TP53 disruptive mutation predicts platinum-based chemotherapy and PD-1/PD-L1 blockade response in urothelial carcinoma.

TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co-occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild-type TP53. Significantly, patients with TP53Disruptive mutations exhibit an increased probability of responding favorably to PD-1/PD-L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53Disruptive mutations showed an enriched APOBEC- and POLE-related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon-gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD-1/PD-L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics-guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-ß (TGF-ß) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

A phase Ib/II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus anlotinib as first-line treatment in patients with advanced non-small cell lung cancer.

BACKGROUND: Cadonilimab is a bispecific antibody that simultaneously targets programmed cell death receptor-1 and cytotoxic T lymphocyte-associated antigen-4. This study aimed to assess the safety and efficacy of cadonilimab plus anlotinib for the first-line treatment of advanced non-small cell lung cancer (NSCLC) without sensitizing EGFR/ALK/ROS1 mutations. METHODS: Patients received cadonilimab 15 mg/kg and 10 mg/kg every three weeks (Q3W) plus anlotinib at doses of 10 or 12 mg once daily for two weeks on a one-week-off schedule. The primary endpoints included safety and objective response rate (ORR). RESULTS: Sixty-nine treatment-naïve patients received cadonilimab 15 mg/kg Q3W combination (n = 49) and 10 mg/kg Q3W combination (n = 20). Treatment-related adverse events (TRAEs) were reported in 48 (98.0%) and 19 (95.0%) patients, with grade ≥3 TRAEs occurring in 29 (59.2%) and five (25.0%) patients, respectively. TRAEs leading to cadonilimab discontinuation occurred in eight (16.3%) and one (5.0%) patients in the cadonilimab 15 mg/kg Q3W and 10 mg/kg Q3W dosing groups. The confirmed ORRs were 51.0% (25/49) and 60.0% (12/20) accordingly. CONCLUSIONS: Cadonilimab 10 mg/kg Q3W plus anlotinib showed manageable safety and promising efficacy as a first-line chemo-free treatment for advanced NSCLC. GOV IDENTIFIER: NCT04646330.

Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer.

BACKGROUND: Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC. METHODS: This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC. RESULTS: Among patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy. CONCLUSIONS: We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.

Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile.

BACKGROUND: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. METHODS: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. RESULTS: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. CONCLUSION: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

Consolidation chemotherapy after definitive concurrent chemoradiotherapy in patients with inoperable esophageal squamous cell carcinoma: a multicenter non-inferiority phase III randomized clinical trial.

BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. METHODS: This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. DISCUSSION: This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. TRIAL REGISTRATION: ChiCTR1800017646.

Photocatalytic Synthesis of Ammonia from Hollow Coral-Like Graphitic Carbon Nitride/FeOCl Loaded with Fe-1T MoS2 Nanosheets as Cocatalysts.

Photocatalytic ammonia synthesis (PAS) represents an emerging environmentally friendly approach to ammonia production. In this work, we employed Fe doping to modify the cocatalyst 1T MoS2, enhancing the active N2 sites on Fe-1T MoS2 by inducing defects on the surface of 1T MoS2. Afterward, Fe-1T MoS2 was loaded onto a hollow coral-like graphitic carbon nitride (CCN)/FeOCl composite. Under simulated sunlight, the efficiency of 5% Fe-1T MoS2@CCN/FeOCl (Fe-MCN/FeOCl) reached 367.62 µmol g-1 h-1, surpassing 1T MoS2@CCN(MCN) by 3.2 times, CCN by 16.9 times, and g-C3N4 by 32.5 times, where 5% means the doping amount of Fe in 1T MoS2. The good performance of Fe MCN/FeOCl should be attributed to the Fe doping in Fe-MCN/FeOCl which not only increases the separation efficiency of active sites and charge carriers, but also reduces the sample impedance significantly through the heterojunction formed between CCN and FeOCl. This work also presents a method for creating more efficient and stable photocatalysts for ammonia synthesis.

InCl3/TfOH-Mediated Convenient Synthesis of 3-Alkylideneoxindoles from 2-Oxindoles with 1,3-Diones, Ketones, or Aldehydes.

