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BackgroundLong non-coding RNAs (lncRNAs) have been increasingly uncovered to participate in multiple human cancers, including pancreatic cancer (PC). However, the underlying mechanisms of most of the lncRNAs have not been fully understood yet.AimsIn this study, we probed the role and latent mechanism of LINC01420 in PC.MethodsSeveral online tools were applied. Gene expression was evaluated by qRT-PCR or Western blot. Both in vitro and in vivo assays were conducted to probe LINC01420 function in PC. ChIP, RIP, and luciferase reporter assays were performed to determine relationships between genes.ResultsThe bioinformatics analyses revealed LINC01420 was highly expressed in PC tissues. Besides, LINC01420 was pronouncedly upregulated in PC cell lines and its depletion controlled PC cell proliferation and EMT in vitro and hindered tumor growth in vivo. Importantly, KRAS was proved to mediate LINC01420-facilitated PC cell proliferation. Further, we explained that KRAS transcription was regulated by MYC, while LINC01420 enhanced the binding of MYC to KRAS promoter in the nucleus of PC cells. Intriguingly, LINC01420 boosted MYC expression in the cytoplasm of PC cells by sponging miR-494-3p.ConclusionThis study illustrated that LINC01420 accelerates PC progression through releasing miR-494-3p-silenced MYC in cytoplasm and upregulating MYC-activated KRAS in nucleus, unveiling LINC01420 as a latent therapeutic strategy for PC patients.

The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions 1 , 2 . Here we identify a stable association between the genome-stability regulator sensor of single-stranded DNA (SOSS) 3 and the transcription regulator Integrator-PP2A (INTAC) 4 , 5 – 6 . Through SSB1-mediated recognition of single-stranded DNA, SOSS–INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability. SOSS–INTAC-dependent attenuation of R-loops is enhanced by the ability of SSB1 to form liquid-like condensates. Deletion of NABP2 (encoding SSB1) or introduction of cancer-associated mutations into its intrinsically disordered region leads to a pervasive accumulation of R-loops, highlighting a genome surveillance function of SOSS–INTAC that enables timely termination of transcription at promoters to constrain R-loop accumulation and ensure genome stability. SOSS–INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability.

The formation of transcription regulatory complexes by the association of Smad4 with Smad2 and Smad3 (Smad2/3) is crucial in the canonical TGFβ pathway. Although the central requirement of Smad4 as a common mediator is emphasized in regulating TGFβ signaling, it is not obligatory for all responses. The role of Smad2/3 independently of Smad4 remains understudied. Here, we introduce a stepwise paradigm in which Smad2/3 regulate the lineage priming and differentiation of mouse embryonic stem cells (mESCs) by collaboration with different effectors. During the naïve-to-primed transition, Smad2/3 upregulate DNA methyltransferase 3b (Dnmt3b), which establishes the proper DNA methylation patterns and, in turn, enables Smad2/3 binding to the hypomethylated centers of promoters and enhancers of epiblast marker genes. Consequently, in the absence of Smad2/3, Smad4 alone cannot initiate epiblast-specific gene transcription. When primed epiblast cells begin to differentiate, Dnmt3b becomes less actively engaged in global genome methylation, and Smad4 takes over the baton in this relay race, forming a complex with Smad2/3 to support mesendoderm induction. Thus, mESCs lacking Smad4 can undergo the priming process but struggle with the downstream differentiation. This work sheds light on the intricate mechanisms underlying TGFβ signaling and its role in cellular processes. The role of Smad2/3 in the TGFβ pathway, independent of Smad4, is understudied. Authors reveal distinct roles for Smad2/3 and Smad4 during mESC priming to differentiation, and uncover a collaboration of Smad2/3 with Dnmt3b in epiblast formation.

