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Background The prognosis is very poor for lung cancer patients with bone metastasis. Unfortunately, a suitable method has yet to become available for the early diagnosis of bone metastasis in lung cancer patients. The present work describes an attempt to develop a novel model for the early identification of lung cancer patients with bone metastasis risk. Methods As the test group, 205 primary lung cancer patients were recruited, of which 127 patients had bone metastasis; the other 78 patients without bone metastasis were set as the negative control. Additionally, 106 healthy volunteers were enrolled as the normal control. Serum levels of several cytokines in the bone microenvironment (CaN, OPG, PTHrP, and IL-6) and bone turnover markers (tP1NP, β-CTx) were detected in all samples by ECLIA or ELISA assay. Receiver operating characteristic (ROC) curves and multivariate analyses were performed to evaluate diagnostic abilities and to assess the attributable risk of bone metastasis for each of these indicators; the diagnostic model was established via logistic regression analysis. The prospective validation group consisted of 44 patients with stage IV primary lung cancer on whom a follow-up of at least 2 years was conducted, during which serum bone biochemical marker concentrations were monitored. Results The serological molecular model for the diagnosis of bone metastasis was logit (p). ROC analysis showed that when logit (p) > 0.452, the area under curve of the model was 0.939 (sensitivity: 85.8%, specificity: 89.7%). Model validation demonstrated accuracy with a high degree of consistency (specificity: 85.7%, specificity: 87.5%, Kappa: 0.770). The average predictive time for bone metastasis occurrence of the model was 9.46 months earlier than that of the bone scan diagnosis. Serum OPG, PTHrP, tP1NP, β-CTx, and the diagnostic model logit (p) were all positively correlated with bone metastasis progression ( P  < 0.05). Conclusions This diagnostic model has the potential to be a simple, non-invasive, and sensitive tool for diagnosing the occurrence and monitoring the progression of bone metastasis in patients with lung cancer.

Dihydroxyacid dehydratase (DHAD), a key enzyme in branched-chain amino acid synthesis in plants, is a promising yet unexploited herbicide target. Inspired by the natural DHAD inhibitor aspterric acid, we design benzoxazinone derivatives with α-hydroxycarboxylic acid moieties as potential inhibitors and develop an eco-friendly α-C(sp³)-H hydroxylation method for accessing carbonyl compounds. Among the derivatives, 7-fluoro-2-hydroxy-3-oxo-4-propyne-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (I-6e) completely inhibits Arabidopsis thaliana germination and suppress six weed species by > 50%, with 100% efficacy against Avena fatua and Setaria viridis at 150 g ai/ha. This broad-spectrum activity and rice crop safety highlight its potential as an herbicide lead compound. Compound I-6e exhibits stronger affinity for DHAD (K  = 1 µM) than that of the natural substrate (K  = 5.39 µM). The 2.19 Å cocrystal structure of the AtDHAD-I-6e complex reveals a unique binding mechanism, confirming the critical role of the α-hydroxycarboxylic acid scaffold. This study provides a blueprint for rational DHAD inhibitor design.