Two efficient and convenient methods for the synthesis of 3-alkylideneoxindoles are described in this paper. The InCl3/TfOH-mediated tandem Knoevenagel condensation-deacylation sequence of various 2-oxindoles with 1,3-diones or acetoacetate furnished 3-alkylideneoxindoles in satisfactory to excellent yields (up to >99% yield). Employing the reaction system, the condensation of 2-oxindoles with ketones or aldehydes also proceeded smoothly to produce 3-alkylideneoxindoles. This protocol can be amenable to scale up. The effect of acids on this condensation reaction and intermolecular competition experiments were investigated to understand the aspect of the reaction.

Identification of MYB gene family in medicinal tea tree Melaleuca alternifolia (Maiden and Betche) cheel and analysis of members regulating terpene biosynthesis.

BACKGROUND: The tea tree (Melaleuca alternifolia) is renowned for its production of tea tree oil, an essential oil primarily composed of terpenes extracted from its shoot. MYB transcription factors, which are one of the largest TF families, play a crucial role in regulating primary and secondary metabolite synthesis. However, knowledge of the MYB gene family in M. alternifolia is limited. METHODS AND RESULTS: Here, we conducted a comprehensive genome-wide analysis of MYB genes in M. alternifolia, referred to as MaMYBs, including phylogenetic relationships, structures, promoter regions, and GO annotations. Our findings classified 219 MaMYBs into four subfamilies: one 5R-MYB, four 3R-MYBs, sixty-one MYB-related, and the remaining 153 are all 2R-MYBs. Seven genes (MYB189, MYB146, MYB44, MYB29, MYB175, MYB162, and MYB160) were linked to terpenoid synthesis based on GO annotation. Phylogenetic analysis with Arabidopsis homologous MYB genes suggested that MYB193 and MYB163 may also be involved in terpenoid synthesis. Additionally, through correlation analysis of gene expression and metabolite content, we identified 42 MYB genes associated with metabolite content. CONCLUSION: The results provide valuable insights into the importance of MYB transcription factors in essential oil production in M. alternifolia. These findings lay the groundwork for a better understanding of the MYB regulatory network and the development of novel strategies to enhance essential oil synthesis in M. alternifolia.

Characterization of the prognostic, diagnostic, and immunological roles of DSCC1 and its genomic alteration and instability in human cancers.

DNA replication and sister chromatid cohesion 1 (DSCC1) exerts various functions including sister chromatid cohesion. DSCC1 overexpression plays an important role in cancer development, such as in colorectal, breast, and hepatocellular cancers. The specific role of DSCC1 in tumor progression remains largely unknown, necessitating a pan-cancer investigation to understand the potential function of DSCC1 in various cancers. In this study, we obtained data on physiological conditions, transcriptional expression, survival prognosis, genomic alteration, genomic instability, enriched pathways, immune infiltration, and immunotherapy from The Cancer Genome Atlas, The Genotype-Tissue Expression, cBioPortal, and other publicly available databases to systematically characterize the oncogenic and immunological roles of DSCC1 in 33 different cancers. We found that DSCC1 expression was upregulated at both mRNA and protein levels in various cancers. Additionally, DSCC1 expression was associated with higher tumor stage and grade in specific cancers. DSCC1 was a potential pan-cancer prognostic biomarker for its close association with patient prognosis and a diagnostic biomarker for its high predictive value in distinguishing tumor tissues from normal tissues. DSCC1 was universally amplified across different cancers and tightly associated with genomic instability. Moreover, DSCC1 had a close relationship with tumor immune cell infiltration; thus, it could be used as a potential biomarker for predicting the response and survival of patients with cancer who receive immune checkpoint blockade treatment. To sum up, our study revealed that DSCC1 is a promising target for tumor therapy.

A Data-Mining Interpretation Method of Pavement Dynamic Response Signal by Combining DBSCAN and Findpeaks Function.

