Sodium Houttuyniae attenuates ferroptosis by regulating TRAF6-c-Myc signaling pathways in lipopolysaccharide-induced acute lung injury (ALI).

The impact of Sodium Houttuyniae (SH) on lipopolysaccharide (LPS)-induced ALI has been investigated extensively. However, it remains ambiguous whether ferroptosis participates in this process. This study aimed to find out the impacts and probable mechanisms of SH on LPS-induced ferroptosis. A rat ALI model and type II alveolar epithelial (ATII) cell injury model were treated with LPS. Enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (HE) staining, and Giemsa staining were executed to ascertain the effects of SH on LPS-induced ALI. Moreover, Transmission electron microscopy, Cell Counting Kit-8 (CCK8), ferrous iron colorimetric assay kit, Immunohistochemistry, Immunofluorescence, Reactive oxygen species assay kit, western blotting (Wb), and qRT-PCR examined the impacts of SH on LPS-induced ferroptosis and ferroptosis-related pathways. Theresults found that by using SH treatment, there was a remarkable attenuation of ALI by suppressing LPS-induced ferroptosis. Ferroptosis was demonstrated by a decline in the levels of glutathione peroxidase 4 (GPX4), FTH1, and glutathione (GSH) and a surge in the accumulation of malondialdehyde (MDA), reactive oxygen species (ROS), NOX1, NCOA4, and Fe2+, and disruption of mitochondrial structure, which were reversed by SH treatment. SH suppressed ferroptosis by regulating TRAF6-c-Myc in ALI rats and rat ATII cells. The results suggested that SH treatment attenuated LPS-induced ALI by repressing ferroptosis, and the mode of action can be linked to regulating the TRAF6-c-Myc signaling pathway in vivo and in vitro.

Monosome Stalls the Translation Process Mediated by IGF2BP in Arcuate Nucleus for Puberty Onset Delay.

Puberty onset through hypothalamic-pituitary-gonad (HPG) axis as an important reproductive event in postnatal development is initiated from hypothalamic arcuate nucleus (ARC). The growing evidence indicates that translational control also plays an essential role in the final expression of gonadotropin genes. To investigate the role of protein translation and behavior of ribosomes in pubertal onset, the global profiles of transcriptome, single ribosome (monosome), polysome, and tandem mass tag proteome were comprehensively investigated in rat hypothalamic ARCs of different pubertal stages using RNA sequencing, polyribo sequencing, and mass spectrum. Transcriptome-wide enrichments of N6-methyladenosine and IGF2BP2 were investigated using meRIP and RIP sequencing. Monosome was robustly enriched on a large proportion of mRNA in early puberty rats (postnatal day (PND)-25) compared to late puberty (PND-35 and PND-45). Monosome-enriched mRNAs, including HPG axis-related genes, had a large number of upstream ORFs (uORF, < 100 nt) and displayed translational repression in early puberty. Furthermore, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) could particularly interact with and facilitate monosome to bind with mRNA in early puberty. Finally, ectopic over-expression of IGF2BP2 in hypothalamic ARC via lateral ventricle injection in vivo could recruit monosome to aggregate on mRNA and delay puberty onset. We uncovered a novel regulatory mechanism of IGF2BP2 and monosome for translational control in puberty onset, which shed light on the neuroendocrine regulatory network involved in HPG axis activation.

Structure and inhibition of SARS-CoV-2 spike refolding in membranes.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the receptor angiotensin converting enzyme 2 (ACE2) and drives virus-host membrane fusion through refolding of its S2 domain. Whereas the S1 domain contains high sequence variability, the S2 domain is conserved and is a promising pan-betacoronavirus vaccine target. We applied cryo-electron tomography to capture intermediates of S2 refolding and understand inhibition by antibodies to the S2 stem-helix. Subtomogram averaging revealed ACE2 dimers cross-linking spikes before transitioning into S2 intermediates, which were captured at various stages of refolding. Pan-betacoronavirus neutralizing antibodies targeting the S2 stem-helix bound to and inhibited refolding of spike prehairpin intermediates. Combined with molecular dynamics simulations, these structures elucidate the process of SARS-CoV-2 entry and reveal how pan-betacoronavirus S2-targeting antibodies neutralize infectivity by arresting prehairpin intermediates.

Clinical Value of Serum Secretoneurin Levels in Prediction of Delayed Cerebral Ischemia and Prognostic Analysis of Aneurysmal Subarachnoid Hemorrhage: A Prospective Cohort Study.