BackgroundThe global outbreak of coronavirus disease 2019 (COVID-19) has turned into a worldwide public health crisis and caused more than 100,000,000 severe cases. Progressive lymphopenia, especially in T cells, was a prominent clinical feature of severe COVID-19. Activated HLA-DR+CD38+ CD8+ T cells were enriched over a prolonged period from the lymphopenia patients who died from Ebola and influenza infection and in severe patients infected with SARS-CoV-2. However, the CD38+HLA-DR+ CD8+ T population was reported to play contradictory roles in SARS-CoV-2 infection.MethodsA total of 42 COVID-19 patients, including 32 mild or moderate and 10 severe or critical cases, who received care at Beijing Ditan Hospital were recruited into this retrospective study. Blood samples were first collected within 3 days of the hospital admission and once every 3–7 days during hospitalization. The longitudinal flow cytometric data were examined during hospitalization. Moreover, we evaluated serum levels of 45 cytokines/chemokines/growth factors and 14 soluble checkpoints using Luminex multiplex assay longitudinally.ResultsWe revealed that the HLA-DR+CD38+ CD8+ T population was heterogeneous, and could be divided into two subsets with distinct characteristics: HLA-DR+CD38dim and HLA-DR+CD38hi. We observed a persistent accumulation of HLA-DR+CD38hi CD8+ T cells in severe COVID-19 patients. These HLA-DR+CD38hi CD8+ T cells were in a state of overactivation and consequent dysregulation manifested by expression of multiple inhibitory and stimulatory checkpoints, higher apoptotic sensitivity, impaired killing potential, and more exhausted transcriptional regulation compared to HLA-DR+CD38dim CD8+ T cells. Moreover, the clinical and laboratory data supported that only HLA-DR+CD38hi CD8+ T cells were associated with systemic inflammation, tissue injury, and immune disorders of severe COVID-19 patients.ConclusionsOur findings indicated that HLA-DR+CD38hi CD8+ T cells were correlated with disease severity of COVID-19 rather than HLA-DR+CD38dim population.

The involvement of HOXA4 in colorectal cancer and epithelial ovarian cancer has been reported. Although it has been reported that the Hoxa4 gene is involved in the patterning of the mouse lung during embryonic development, little is known about the biological functions of HOXA4 in lung cancer. In the current study, HOXA4 expression was down-regulated in lung cancer tissues when compared with non-cancerous tissues. HOXA4 expression was associated with tumor size, TNM stage, lymph node metastasis and prognosis. Bioinformatics analysis revealed that HOXA4 expression was negatively correlated with cell cycle, metastasis, and the Wnt signaling pathway. Moreover, HOXA4 overexpression in lung cancer cell lines suppressed cell proliferation, migration, and invasion. HOXA4 decreased the protein expression levels of β-catenin, Cyclin D1, c-Myc and Survivin, indicating the inhibition of Wnt signaling. HOXA4 significantly increased the protein and mRNA levels of glycogen synthase kinase-3β (GSK3β) by promoting its transcription. Furthermore, inhibition of GSK3β by LiCl abolished the suppression of cell growth, migration, and invasion mediated by HOXA4. Overexpression of HOXA4 in xenograft tumors also decreased tumor growth and Wnt signaling. Collectively, these data suggest that HOXA4 is a potential diagnostic and prognostic marker in lung cancer, and its overexpression could inhibit lung cancer progression in part by promoting GSK3β transcription.

Background Type 2 diabetes mellitus (T2DM) and metabolic-associated fatty liver disease (MAFLD) are linked to endocytic clearance dysfunction in liver sinusoidal endothelial cells (LSECs), which accelerates their synergistic progression. Long noncoding RNA TUG1 (lncRNA TUG1) bridges these two diseases, but its mechanism in alleviating high glucose-induced endocytic impairment in human LSECs (HLSECs) remains unclear. Methods HLSECs were cultured under standard conditions. A lentiviral lncRNA TUG1 overexpression vector (LV-lncRNA TUG1) was generated via genetic recombination and transduced into HLSECs. Six experimental groups were established: negative control (NC), high glucose (HG), HG + LV-lncRNA TUG1, HG + empty vector control (LV-CON), HG + LV-lncRNA TUG1 + XAV939, HG + LV-CON + XAV939. Quantitative real-time polymerase chain reaction (qRT-PCR) detected lncRNA TUG1 expression levels. β-Catenin and other relevant molecules were assayed by qRT-PCR and Western blot. Immunofluorescence staining detected β-catenin localization to assess Wnt/β-catenin pathway activation. Dil-labeled low-density lipoprotein (Dil-LDL) and fluorescence microscopy evaluated cellular LDL uptake. We further explored TUG1’s regulatory effects on downstream molecules and mechanisms under high glucose. Results High glucose downregulates lncRNA TUG1 expression in HLSECs, which in turn induces endocytic clearance dysfunction—characterized by elevated CAV-1 expression, reduced PLVAP levels, and impaired DiI-LDL endocytic activity—and concurrently activates the Wnt/β-catenin pathway (enhanced β-catenin phosphorylation and nuclear translocation, as well as upregulated Cyclin D1 expression). TUG1 overexpression significantly attenuates these pathological changes, while the Wnt/β-catenin pathway inhibitor XAV939 further potentiates TUG1’s protective effect. Discussion This study identifies a novel mechanism by which high glucose-induced TUG1 downregulation activates the Wnt/β-catenin pathway, contributing to HLSEC endocytic impairment. TUG1 overexpression mitigates these pathological processes, with XAV939 enhancing its protective role, providing new insights into MAFLD’s mechanistic basis. However, the study is limited to in vitro experiments, requiring in vivo validation to confirm TUG1’s therapeutic potential. Conclusions LncRNA TUG1 attenuates high glucose-induced endocytic clearance dysfunction in HLSECs, potentially via regulating the Wnt/β-catenin pathway. As a key regulatory target for HLSEC endocytic function, TUG1 offers novel perspectives for understanding MAFLD’s pathogenesis and developing targeted therapies.

