxybenzoic acid and Cer(t18:0/16:1) had significant indirect effects on the strontium-OP association. The five candidate metabolites mediated 83.79 % of the strontium-OP association. Plasma strontium level was associated with reduced OP risk in the Han population in Wuhan. Thus, plasma metabolite profiling revealed five BMD/OP-associated metabolites that acted as mediators in the strontium-OP association. Our findings provided evidence of the mediating role of host plasma metabolites in strontium's effect on OP pathology.

Development of nomogram for predicting major complications in patients with esophageal cancer in the early postoperative period.

PURPOSE: To investigate the predictive value of the Prognostic Nutrition Index (PNI) in major complications after esophagectomy for esophageal cancer and to develop a Nomogram risk prediction model. METHOD: The clinical data of 386 patients who underwent radical esophageal cancer surgery from May 2019 to March 2022 were retrospectively analyzed. Logistic regression analysis was performed to screen independent risk factors associated with major postoperative complications. A nomogram risk prediction model for major postoperative complications was developed based on the predictors, and the clinical utility of the model was assessed by decision curve analysis(DCA). RESULT: In this study logistic univariate regression analysis found that age, preoperative radiotherapy, American Society of Anesthesiologists physical status (ASA score), length of surgery, and PNI may be associated with the development of major postoperative complications. logistic multifactorial analysis showed that the above risk factors were independent risk factors for the development of major postoperative complications in esophageal cancer. Nomogram was developed by incorporating the above risk factors with ASA classification. The calibration curves showed that the model had a good agreement. The decision curves showed that the model has good clinical application. CONCLUSION: Individualized nomograms based on PNI combined with clinical indicators can be used to predict major complications in the early postoperative period and help to enhance perioperative management.

Joint effects of phenol, chlorophenol pesticide, phthalate, and polycyclic aromatic hydrocarbon on bone mineral density: comparison of four statistical models.

Exposure to phenols, phthalates, pesticides, and polycyclic aromatic hydrocarbons (PAHs) can harm the skeleton. However, data about the joint effects of these chemicals' mixture on bone health are limited. The final analysis involved 6766 participants aged over 20 years recruited from the National Health and Nutrition Examination Survey. Generalized linear regression, weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and quantile g-computation (qgcomp) were performed to investigate the association of the urinary levels of chemicals (three phenols, two chlorophenol pesticides, nine phthalates, and six polycyclic aromatic hydrocarbon [PAH] metabolites) with bone mineral density (BMD) measurements and osteoporosis (OP) risk. Generalized linear regression identified that benzophenone-3, 2,4-dichlorophenol, mono-n-butyl phthalate, 1-napthol, 3-fluorene, 2-fluorene, and 1-phenanthrene were significantly associated with lower BMD and increased OP risk. The WQS index was negatively associated with total femur, femoral neck, and lumbar spine vertebra 1 (L1) BMD among all the participants, with corresponding ß (95% confidence interval) values of -0.028 g/cm2 (-0.040, -0.017), -0.015 g/cm2 (-0.025, -0.004), and -0.018 g/cm2 (-0.033, -0.003). In the BKMR analysis, the overall effect of the mixture was significantly associated with femoral neck BMD among males and OP risk among females. The qgcomp model found a significant association between co-exposure and L1 BMD among all the participants and among males. Our study presents compelling epidemiological evidence that co-exposure to phenols, chlorophenol pesticides, phthalates, and PAHs is associated with reduced BMD and elevated OP risk. It provides epidemiologic evidence for the detrimental effects of these chemicals on bone health.

Absolute Configuration, Enantioselective Bioactivity, and Mechanism Study of the Novel Chiral Fungicide Benzovindiflupyr.

Benzovindiflupyr has gained increasing attention as a new chiral succinate dehydrogenase inhibitor fungicide; however, its determination, bioactivity, and mechanism at the enantiomeric level are very limited. In the present study, optical rotation determination and X-ray single-crystal diffraction results identified that the absolute configurations were (+)-(1R,4S)-benzovindiflupyr and (-)-(1S,4R)-benzovindiflupyr. A quantitative determination method for enantiomers was established using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) for pesticide detection. The stereoselective bioactivity assay indicated that (-)-(1S,4R)-benzovindiflupyr exhibited greater potency than (+)-(1R,4S)-benzovindiflupyr against seven phytopathogenic fungi. Molecular docking analysis showed that (-)-(1S,4R)-benzovindiflupyr possessed a stronger binding affinity to succinate dehydrogenase than (+)-(1R,4S)-benzovindiflupyr. The binding modes between enantiomers and the mutant with H272(B) predicted that the phytopathogenic fungi with H272(B) of succinate dehydrogenase mutation would not be resistant to benzovindiflupyr enantiomers. This study provides a basis for residue evaluation, risk assessment, and the safe application of benzovindiflupyr at the enantiomer level.