Background: Secretoneurin is a neuropeptide with several neuroprotective properties. Here, we discuss the importance of serum secretoneurin in assessing severity and predicting delayed cerebral ischemia (DCI) and functional outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Methods: A prospective cohort study of 167 patients with aSAH and 100 controls was performed to determine serum secretoneurin levels. Severity was reflected by the Hunt-Hess and modified Fisher scores. Prognostic parameters included DCI and poor 6-month prognosis (extended Glasgow outcome scale scores of 1-4). Univariate analysis followed by multivariate analysis was performed to determine the correlation between severity and prognosis. Results: Compared to controls, patients exhibited a marked elevation in serum secretoneurin levels. Serum secretoneurin levels, which were independently correlated with Hunt-Hess scores and modified Fisher scores, independently predicted DCI and bad 6-month prognosis. Serum secretoneurin levels, which were linearly related to the risk of DCI and poor prognosis under a restricted cubic spline, effectively distinguished the risks under the receiver operating characteristic (ROC) curve. Subgroup analysis for prognosis or DCI prediction revealed no substantial interactions between serum secretoneurin levels and other variables, such as age, sex, hypertension, diabetes, alcohol consumption, and cigarette consumption. In addition, the prognosis model, in which serum secretoneurin, Hunt-Hess scale, and modified Fisher scale were merged, was graphically represented by a nomogram and performed well under the calibration, decision, and ROC curves. Conclusion: Serum secretoneurin levels significantly increased after aSAH, which was intimately correlated with disease severity and independently associated with DCI and worse outcomes, indicating that serum secretoneurin may be a potential prognostic biomarker of aSAH.

Generation of B7-H3 isoform regulated by ANXA2/NSUN2/YBX1 axis in human glioma.

In recent years, in the development of emerging immunotherapy, B7-H3 is also termed as CD276 and has become a novel chimeric antigen receptor (CAR)-T target against glioma and other tumours, and aroused extensive attention. However, B7-H3 has three isoforms (2, 3 and 4Ig) with the controversial expression and elusive function in tumour especially glioma. The current study mainly focuses on the regulatory factors and related mechanisms of generation of different B7-H3 isoforms. First, we have determined that 2Ig is dominant in glioma with high malignancy, and 4Ig is widely expressed, whereas 3Ig shows negative expression in all glioma. Next, we have further found that RNA binding protein annexin A2 (ANXA2) is essential for B7-H3 isoform maintenance, but fail to determine the choice of 4Ig or 2Ig. RNA methyltransferase NOP2/Sun RNA methyltransferase 2 (NSUN2) and 5-methylcytosine reader Y-box binding protein 1 (YBX1) facilitate the production of 2Ig. Our findings have uncovered a series of factors (ANXA2/NSUN2/YBX1) that can determine the alternative generation of different isoforms of B7-H3 in glioma. Our result aims to help peers gain a clearer understanding of the expression and regulatory mechanisms of B7H3 in tumour patients, and to provide better strategies for designing B7H3 as a target in immunotherapy.

All-RNA-mediated targeted gene integration in mammalian cells with rationally engineered R2 retrotransposons.

All-RNA-mediated targeted gene integration methods, rendering reduced immunogenicity, effective deliverability with non-viral vehicles, and a low risk of random mutagenesis, are urgently needed for next-generation gene addition technologies. Naturally occurring R2 retrotransposons hold promise in this context due to their site-specific integration profile. Here, we systematically analyzed the biodiversity of R2 elements and screened several R2 orthologs capable of full-length gene insertion in mammalian cells. Robust R2 system gene integration efficiency was attained using combined donor RNA and protein engineering. Importantly, the all-RNA-delivered engineered R2 system showed effective integration activity, with efficiency over 60% in mouse embryos. Unbiased high-throughput sequencing demonstrated that the engineered R2 system exhibited high on-target integration specificity (99%). In conclusion, our study provides engineered R2 tools for applications based on hit-and-run targeted DNA integration and insights for further optimization of retrotransposon systems.

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

BACKGROUND: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03849768.

Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. METHODS: This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. FINDINGS: Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. INTERPRETATION: Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. FUNDING: Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

Accumulation and ecological risk assessment of diazinon in surface sediments of Baiyangdian lake and its potential impact on probiotics and pathogens.