To evaluate the effectiveness of Spot photoscreener and SW800 vision screener in detecting amblyopia risk factors in Chinese children between 4 and 6 years of age. One hundred and thirteen children (226 eyes) underwent complete ophthalmologic examination, cycloplegic retinoscopy refraction, prism cover tests and photoscreen using both Spot (v2.1.4) and SW800 (v1.0.1.0) photoscreeners. The agreement of results obtained from photoscreener and retinoscopy was evaluated by paired t-test as well as Pearson correlation test. The sensitivity and specificity of detecting amblyopia risk factors were calculated based on the American Association of Pediatric Ophthalmology and Strabismus 2013 guidelines. The overall effectiveness of detecting amblyopia risk factors by using either photoscreener was analysed by receiver operating characteristic (ROC) curves. A strong linear agreement was observed between Spot and retinoscopy (p<0.01) in aspects of spherical equivalent (SE, Pearson's r=0.95), dioptre sphere (DS, r=0.97), dioptre cylinder (DC, r=0.84) and horizontal deviation (Hdev, r=0.91), with overall -0.17 D myopic shift of SE. Significant correlation was also shown between SW800 and retinoscopy (p<0.01) in aspects of SE (r=0.90), DS (r=0.93), DC (r=0.82) and Hdev (r=0.80), with overall -0.12 D myopic shift of SE. The overall sensitivity and specificity in detecting amblyopia risk factors were 94.0% and 80.0% for Spot and 88.8% and 81.1% for SW800. The measurements of Spot and SW800 photoscreener showed a strong agreement with cycloplegic retinoscopy refraction and prism cover tests. The performance of both screeners in detecting individual amblyopia risk factors is satisfactory. ROC analysis indicates that the Spot and SW800 performed very similarly in detecting amblyopia risk factors.

The spread of SARS-CoV-2 in Beijing before May, 2020 resulted from transmission following both domestic and global importation of cases. Here we present genomic surveillance data on 102 imported cases, which account for 17.2% of the total cases in Beijing. Our data suggest that all of the cases in Beijing can be broadly classified into one of three groups: Wuhan exposure, local transmission and overseas imports. We classify all sequenced genomes into seven clusters based on representative high-frequency single nucleotide polymorphisms (SNPs). Genomic comparisons reveal higher genomic diversity in the imported group compared to both the Wuhan exposure and local transmission groups, indicating continuous genomic evolution during global transmission. The imported group show region-specific SNPs, while the intra-host single nucleotide variations present as random features, and show no significant differences among groups. Epidemiological data suggest that detection of cases at immigration with mandatory quarantine may be an effective way to prevent recurring outbreaks triggered by imported cases. Notably, we also identify a set of novel indels. Our data imply that SARS-CoV-2 genomes may have high mutational tolerance. In this study, Chen and colleagues present genomic sequences of 102 SARS-CoV-2 isolates collected in Beijing. They look closely at genomic variation between isolates that arose as a result of domestic and global transmission. Their data suggest that SARS-CoV-2 genomes have a high mutational tolerance, which may have potential implications for the development of vaccines.

