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At the present time, COVID-19 is spreading rapidly [1]. The global prevention and control of COVID-19 is focused on the estimation of the relevant incubation period, basic reproduction number (R0), effective reproduction number (Rt) and death risk. Although the prevention and control of COVID-19 requires a reliable estimation of the relevant incubation period, R0, Rt and death risk. Another key epidemiological parameter-asymptomatic ratio that provides strength and range for social alienation strategies of COVID-19, which is widely defined as the proportion of asymptomatic infections among all disease infections. In fact, the ratio of asymptomatic infection is a useful indicator of the burden of disease and a better measurement of the transmissibility of the virus. So far, people have not paid enough attention to asymptomatic carriers. The asymptomatic carriers discussed in this study are recessive infections, that is, those who have never shown symptoms after onset of infection. We will discuss three aspects: detection, infectivity and proportion of healthy carriers.

The survival of malignant tumors is highly dependent on their intrinsic self-defense pathways such as heat shock protein (HSP) during cancer therapy. However, precisely dismantling self-defenses to amplify antitumor potency remains unexplored. Herein, we demonstrate that nanoparticle-mediated transient receptor potential vanilloid member 1 (TRPV1) channel blockade potentiates thermo-immunotherapy via suppressing heat shock factor 1 (HSF1)-mediated dual self-defense pathways. TRPV1 blockade inhibits hyperthermia-induced calcium influx and subsequent nuclear translocation of HSF1, which selectively suppresses stressfully overexpressed HSP70 for enhancing thermotherapeutic efficacy against a variety of primary, metastatic and recurrent tumor models. Particularly, the suppression of HSF1 translocation further restrains the transforming growth factor β (TGFβ) pathway to degrade the tumor stroma, which improves the infiltration of antitumor therapeutics (e.g. anti-PD-L1 antibody) and immune cells into highly fibrotic and immunosuppressive pancreatic cancers. As a result, TRPV1 blockade retrieves thermo-immunotherapy with tumor-eradicable and immune memory effects. The nanoparticle-mediated TRPV1 blockade represents as an effective approach to dismantle self-defenses for potent cancer therapy. TRPV1 has been associated with proliferation and survival of tumors, and can be activated by heat and other stimuli. Here, the authors block TRPV1 using photothermal nanoparticles encapsulating a TRPV1 antagonist in different cancer types, which can enhance thermo-immunotherapy in pancreatic cancer models.

Transcription activation by cyclic AMP (cAMP) receptor protein (CAP) is the classic paradigm of transcription regulation in bacteria. CAP was suggested to activate transcription on class-II promoters via a recruitment and isomerization mechanism. However, whether and how it modifies RNA polymerase (RNAP) to initiate transcription remains unclear. Here, we report cryo-electron microscopy (cryo-EM) structures of an intact Escherichia coli class-II CAP-dependent transcription activation complex (CAP-TAC) with and without de novo RNA transcript. The structures reveal two distinct architectures of TAC and raise the possibility that CAP binding may induce substantial conformational changes in all the subunits of RNAP and transiently widen the main cleft of RNAP to facilitate DNA promoter entering and formation of the initiation open complex. These structural changes vanish during further RNA transcript synthesis. The observations in this study may reveal a possible on-pathway intermediate and suggest a possibility that CAP activates transcription by inducing intermediate state, in addition to the previously proposed stabilization mechanism.

Thioredoxin-interacting protein (TXNIP) plays a pivotal role in glucose metabolism and redox signaling. Its emerging function as a potent suppressor of cell proliferation in various cancer contexts underscores its importance in cancer development. In a previous study, we found TXNIP activation by UNC0642, an inhibitor of histone methyltransferase G9A, significantly inhibited MDA-MB-231 breast cancer cell proliferation in vitro and tumor growth in vivo. Here, we demonstrated that TXNIP knockdown increased MDA-MB-231 tumor growth and metastasis in a mouse model. Reintroducing TXNIP into TXNIP-deficient HCC-1954 breast cancer cells decreased cell proliferation and migration while boosting the generation of reactive oxygen species, alongside reductions in mitochondrial respiration, mitochondrial membrane potential, and glycolysis. To elucidate the mechanisms underlying TXNIP’s antitumor effects in breast cancer cells, we conducted co-immunoprecipitation and proteomic analyses that revealed calpastatin (CAST) as a novel TXNIP-interacting protein in MDA-MB-231 and HCC-1954 cells. Overexpression of CAST, an endogenous inhibitor of calpains, significantly increased xenograft tumor growth for both MDA-MB-231 and HCC-1954 cells, underscoring its novel role as a tumor promoter. In addition, we identified a positive correlation between the expression of TXNIP and interleukin-24 (IL-24), a molecule that induces cancer-specific apoptosis in several breast cancer cell lines. Our findings also show TXNIP’s ability to decrease activation of STAT3, a key driver of oncogenesis. Finally, cells with high levels of TXNIP expression displayed increased susceptibility to IL-24 and WP1066, a specific STAT3 inhibitor, suggesting possible predictive value for TXNIP. Collectively, these findings unveil novel TXNIP-dependent pathways that may contribute to breast cancer pathogenesis, enriching our understanding of this molecule’s intricate role in cancer and potentially paving the way for clinical translation.