During a heavy traffic flow featuring a substantial number of vehicles, the data reflecting the strain response of asphalt pavement under the vehicle load exhibit notable fluctuations with abnormal values, which can be attributed to the complex operating environment. Thus, there is a need to create a real-time anomalous-data diagnosis system which could effectively extract dynamic strain features, such as peak values and peak separation from the large amount of data. This paper presents a dynamic response signal data analysis method that utilizes the DBSCAN clustering algorithm and the findpeaks function. This method is designed to analyze data collected by sensors installed within the pavement. The first step involves denoising the data using low-pass filters and other techniques. Subsequently, the DBSCAN algorithm, which has been improved using the K-Dist method, is used to diagnose abnormal data after denoising. The refined findpeaks function is further implemented to carry out the adaptive feature extraction of the denoised data which is free from anomalies. The enhanced DBSCAN algorithm is tested via simulation and illustrates its effectiveness while detecting abnormal data in the road dynamic response signal. The findpeaks function enables the relatively accurate identification of peak values, thus leading to the identification of strain signal peaks of complex multi-axle lorries. This study is valuable for efficient data processing and effective information utilization in pavement monitoring.

Smart roofs featuring predictive control: An upgrade for mitigating precipitation extreme-induced pluvial floods.

In the face of escalating urban pluvial floods exacerbated by climate change, conventional roof systems fall short of effectively managing precipitation extremes. This paper introduces a smart predictive solution: the Smart Internal Drainage Roof (SIDR) system, which leverages forecasted data to enhance the mitigation of pluvial floods in Central Business District (CBD) areas. Unlike traditional approaches, SIDRs utilize a synergistic combination of Rule-based Control (RBC) and Model Predictive Control (MPC) algorithms, tailored to optimize the operational efficiency of both grey and green roofs. Within the examined 1.3 km2 area in Beijing, China, SIDRs, covering 11% of the site, decreased total flooded areas by 30%-50% and eliminated 60%-100% of high-risk zones during three actual events. Moreover, SIDRs streamlined outflow processes without extending discharge time and reduced flood duration at a high-risk underpass by more than half. The SIDR's distinct features, including a high control resolution of 5 min, integration with existing waterproofs, and advanced 2D dynamic runoff visualization, position it as a scalable and cost-efficient upgrade in urban flood resilience strategies.

Cavity-enhanced and temporally multiplexed atom-photon entanglement interface.

Practical realization of quantum repeaters requires quantum memories with high retrieval efficiency, multi-mode storage capacities, and long lifetimes. Here, we report a high-retrieval-efficiency and temporally multiplexed atom-photon entanglement source. A train of 12 write pulses in time is applied to a cold atomic ensemble along different directions, which generates temporally multiplexed pairs of Stokes photons and spin waves via Duan-Lukin-Cirac-Zoller processes. The two arms of a polarization interferometer are used to encode photonic qubits of 12 Stokes temporal modes. The multiplexed spin-wave qubits, each of which is entangled with one Stokes qubit, are stored in a "clock" coherence. A ring cavity that resonates simultaneously with the two arms of the interferometer is used to enhance retrieval from the spin-wave qubits, with the intrinsic retrieval efficiency reaching 70.4%. The multiplexed source gives rise to a ∼12.1-fold increase in atom-photon entanglement-generation probability compared to the single-mode source. The measured Bell parameter for the multiplexed atom-photon entanglement is 2.21(2), along with a memory lifetime of up to ∼125 µs.

A platform for qualitative and quantitative characterization of α-Gal and NeuGc at the oligosaccharide level.

Glycosylation modification serves as a pivotal quality attribute in glycoprotein-based therapeutics, emphasizing its role in drug safety and efficacy. Prior studies have underscored the potential immunogenic risks posed by the presence of galactose-α-1,3-galactose (α-Gal) and N-glycolylneuraminic acid (NeuGc) in glycoprotein formulations. This accentuates the imperative for developing robust qualitative and quantitative analytical methods to monitor these immunogenic epitopes, thereby ensuring drug safety. In the present investigation, α-Gal and NeuGc were accurately quantified using UPLC-FLR-MS/MS at the oligosaccharide level. Remarkably, α-Gal could be identified when the ion intensity ratio or the mass-to-charge ratio (m/z) of 528.19 to 366.14 exceeded 1. Concurrently, NeuGc and N-acetylneuraminic acid (NeuAc) could be unambiguously identified through their respective fragment ions at m/z 673.23 and m/z 657.23. Furthermore, relative quantification of α-Gal and NeuGc was achieved using fluorescence signals. This study introduces a sensitive and reliable analytical approach for the qualitative and quantitative assessment of α-Gal and NeuGc in glycoprotein pharmaceuticals. The methodology offers significant potential for application in process control and optimization of glycoprotein production, aimed at minimizing immunogenicity and enhancing product quality.