To evaluate the therapeutic efficacy and safety of 25-gauge (25G) 10,000 cpm (10K) beveled-tip microincision vitrectomy (MIVS) versus 25-gauge (25G) flat-tip MIVS in managing proliferative diabetic retinopathy (PDR). This retrospective study involved 60 eyes with proliferative diabetic retinopathy (PDR) from 60 patients, all requiring epiretinal membrane removal. The patients were assigned to either the 25G 10K cpm beveled-tip MIVS group or the 25G flat-tip MIVS group. Surgical outcomes, including membrane removal efficiency, vitrectomy probe (VP) and microforceps exchanges, total procedure duration, vitrectomy time, and intraoperative complications, were documented. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), and postoperative complications were assessed during a 6-month follow-up period. Fifty-eight eyes (from 58 patients) completed follow-up, including 30 eyes in the 25G 10K cpm beveled-tip group and 28 eyes in the 25G flat-tip group. During surgery, the 25G 10k cpm beveled-tip group demonstrated more effective membrane cutting (  = 0.001) and required fewer exchanges between the vitrectomy probe and microforceps (  = 0.001). The total surgery time and vitrectomy time were both reduced in this group (  = 0.001 and  = 0.001, respectively). Additionally, fewer intraoperative hemostasis maneuvers were needed in the 25G 10K cpm beveled-tip group. All follow-up outcomes indicated no significant differences between the two groups. In the surgical treatment of PDR, the 25G 10K cpm beveled-tip MIVS group showed no statistically significant difference compared to conventional 25G flat-tip MIVS in terms of visual acuity improvement and postoperative intraocular pressure. However, the former demonstrated advantages such as reduced surgical time, decreased intraoperative use of electrocoagulation, and fewer instrument exchanges within the eye, providing robust evidence for its efficacy in PDR surgical management.

Activation-induced deaminase (AID) mediates the somatic hypermutation (SHM) of Ig variable (V) regions that is required for the affinity maturation of the antibody response. An intensive analysis of a published database of somatic hypermutations that arose in theIGHV3-23*01human V region expressed in vivo by human memory B cells revealed that the focus of mutations in complementary determining region (CDR)1 and CDR2 coincided with a combination of overlapping AGCT hotspots, the absence of AID cold spots, and an abundance of polymerase eta hotspots. If the overlapping hotspots in the CDR1 or CDR2 did not undergo mutation, the frequency of mutations throughout the V region was reduced. To model this result, we examined the mutation of the humanIGHV3-23*01biochemically and in the endogenous heavy chain locus of Ramos B cells. Deep sequencing revealed thatIGHV3-23*01in Ramos cells accumulates AID-induced mutations primarily in the AGCT in CDR2, which was also the most frequent site of mutation in vivo. Replacing the overlapping hotspots in CDR1 and CDR2 with neutral or cold motifs resulted in a reduction in mutations within the modified motifs and, to some degree, throughout the V region. In addition, some of the overlapping hotspots in the CDRs were at sites in which replacement mutations could change the structure of the CDR loops. Our analysis suggests that the local sequence environment of the V region, and especially of the CDR1 and CDR2, is highly evolved to recruit mutations to key residues in the CDRs of the IgV region.

Rice is one of the most-consumed foods worldwide. However, the productivity and quality of rice grains are severely constrained by pathogenic microbes. Over the last few decades, proteomics tools have been applied to investigate the protein level changes during rice–microbe interactions, leading to the identification of several proteins involved in disease resistance. Plants have developed a multi-layered immune system to suppress the invasion and infection of pathogens. Therefore, targeting the proteins and pathways associated with the host’s innate immune response is an efficient strategy for developing stress-resistant crops. In this review, we discuss the progress made thus far with respect to rice–microbe interactions from side views of the proteome. Genetic evidence associated with pathogen-resistance-related proteins is also presented, and challenges and future perspectives are highlighted in order to understand the complexity of rice–microbe interactions and to develop disease-resistant crops in the future.