Protecting the telomere: a complex tale The ends of linear eukaryotic chromosomes are capped by sequences known as telomeres. Although these are essentially one half of a DNA double-strand break, which is a pathogenic lesion that must be repaired to maintain the genome's integrity, telomeres do not normally activate DNA damage repair pathways. A major player in the process of telomere maintenance is the MRN complex, made up of three proteins (MRE11, RAD50 and NBS1). Now a study in mice using alleles that inactivate either the whole MRN complex or just the nuclease activity of MRE1, shows that MRE11 serves two functions at the telomere. It protects newly synthesized telomeric ends from repair factors by promoting the formation of an overhanging DNA end, and it degrades the overhang to promote fusion repair when the telomere is not functioning properly. The ends of linear eukaryotic chromosomes are capped by sequences known as telomeres. Although telomeres are essentially one half of a DNA double-strand break, which is a pathogenic lesion that must be repaired, telomeres do not normally activate DNA damage repair pathways. Here, the three-member MRN complex is shown to serve two roles at the telomere: it protects newly synthesized telomeric ends from repair factors and it promotes a type of fusion repair when the telomere is not functioning properly. Progressive telomere attrition or uncapping of the shelterin complex elicits a DNA damage response as a result of a cell’s inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks 1 . Telomere deprotection activates both ataxia telangiectasia mutated (ATM) and telangiectasia and Rad3-related (ATR) kinase-dependent DNA damage response pathways, and promotes efficient non-homologous end-joining (NHEJ) of dysfunctional telomeres 2 , 3 , 4 , 5 . The mammalian MRE11–RAD50–NBS1 (MRN; NBS1 is also known as NBN) complex interacts with ATM to sense chromosomal double-strand breaks and coordinate global DNA damage responses 6 , 7 . Although the MRN complex accumulates at dysfunctional telomeres, it is not known whether mammalian MRN promotes repair at these sites. Here we address this question by using mouse alleles that either inactivate the entire MRN complex or eliminate only the nuclease activities of MRE11 (ref. 8 ). We show that cells lacking MRN do not activate ATM when telomeric repeat binding factor 2 (TRF2) is removed from telomeres, and ligase 4 (LIG4)-dependent chromosome end-to-end fusions are markedly reduced. Residual chromatid fusions involve only telomeres generated by leading strand synthesis. Notably, although cells deficient for MRE11 nuclease activity efficiently activate ATM and recruit 53BP1 (also known as TP53BP1) to deprotected telomeres, the 3′ telomeric overhang persists to prevent NHEJ-mediated chromosomal fusions. Removal of shelterin proteins that protect the 3′ overhang in the setting of MRE11 nuclease deficiency restores LIG4-dependent chromosome fusions. Our data indicate a critical role for the MRN complex in sensing dysfunctional telomeres, and show that in the absence of TRF2, MRE11 nuclease activity removes the 3′ telomeric overhang to promote chromosome fusions. MRE11 can also protect newly replicated leading strand telomeres from NHEJ by promoting 5′ strand resection to generate POT1a–TPP1-bound 3′ overhangs.

Objectives The present study was committed to investigate the role of miR‐148a‐3p in HCC infected with hepatitis C virus (HCV) and the regulatory mechanism of miR‐148a‐3p/c‐Jun/MAPK signalling pathway. Methods Differential analysis and GSEA analysis were performed with R packages. QRT‐PCR and Western blot were used to detect RNA or protein level, respectively. The targeted relationship between miR‐148a‐3p and c‐Jun was predicted by TargetScan database and determined by double luciferase reporter assay. MTT assay and flow cytometry were used to evaluate cell proliferation, cell cycle and cell apoptosis, respectively. Results C‐Jun was up‐regulated, and MAPK signalling pathway was activated in HCV‐infected HCC cells. C‐Jun expression regulated inflammation‐related gene expression and had an influence on cell proliferation, cell cycle and cell apoptosis. MiR‐148a‐3p, down‐regulated in HCV‐infected HCC cells, could target c‐Jun mRNA to suppress c‐Jun protein expression. Conclusions MiR‐148a‐3p suppressed the proliferation of HCC cells infected with HCV through targeting c‐Jun mRNA.