Diazinon is an organophosphorus pesticide widely used in agriculture and household pest control, and its use also poses several environmental and health hazards. In this study, we investigated the spatial and temporal distribution of diazinon in Baiyangdian, evaluated its potential ecological risk and toxicity to aquatic organisms based on RQ (Risk quotient) and TU (Toxic unit) analysis, and assessed the potential effects of diazinon accumulation on probiotics and pathogens based on statistical analysis of high-throughput sequencing data. The results showed that diazinon in Baiyangdian posed a low to moderate chronic risk to sediment-dwelling organisms and a low toxicity effect on aquatic invertebrates, which was mainly concentrated in October and human-intensive areas. Meanwhile, increases in sediment electrical conductivity (EC), amorphous iron oxides content and phenol oxidase activity favored diazinon accumulation in sediments, whereas the opposite was the case for sediment organic carbon, ß-1,4-glucosidase, phosphatase, catalase and pH, suggesting that environmental indicators play a key role in the behavior and distribution of diazinon. In addition, diazinon in heavily contaminated areas seem to inhibit the rare probiotics (Bifidobacterium adolescentis and Serratia sp.), while promoted dominant pathogens (e.g., Burkholderia cenocepacia), which can lead to increased disease risk to humans and ecosystems, disruption of ecological balance and potential health problems. However, probiotic Streptomyces xiamenensis resist to diazinon would be a potential degrader for diazinon remove. In conclusion, this study unveiled the effects of diazinon pollution on wetland ecosystems, emphasizing ecological impacts and potential health concerns. In addition, the discovery of diazinon resistant probiotics provided new insights into wetland ecological restoration.

A Prospective Longitudinal Cohort Study of Serum Stanniocalcin-1 as a Potential Prognostic Biomarker of Severe Traumatic Brain Injury.

Background: Stanniocalcin-1 (STC1) may harbor anti-inflammatory and anti-oxidative properties, thereby exerting neuroprotective effects. This study was done with the intent to determine the role of serum STC1 in severity assessment and prognosis prediction of severe traumatic brain injury (sTBI). Methods: In this prospective longitudinal cohort study of 104 sTBI patients and 104 healthy individuals (controls), serum STC1 levels were quantified. Severity indicators were Glasgow Coma Scale (GCS) and Rotterdam computed tomography classification. Follow-up time was 180 days and extended Glasgow outcome scale (GOSE) score 1-4 was deemed as poor prognosis. Multivariate analyses were applied to assess severity correlations and prognosis associations. Discriminative efficiencies were estimated in terms of area under receiver operating characteristic curve (AUC). Results: Patients exhibited significantly higher serum STC1 levels than controls. Serum STC1 levels were substantially elevated in order of GCS scores from 8 to 3, Rotterdam scores from 3 to 6 and 180-day GOSE scores from 8 to 1. Also, serum STC1 levels were independently correlated with GCS scores, Rotterdam scores and 180-day GOSE scores. Serum STC1 levels were independently associated with 180-day death, overall survival and poor prognosis, as well as were efficiently predictive of death and poor prognosis. Prediction model containing GCS scores, Rotterdam scores and serum STC1 levels, as opposed to any of them, showed higher discriminative ability for the risks of death and poor prognosis. Alternatively, serum STC1 levels were linearly correlated with risk of death, overall survival and poor prognosis under restricted cubic spline. Subgroup analysis showed that serum STC1 levels non-statistically significantly interacted with age, gender, hypertension, diabetes mellitus, etc. Conclusion: A significant elevation of serum STC1 levels is highly related to severity and clinical outcome, suggesting that serum STC1 may be a potential prognostic biomarker of sTBI.

Clear cell hidradenoma of the breast with MAML2 gene rearrangement.

Clear cell hidradenoma is a rare benign tumor of the breast, its origin and pathogenesis are controversial. We have experienced a case of breast clear cell hidradenoma with mastermind like transcriptional coactivator 2 (MAML2) gene rearrangement. The patient found a painless mass with a hard texture in the left breast areola without nipple discharge. Microscopically, the tumor was cystic and solid, locally arranged in a glandular structure, covered by single cuboidal cells; it was composed of clear cells, epidermoid cells, and basaloid cells; there were no necrosis or mitotic figures. Immunohistochemical staining showed that the tumor cells positively expressed low-molecular cytokeratin 7, low-molecular cytokeratins (Cam5.2), high-molecular cytokeratin 5/6, cytokeratin 14, CD117, and p63; and did not express calponin, and smooth muscle myosin heavy chain. The cuboidal cells were positive for SOX10 but negative for p63. Additionally, periodic acid-Schiff reaction showed purple-red granules in the tumor cytoplasm, but Alcian blue staining showed no blue mucus in the cytoplasm. The split signals of MAML2 gene were detected by fluorescence in situ hybridization. Subtle histological and immunophenotypical differences may help to distinguish breast clear cell hidradenoma from common breast tumors. Furthermore, the MAML2 gene rearrangement may be a molecular genetic characteristic of breast clear cell hidradenoma.