Universal protocol and standard-spiking strategy for profiling of host cell proteins in therapeutic growth hormone.

Liquid chromatography coupled to mass spectrometry (LC-MS) is widely used for host cell proteins (HCP) identification in antibody drug development because of its sensitivity, selectivity, and adaptability. However, LC-MS based identification of HCP in biotherapeutics produced from the prokaryotic Escherichia coli-derived growth hormone (GH) has rarely been reported. Herein, we developed a universal and powerful workflow by combining optimized sample preparation with one-dimension ultra-high performance LC-MS based shotgun proteomics to support HCP profiling in GH samples from downstream pools and the final product, which would be beneficial to direct the purification process development and compare the difference of impurity of different products for guiding the development of the biosimilar. A standard-spiking strategy was also developed to increase the depth of HCP identification. Spiking with standards enables additional identification of HCP species, which is promising for trace-level HCP analysis. Our universal and standard-spiking protocols would open an avenue for profiling HCP in biotherapeutics derived from prokaryotic host cells.

Study on the Bouncing Behaviors of a Non-Newtonian Fluid Droplet Impacting on a Hydrophobic Surface.

The control of a droplet bouncing on a substrate is of great importance not only in academic research but also in practical applications. In this work, we focus on a particular type of non-Newtonian fluid known as shear-thinning fluid. The rebound behaviors of shear-thinning fluid droplets impinging on a hydrophobic surface (equilibrium contact angle θeq ≈ 108°and contact angle hysteresis Δθ ≈ 20°) have been studied experimentally and numerically. The impact processes of Newtonian fluid droplets with various viscosities and non-Newtonian fluid droplets with dilute xanthan gum solutions were recorded by a high-speed imaging system under a range of Weber numbers (We) from 12 to 208. A numerical model of the droplet impact on the solid substrate was also constructed using a finite element scheme with the phase field method (PFM). The experimental results show that unlike the Newtonian fluid droplets where either partial rebound or deposition occurs, complete rebound behavior was observed for non-Newtonian fluid droplets under a certain range of We. Moreover, the minimum value of We required for complete rebound increases with xanthan concentration. The numerical simulations indicate that the shear-thinning property significantly affects the rebound behavior of the droplets. As the amount of xanthan increases, the high shear rate regions shift to the bottom of the droplet and the receding of the contact line accelerates. Once the high shear rate region appears only near the contact line, the droplet tends to fully rebound even on a hydrophobic surface. Through the impact maps of various droplets, we found that the maximum dimensionless height Hmax* of the droplet increases almost linearly with We as Hmax* ∼ αWe. In addition, a critical value Hmax, c* for the distinction between deposition and rebound for droplets on the hydrophobic surface has been theoretically derived. The prediction of the model shows good consistency with the experimental results.

Cu-catalyzed convenient synthesis of 2-trifluoromethyl benzimidazoles via cyclization of o-phenylenediamines with hexafluoroacetylacetone.

An efficient and convenient method for the synthesis of 2-trifluoromethyl benzimidazoles is described in this paper. The cyclization reaction of various o-phenylenediamines with hexafluoroacetylacetone proceeded smoothly in the presence of Cu2O as the catalyst to produce 2-trifluoromethyl benzimidazoles in satisfactory to excellent yields (up to >99% yield). The CF3 source, hexafluoroacetylacetone, acted not only as cyclization partner, but also acted as a ligand for the Cu catalyst. Various synthetically useful functional groups, such as halogen atoms, cyano, and methoxycarbonyl groups, remained intact during the cyclization reactions. The reaction mechanism was thoroughly investigated and was determined to involve a seven-membered cyclic diimine intermediate.

Stable Isotope Ratios Trace the Rice Uptake of Cadmium from Atmospheric Deposition via Leaves and Roots.