Transposon-associated ribonucleoprotein TnpB is known to be the ancestry endonuclease of diverse Cas12 effector proteins from type-V CRISPR system. Given its small size (408 aa), it is of interest to examine whether engineered TnpB could be used for efficient mammalian genome editing. Here, we showed that the gene editing activity of native TnpB from Deinococcus radiodurans (ISDra2 TnpB) in mouse embryos was already higher than previously identified small-sized Cas12f1. Further stepwise engineering of noncoding RNA (ωRNA or reRNA) component of TnpB significantly elevated the nuclease activity of TnpB. Notably, an optimized TnpB-ωRNA system could be efficiently delivered in vivo with single adeno-associated virus (AAV) and corrected the disease phenotype in a tyrosinaemia mouse model. Thus, the engineered miniature TnpB system represents a new addition to the current genome editing toolbox, with the unique feature of the smallest effector size that facilitate efficient AAV delivery for editing of cells and tissues. Miniature gene editing tools are highly desired for efficient in vivo delivery and disease treatment. Here, the authors reported engineering hypercompact TnpB-ωRNA for robust gene editing with minimal off-target effect in cultured cells and use it to rescue fatal genetic liver disease in a tyrosinaemia mouse model.

In this paper, the volatile compounds and profile of sugar-smoked chicken thighs were studied, which were proceed by using dividual smoking materials such as sucrose, maltose, glucose, fructose and xylose. A total of 33 volatile compounds in sugar-smoked samples were identified and quantitated by gas chromatography/mass spectrometry (GC/MS). The furfural, 5-methylfurfural, 1-octene-3-ol, hexanal, heptanal and nonanal were the most important volatile compounds with odour activity values (OAVs) greater than 1, among which furfural and 5-methylfurfural contributed mainly to the smoky aroma. The sucrose, glucose and fructose pyrolysis all produced high yield of furans, such as furfural (FF) and 5-hydroxymethylfurfural (5-HMF) based on pyrolysis mass spectrometry and gas chromatography/mass spectrometry (Py-GC/MS). During the smoking process, then the 5-HMF pyrolyzed into 5-methylfurfural. The sucrose was the good carbohydrate to form furans with smoky aroma.

The whey protein β-lactoglobulin (BLG) is a major milk allergen which is absent in human milk. Here, we for the first time generated DNA-free BLG bi-allelic knockout cow by zinc-finger nuclease (ZFNs) mRNA and produced BLG-free milk. According to the allergenicity evaluation of BLG-free milk, we found it can trigger lower allergic reaction of Balb/c mice including the rectal temperature drop and the allergen-specific immunoglobulin IgE production; BLG free-milk was easily digested by pepsin at 2 min, while BLG in control milk was still not completely digested after 60 min, and the binding of IgE from cow’s milk allergy (CMA) patients to BLG free-milk was significantly lower than that to the control milk. Meanwhile, the genome sequencing revealed that our animal is free of off-target events. Importantly, editing animal genomes without introducing foreign DNA into cells may alleviate regulatory concerns related to foods produced by genome edited animals. Finally, the ZFNs-mediated targeting in cow could be transmitted through the germline by breeding. These findings will open up unlimited possibilities of modifying milk composition to make it more suitable for human health and also improve the functional properties of milk.

AbstractObjectiveTo investigate whether the reliability of telesurgery is non-inferior to that of standard local surgery in patients undergoing urological robotic operations.DesignMulticentre, non-inferiority, randomised controlled trial.SettingFive hospitals in China from December 2023 to June 2024.ParticipantsPatients scheduled to undergo radical prostatectomy or partial nephrectomy.InterventionsPatients were randomly assigned 1:1 to undergo telesurgery or local surgery.Main outcome measuresThe primary outcome was the probability of success of surgery, determined by the medical team on the basis of pre-established criteria. The pre-specified non-inferiority margin was an absolute reduction in probability of 0.1. Thirteen clinical secondary outcomes were associated with the operation and early recovery, and one secondary outcome related to the workload of the medical team. Four technical secondary outcomes for the surgical system were also explored, including network latency, display latency, frame loss during telesurgery, and system malfunction. The participants were followed up at four and six weeks postoperatively for the secondary outcomes of recovery and complications.ResultsA total of 72 participants were enrolled in the study and randomised 1:1 to the telesurgery group and the local surgery group for the intention-to-treat set. The median age of patients was 61.0 (interquartile range 57.5-68.0) years in the telesurgery group and 65.0 (56.5-70.0) years in the local surgery group. Telesurgery was not inferior to local surgery in terms of the probability of surgical success in the intention-to-treat population, accounting for clustering by surgeon (success probability difference 0.02 (95% credible interval −0.03 to 0.15) with bayesian posterior probability of 0.99 for non-inferiority). The telesurgery system was stable with a distance from 1000 km to 2800 km, a mean round trip network latency of 20.1-47.5 ms, and frame loss of 0-1.5 per telesurgery. Secondary outcomes, including operative basic data, complications, early recovery, oncological outcome, and medical team workload, did not differ substantially between the two groups.ConclusionsThe reliability of telesurgery was non-inferior to that of local robotic surgery according to the non-inferiority margin of a 0.1 reduction in success probability.Trial registrationChiCTR.org ChiCTR2300077721.