Inflammation conditional genome editing mediated by the CRISPR-Cas9 system.

The specificity of CRISPR-Cas9 in response to particular pathological stimuli remains largely unexplored. Hence, we designed an inflammation-inducible CRISPR-Cas9 system by grafting a sequence that binds with NF-κB to the CRISPR-Cas9 framework, termed NBS-CRISPR. The genetic scissor function of this developed genome-editing tool is activated on encountering an inflammatory attack and is inactivated or minimized in non-inflammation conditions. Furthermore, we employed this platform to reverse inflammatory conditions by targeting the MyD88 gene, a crucial player in the NF-κB signaling pathway, and achieved impressive therapeutic effects. Finally, during inflammation, P65 (RELA) can translocate to the nucleus from the cytoplasm. Herein, to avoid Cas9 leaky DNA cleavage activity i, we constructed an NBS-P65-CRISPR system expressing the Cas9-p65 fusion protein. Our inflammation inducible Cas9-mediated genome editing strategy provides new perspectives and avenues for pathological gene interrogation.

Triphosphate Tunnel Metalloenzyme 2 Acts as a Downstream Factor of ABI4 in ABA-Mediated Seed Germination.

Seed germination is a complex process that is regulated by various exogenous and endogenous factors, in which abscisic acid (ABA) plays a crucial role. The triphosphate tunnel metalloenzyme (TTM) superfamily exists in all living organisms, but research on its biological role is limited. Here, we reveal that TTM2 functions in ABA-mediated seed germination. Our study indicates that TTM2 expression is enhanced but repressed by ABA during seed germination. Promoted TTM2 expression in 35S::TTM2-FLAG rescues ABA-mediated inhibition of seed germination and early seedling development and ttm2 mutants exhibit lower seed germination rate and reduced cotyledon greening compared with the wild type, revealing that the repression of TTM2 expression is required for ABA-mediated inhibition of seed germination and early seedling development. Further, ABA inhibits TTM2 expression by ABA insensitive 4 (ABI4) binding of TTM2 promoter and the ABA-insensitive phenotype of abi4-1 with higher TTM2 expression can be rescued by mutation of TTM2 in abi4-1 ttm2-1 mutant, indicating that TTM2 acts downstream of ABI4. In addition, TTM1, a homolog of TTM2, is not involved in ABA-mediated regulation of seed germination. In summary, our findings reveal that TTM2 acts as a downstream factor of ABI4 in ABA-mediated seed germination and early seedling growth.

A novel prognostic index for diffuse large B-cell lymphoma combined baseline metabolic tumour volume with clinical and pathological risk factors.

OBJECTIVES: This study aimed to develop a novel prognostic index integrating baseline metabolic tumour volume (MTV) along with clinical and pathological parameters for diffuse large B-cell lymphoma (DLBCL). METHODS: This prospective trial enrolled 289 patients with newly diagnosed DLBCL. The predictive value of novel prognostic index was compared with Ann Arbor staging and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI). We used the concordance index (C-index) and a calibration curve to determine its predictive capacity. RESULTS: Multivariate analysis revealed high MTV (>191 cm 3 ), Ann Arbor stage (III-IV) and MYC/BCL2 double expression lymphoma (DEL) to be independently associated with inferior progression-free survival (PFS) and overall survival (OS). Ann Arbor stage and DEL could be stratified by MTV. Our index, combining MTV with Ann Arbor stage and DEL status, identified four prognostic groups: group 1 (no risk factors,), group 2 (one risk factor), group 3 (two risk factors), and group 4 (three risk factors). The 2-year PFS rates were 85.5, 73.9, 53.6, and 13.9%; 2-year OS rates were 94.6, 87.0, 67.5, and 24.2%, respectively. The C-index values of the novel index were 0.697 and 0.753 for PFS and OS prediction, which was superior to Ann Arbor stage and NCCN-IPI. CONCLUSION: The novel index including tumour burden and clinicopathological features may help predict outcome of DLBCL (clinicaltrials.gov identifier: NCT02928861).