Cadmium (Cd) stable isotopes provide a novel technique to investigate the fate of Cd in the environment, but challenges exist for tracing the sources in the plants. We performed individual rice leaf and root exposures to dry and wet deposition using customized open-top chambers (OTCs) in the greenhouse and in the field next to a smelter, respectively. The field experiment also included a control without Cd deposition and a "full" treatment. The exposure experiments and isotope signatures showed that leaves can directly take up atmospheric Cd and then translocate within rice plants to other tissues, contributing 52-70% of Cd in grains, which exceeded the contribution (30-48%) by root exposure. The Cd isotopes in leaves, nodes, internodes, and grains demonstrate that roots preferentially take up Cd from wet deposition, but leaves favor uptake of Cd from dry deposition. The Cd uptake by leaves is redistributed via nodes, allowing for upward transport to the grains but preventing downward transport to the roots. Leaves favor uptake of heavy isotopes from atmospheric deposition (ΔCd114/110Leaf-Dust: 0.10 ± 0.02‰) but retain light isotopes and transport heavy isotopes to the nodes and further to grains. These findings highlight the contribution of atmospheric deposition to rice and Cd isotopes as a useful tracer for quantifying sources in plants when different isotopic compositions are in sources.

Draft genome of the medicinal tea tree Melaleuca alternifolia.

BACKGROUND: Melaleuca alternifolia is a commercially important medicinal tea tree native to Australia. Tea tree oil, the essential oil distilled from its branches and leaves, has broad-spectrum germicidal activity and is highly valued in the pharmaceutical and cosmetic industries. Thus, the study of genome, which can provide reference for the investigation of genes involved in terpinen-4-ol biosynthesis, is quite crucial for improving the productivity of Tea tree oil. METHODS AND RESULTS: In our study, the next-generation sequencing was used to investigate the whole genome of Melaleuca alternifolia. About 114 Gb high quality sequence data were obtained and assembled into 1,838,159 scafolds with an N50 length of 1021 bp. The assembled genome size is about 595 Mb, twice of that predicted by flow cytometer (300 Mb) and k-mer analysis (345 Mb). Benchmarking Universal Single-Copy Orthologs analyses indicated that only 11.3% of the conserved single-copy genes were miss. Repetitive regions cover over 40.43% of the genome. A total of 44,369 protein-coding genes were predicted and annotated against Nr, Swissprot, Refseq, COG, KOG, and KEGG database. Among these genes, 32,909 and 16,241 genes were functionally annotated in Nr and KEGG, respectively. Moreover, 29,411 and 14,435 genes were functionally annotated in COG and KOG. Additionally, 457,661 simple sequence repeats and 1109 transcription factors (TFs) form 67 TF families were identified in the assembled genome. CONCLUSION: Our findings provide a draft genome sequencing of M. alternifolia which can act as a reference for the deep sequencing strategies, and are useful for future functional and comparative genomics analyses.

Relationship between food-derived antioxidant vitamin intake and breast cancer risk: a mendelian randomized study.

BACKGROUND: In previous observational studies, food-derived antioxidant vitamins have been suggested to be associated with breast cancer. However, the findings were inconsistent and the causal relationship could not be clearly elucidated. To confirm the potential causal relationship between food-derived antioxidants (retinol, carotene, vitamin C and vitamin E) and the risk of breast cancer, we conducted a two-sample Mendelian randomization (MR) study. METHODS: The instrumental variables (IVs) as proxies of genetic liability to food-derived antioxidant vitamins were obtained from the UK Biobank Database. We extracted breast cancer data (122,977 cases and 105,974 controls) from the Breast Cancer Consortium (BCAC). In addition, we studied estrogen expression status categorically, including estrogen receptor positive (ER+) breast cancer (69,501 cases and 105,974 controls) and versus estrogen receptor (ER-) negative breast cancer (21,468 cases and 105,974 controls). We performed two-sample Mendelian randomization study, and inverse variance-weighted (IVW) test was regarded as main analysis. Sensitivity analyses were further conducted to assess heterogeneity and horizontal pleiotropy. RESULTS: The results of IVW showed that among the four food-derived antioxidants, only vitamin E had protective effect on the risk of overall breast cancer (OR = 0.837, 95% CI 0.757-0.926, P = 0.001) and ER+ breast cancer (OR = 0.823, 95% CI 0.693-0.977, P = 0.026). However, we found no association between food-derived vitamin E and ER- breast cancer. CONCLUSIONS: Our study suggested food-derived vitamin E can decrease the risk of breast cancer overall and ER+ breast cancer, and the robustness of our results was confirmed by sensitivity analyses.