7-Met, a derivative of soybean isoflavone, is a natural flavonoid compound that has been reported to have multiple signaling pathways regulation effects. This study investigated the therapeutic effects of 7-Met on mice with atopic dermatitis induced by fluorescein isothiocyanate (FITC), or oxazolone (OXZ). 7-Met ameliorated FITC or OXZ-induced atopic dermatitis symptoms by decreasing ear thickness, spleen index, mast cell activation, neutrophil infiltration and serum IgE levels in female BALB/c mice. In FITC-induced atopic dermatitis mice, 7-Met reduced Th1 cytokines production and regulated Th1/Th2 balance by downregulating the secretion of thymic stromal lymphopoietin (TSLP) via inactivation of the NF-κB pathway. In OXZ-induced atopic dermatitis, 7-Met functioned through the reduction of Th17 cytokine production. Our study showed that 7-Methoxyisoflavone alleviated atopic dermatitis by regulating multiple signaling pathways and downregulating chemokine production.

Small cell lung cancer (SCLC) is the most aggressive and lethal subtype of lung cancer. Cancer stem‐like cells (CSLCs) are primarily responsible for carcinogenesis, therapeutic resistance, and tumor recurrence. This study reported that high level of mucin1 (MUC1) is associated with poor patient survival in SCLC. MUC1 expression peaks during the G2/M phase and facilitates symmetric division and expansion of CSLCs. Mechanistically, the interaction of MUC1 and protein phosphatase 2A (PP2A) results in augmented PP2A activity, which leads to reduced phosphorylation of protein kinase C ζ (PKCζ), ultimately decreases phosphorylation of NUMB. Both pharmacological and genetic strategies demonstrate that targeted‐inhibition of the MUC1‐PP2A axis pointedly rescues phosphorylation of PKCζ and NUMB, thereby shifting CSLCs towards asymmetric division and represses CSLCs proliferation. Conversely, inhibitor of PKCζ suppresses phosphorylation of NUMB, promotes symmetric division and induces enrichment of CSLCs. Moreover, combination of etoposide and inhibitors of MUC1‐PP2A pathway efficiently constrains tumor growth in vitro and in vivo. Importantly, a negative correlation is observed between MUC1 and phosphorylation of PKCζ and NUMB in SCLC patients. Therefore, this study reveals a novel mechanism by which MUC1‐PP2A awakes CSLC expansion via switching symmetric division, suggesting a potential therapeutic strategy for MUC1‐positive SCLC.

This study was intended to characterize six types of commercial smoked chicken products in China by using gas chromatography-mass spectrometry (GC-MS), odor-activity values (OAVs), and sensory evaluation. Results demonstrated that a total of 89 components were identified in all samples, and 34 were considered as odor-active compounds because their OAVs were greater than one. Liaocheng Chicken that smoked with fruit tree sawdust had more phenols, which contributed to the smoky aroma. Jinshan and Goubangzi Chicken that smoked with sugar had more furans which contributed the overall odor with sweety and caramel aroma. Zhuozishan and Laoting Chicken that smoked with sugar and wood chips had similar flavor and volatile compounds. Tengqiao Chicken that smoked with sugar, tea and rice had significant difference with other chicken in smoky, bittern and caramel aroma (P< .05). The diversity of these smoked chicken flavors was mainly due to the cooking culture differences.