Species Identification and Genetic Diversity Analysis of Medicinal Plants Aconitum pendulum Busch and Aconitum flavum Hand.-Mazz.

The classification system for the genus Aconitum is highly complex. It is also the subject of ongoing debate. Aconitum pendulum Busch and Aconitum flavum Hand.-Mazz. are perennial herbs of the genus Aconitum. Dried roots of these two plants are used in traditional Chinese medicine. In this study, morphological observations and ISSR molecular markers were employed to discriminate between A. flavum and A. pendulum, with the objective of gaining insights into the interspecies classification of Aconitum. The pubescence on the inflorescence of A. flavum was found to be appressed, while that on the inflorescence of A. pendulum was spread. UPGMA (unweighted pair-group method with arithmetic average) cluster analysis, PCoA (principal coordinates analysis), and Bayesian structural analysis divided the 199 individuals (99 individuals from DWM population and 100 individuals from QHL population) into two main branches, which is consistent with the observations of the morphology of pubescence on the inflorescence. These analyses indicated that A. flavum and A. pendulum are distinct species. No diagnostic bands were found between the two species. Two primer combinations (UBC808 and UBC853) were ultimately selected for species identification of A. flavum and A. pendulum. This study revealed high levels of genetic diversity in both A. flavum (He = 0.254, I = 0.395, PPB = 95.85%) and A. pendulum (He = 0.291, I = 0.445, PPB = 94.58%). We may say, therefore, that ISSR molecular markers are useful for distinguishing A. flavum and A. pendulum, and they are also suitable for revealing genetic diversity and population structure.

A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome.

ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.

Massage ameliorates lumbar disc herniation-related radicular pain in rats by suppressing TLR4/NLRP3 inflammasome signaling transduction.

BACKGROUND: Lumbar disc herniation (LDH) is a common spinal disease that can cause severe radicular pain. Massage, also known as Tuina in Chinese, has been indicated to exert an analgesic effect in patients with LDH. Nonetheless, the mechanism underlying this effect of massage on LDH remains unclarified. METHODS: Forty Sprague-Dawley rats were randomly divided into four groups. A rat LDH model was established by autologous nucleus pulpous (NP) implantation, followed by treatment with or without massage. A toll-like receptor 4 (TLR4) antagonist TAK-242 was administrated to rats for blocking TLR4. Behavioral tests were conducted to examine rat mechanical and thermal sensitivities. Western blotting was employed for determining TLR4 and NLRP3 inflammasome-associated protein levels in the spinal dorsal horn (SDH). Immunofluorescence staining was implemented for estimating the microglial marker Iba-1 expression in rat SDH tissue. RESULTS: NP implantation induced mechanical allodynia and thermal hyperalgesia in rat ipsilateral hindpaws and activated TLR4/NLRP3 inflammasome signaling transduction in the ipsilateral SDH. Massage therapy or TAK-242 administration relieved NP implantation-triggered pain behaviors in rats. Massage or TAK-242 hindered microglia activation and blocked TLR4/NLRP3 inflammasome activation in ipsilateral SDH of LDH rats. CONCLUSION: Massage ameliorates LDH-related radicular pain in rats by suppressing microglia activation and TLR4/NLRP3 inflammasome signaling transduction.

Safety and Immunogenicity of the Monovalent Omicron XBB.1.5-Adapted BNT162b2 COVID-19 Vaccine in Individuals ≥12 Years Old: A Phase 2/3 Trial.

Vaccination remains an important mitigation tool against COVID-19. We report 1-month safety and preliminary immunogenicity data from a substudy of an ongoing, open-label, phase 2/3 study of monovalent Omicron XBB.1.5-adapted BNT162b2 (single 30-µg dose). Healthy participants ≥12 years old (N = 412 (12-17 years, N = 30; 18-55 years, N = 174; >55 years, N = 208)) who previously received ≥3 doses of a US-authorized mRNA vaccine, the most recent being an Omicron BA.4/BA.5-adapted bivalent vaccine ≥150 days before study vaccination, were vaccinated. Serum 50% neutralizing titers against Omicron XBB.1.5, EG.5.1, and BA.2.86 were measured 7 days and 1 month after vaccination in a subset of ≥18-year-olds (N = 40) who were positive for SARS-CoV-2 at baseline. Seven-day immunogenicity was also evaluated in a matched group who received bivalent BA.4/BA.5-adapted BNT162b2 in a previous study (ClinicalTrials.gov Identifier: NCT05472038). There were no new safety signals; local reactions and systemic events were mostly mild to moderate in severity, adverse events were infrequent, and none led to study withdrawal. The XBB.1.5-adapted BNT162b2 induced numerically higher titers against Omicron XBB.1.5, EG.5.1, and BA.2.86 than BA.4/BA.5-adapted BNT162b2 at 7 days and robust neutralizing responses to all three sublineages at 1 month. These data support a favorable benefit-risk profile of XBB.1.5-adapted BNT162b2 30 µg. ClinicalTrials.gov Identifier: NCT05997290.