Background Plasma tumor-associated exosomes represent a promising source for cancer biomarkers; however, the role of long non-coding RNAs (lncRNAs) within these exosomes is not well-defined in non-small cell lung cancer (NSCLC). Methods We identified a panel of NSCLC-specific lncRNAs within plasma EpCAM-specific exosomes (Epexo) through a comparative analysis of lncRNA profiles between plasma Epexo and lung tissues. The panel’s diagnostic value was firstly evaluated in a retrospective cohort of 210 NSCLC patients and 245 healthy controls, and validated in a prospective cohort of 192 patients with pulmonary nodules (nodule size < 3 cm in diameter). The evaluation utilized the area under the ROC curve (AUC) based on a random forest model. For precision, repeat testing was conducted with 31 randomly selected samples. Additionally, 39 paired tissue-plasma samples were employed to assess the concordance of lncRNA expression between tissue and plasma within the same individuals. Results The panel, including linc01125, HNF1A-AS1, MIR100HG, linc01160, and ZNRF3-AS1, demonstrated superior capability in distinguishing early-stage NSCLC patients from controls, achieving AUC values of 0.805 and 0.856 in the discovery and validation set, respectively. The panel also showed potential for differentiating adenocarcinoma and squamous cell carcinoma. Repeat sample testing showed a consistency of 90.3% for this panel. The expression levels of MIR100HG and HNF1A-AS1 showed significant correlations between plasma Epexo and cancerous tissues. Conclusions The identified lncRNA panel, consisting of linc01125, HNF1A-AS1, MIR100HG, linc01160, and ZNRF3-AS1, presents a promising diagnostic tool for NSCLC. Clinical trial number not applicable.

Deviations between the design and actual shafting occur due to limitations in ship construction accuracy. Consequently, accurately obtaining the relationship between the actual shafting load and displacement relationship based on the design shafting becomes challenging, leading to inaccurate solutions for bearing displacement values and low alignment efficiency. In this research article, to address the issue of incomplete actual shafting data, a transfer learning-based method is proposed for accurate calculation of bearing displacement values. By combining simulated data from the design shafting with measured data generated during the adjustment process of the actual shafting, higher accuracy can be achieved in calculating bearing displacement values. This research utilizes a certain shafting as an example to carry out the application of the bearing displacement value calculation method. The results show that even under the action of shafting deviation, the actual shafting load and displacement relationship model can become more and more accurate with the shafting adjustment process, and the accuracy of bearing displacement values calculation becomes higher and higher. This method contributes to obtaining precise shafting adjustment schemes, thereby enhancing alignment quality and efficiency of ship shafting.

Background The most common genetic changes identified in human NSCLC are Kras mutations (10–30 %) and p53 mutation or loss (50–70 %). Moreover, NSCLC with mutations in Kras and p53 poorly respond to current therapies, so we are trying to find a new target for the treatment strategies. Methods Flow cytometry, crystal violet staining and immunoblotting were used to assess cell cycle arrest, proliferation and apoptosis in lung cancer cell lines after 2-DG treatment and lentivirus infection by shRNA knock down. IHC and western blotting were carried for NSG xenograft model with 2-DG treatment and lentivirus infection by shRNA knock down. Results Knocking down Kras down-regulated the glycolytic enzyme hexokinase II (HK2) in KP2 (mouse lung cancer cell line with Kras mutation and p53 deletion) and H23 (human lung cancer cell line with Kras mutation and p53 mutation) cell lines. Genetic studies revealed that HK2 was required for the human and mouse lung cancer cell growth in vitro and in vivo. Our pharmacological studies confirmed that 2-DG, an inhibitor of HK2, inhibited human and mouse lung cancer cell growth through inducing cell apoptosis and autophagy. Conclusions HK2 is a promising treatment target for NSCLC with Kras activating and p53 function loss.

To improve the accuracy of bearing load measurement in propulsion shafting, a bearing load measurement method based on redundant strain and jacking data fusion is proposed. Firstly, to address the issue of low measurement accuracy in strain gauge methods (SGM), a redundant strain gauge method (RSGM) is introduced to enhance the precision of strain-based measurements. Secondly, synchronize the measurement of strain data during the jacking phase and fuse the measurement data from the jacking phase based on the Bayesian estimation method to enhance the measurement accuracy of the jack-up method (JM). Lastly, the pre-decision results of the two types of measurement data are integrated at the decision level to obtain the final measured load. Simulation experiments have verified the correctness and applicability of the proposed measurement method. The research results indicate that, compared to the SGM, the RSGM offers higher measurement precision; the fusion measurement method can achieve more accurate results than the JM and RSGM under different bearing support conditions and jack-up scenarios.