Genome-wide identification of the expansin gene family in netted melon and their transcriptional responses to fruit peel cracking.

Introduction: Fruit cracking not only affects the appearance of netted melons (Cucumis melo L. var. reticulatus Naud.) but also decreases their marketability. Methods: Herein, to comprehensively understand the role of expansin (EXP) proteins in netted melon, bioinformatics methods were employed to discover the EXP gene family in the melon genome and analyze its characteristic features. Furthermore, transcriptomics analysis was performed to determine the expression patterns of melon EXP (CmEXP) genes in crack-tolerant and crack-susceptible netted melon varieties. Discussion: Thirty-three CmEXP genes were identified. Chromosomal location analysis revealed that CmEXP gene distribution was uneven on 12 chromosomes. In addition, phylogenetic tree analysis revealed that CmEXP genes could be categorized into four subgroups, among which the EXPA subgroup had the most members. The same subgroup members shared similar protein motifs and gene structures. Thirteen duplicate events were identified in the 33 CmEXP genes. Collinearity analysis revealed that the CmEXP genes had 50, 50, and 44 orthologous genes with EXP genes in cucumber, watermelon, and Arabidopsis, respectively. However, only nine orthologous EXP genes were observed in rice. Promoter cis-acting element analysis demonstrated that numerous cis-acting elements in the upstream promoter region of CmEXP genes participate in plant growth, development, and environmental stress responses. Transcriptomics analysis revealed 14 differentially expressed genes (DEGs) in the non-cracked fruit peels between the crack-tolerant variety 'Xizhoumi 17' (N17) and the crack-susceptible variety 'Xizhoumi 25' (N25). Among the 14 genes, 11 were upregulated, whereas the remaining three were downregulated in N17. In the non-cracked (N25) and cracked (C25) fruit peels of 'Xizhoumi 25', 24 DEGs were identified, and 4 of them were upregulated, whereas the remaining 20 were downregulated in N25. In the two datasets, only CmEXPB1 exhibited consistently upregulated expression, indicating its importance in the fruit peel crack resistance of netted melon. Transcription factor prediction revealed 56 potential transcription factors that regulate CmEXPB1 expression. Results: Our study findings enrich the understanding of the CmEXP gene family and present candidate genes for the molecular breeding of fruit peel crack resistance of netted melon.

Distribution of organophosphorus pesticides and its potential connection with probiotics in sediments of a shallow freshwater lake.

Despite the serious health threats due to wide use of organophosphorus pesticides (OPPs) have been experimentally claimed to be remediated by probiotic microorganisms in various food and organism models, the interactions between OPPs and probiotics in the natural wetland ecosystem was rarely investigated. This study delves into the spatial and temporal distribution, contamination levels of OPPs in the Baiyangdian region, the diversity of probiotic communities in varying environmental contexts, and the potential connection with OPPs on these probiotics. In typical shallow lake wetland ecosystem-Baiyangdian lake in north China, eight OPPs were identified in the lake sediments, even though their detection rates were generally low. Malathion exhibited the highest average content among these pesticides (9.51 ng/g), followed by fenitrothion (6.70 ng/g). Conversely, chlorpyrifos had the lowest detection rate at only 2.14%. The region near Nanliu Zhuang (F10), significantly influenced by human activities, displayed the highest concentration of total OPPs (136.82 ng/g). A total of 145 probiotic species spanning 78 genera were identified in Baiyangdian sediments. Our analysis underscores the relations of environmental factors such as phosphatase activity, pH, and electrical conductivity (EC) with probiotic community. Notably, several high-abundance probiotics including Pseudomonas chlororaphis, Clostridium sp., Lactobacillus fermentum, and Pseudomonas putida, etc., which were reported to exhibit significant potential for the degradation of OPPs, showed strongly correlations with OPPs in the Baiyangdian lake sediments. The outcomes of this research offer valuable insights into the spatiotemporal dynamics of OPPs in natural large lake wetland and the probability of their in-situ residue bioremediation through the phosphatase pathway mediated by probiotic such as Lactic acid bacteria in soils/sediments contaminated with OPPs.