Cereals are a major dietary source of the toxic metal cadmium (Cd). Reducing Cd accumulation in cereal crops such as wheat (Triticum aestivum) is important for food safety and human health. In this ...study, we show that three diverse cultivars of wheat had a high Cd translocation from roots to shoots, similar to a rice (Oryza sativa) cultivar possessing a nonfunctional tonoplast Cd transporter OsHMA3. We investigated the function of TaHMA3 genes in wheat. Three TaHMA3 genes were identified in wheat, all of which encode tonoplast-localized proteins. However, heterologous expression of TaHMA3 genes in yeast showed no transport activities for Cd, which likely explains the low Cd sequestration in wheat roots and subsequently the high Cd translocation to wheat shoots. To increase Cd sequestration in wheat roots, we overexpressed a rice functional OsHMA3 gene in wheat driven by a strong constitutive Ubiquitin promoter. Overexpression of the OsHMA3 gene decreased root-to-shoot Cd translocation in wheat by nearly 10-fold and Cd accumulation in wheat grain by 96%. The results suggest that high Cd translocation is a common trait in wheat caused by a loss of the Cd transport function of TaHMA3 proteins. Transgenic wheat overexpressing a functional OsHMA3 gene offers a highly effective solution to decrease Cd accumulation in wheat grain.
Considerable proportions of rice grains produced in some areas in southern China contain high concentrations of cadmium (Cd), leading to unsafe levels of dietary Cd intake. Cultivars of Indica rice, ...widely grown in southern China, are particularly prone to high Cd accumulation in the grain. Effective methods are needed to decrease Cd accumulation in Indica rice.
OsHMA3, encoding a tonoplast Cd transporter, was overexpressed in an elite Indica rice cultivar (Zhongjiazao 17) driven by CaMV 35S promoter. The effects on Cd translocation, accumulation and tolerance, as well as on the agronomic traits and micronutrient concentrations were evaluated.
OsHMA3 overexpression markedly decreased Cd translocation from roots to shoots and increased Cd tolerance. OsHMA3 overexpression decreased Cd concentrations in brown rice by 94–98%, to levels just above the detection limit, when rice plants were grown in two Cd-contaminated paddy soils. OsHMA3 overexpression generally had no significant effect on grain yield and the concentrations of the essential micronutrients including zinc, iron, copper and manganese in field trials.
Overexpression of OsHMA3 is a highly effective method to reduce Cd accumulation in Indica rice, producing rice grains that were almost Cd free with little effect on grain yield or essential micronutrient concentrations.
•High Cd concentrations of Cd are found in some rice produced in southern China.•Transgenic rice overexpressing OsHMA3 gene was developed in an elite Indica cultivar.•Overexpressing OsHMA3 decreased grain Cd concentration by 94–98%.•Overexpressing OsHMA3 had little effect on grain yield and essential micronutrients.
With the in-depth exploration on cancer therapeutic nanovaccines, increasing evidence shows that the poor delivery of nanovaccines to lymphoid organs has become the culprit limiting the rapid ...induction of anti-tumor immune response. Unlike the conventional prophylactic vaccines that mainly form a depot at the injection site to gradually trigger durable immune response, the rapid proliferation of tumors requires an efficient delivery of nanovaccines to lymphoid organs for rapid induction of anti-tumor immunity. Optimization of the physicochemical properties of nanovaccine (e.g., size, shape, charge, colloidal stability and surface ligands) is an effective strategy to enhance their accumulation in lymphoid organs, and nanovaccines with dynamic structures are also designed for precise targeted delivery of lymphoid organs or their subregions. The recent progress of these nanovaccine delivery strategies is highlighted in this review, and the challenges and future direction are also discussed.
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Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. The primary treatment for CRC is surgical resection, along with chemotherapy in more advanced ...or inoperable cases. There is a growing interest to complement both curative and palliative treatment with immunotherapies such as the programmed cell death-1 (PD-1) and PD-ligand 1 (PDL1) checkpoint inhibitors and transforming growth factor (TGF) β inhibitors. However, the clinical outcomes of current immunotherapeutic strategies are limited by tumor heterogeneity and drug resistance. Nanomedicine-based photothermal therapy (PTT) has shown encouraging results for solid tumor ablation. Herein, we designed and synthesized gold nanocages functionalized with primary macrophage membrane and surface anti-PDL1 antibody, and loaded with a TGFβ inhibitor, galunisertib. The GNC-Gal@CMaP nanocomposites achieved low-temperature PTT and immunogenic cell death, which subsequently enhanced the anti-tumor efficacy of anti-PDL1 antibody and galunisertib via activation of antigen-presenting cells that primed tumor-specific effector T cells. This study provides experimental proof for a combination of immunotherapy and PTT against CRC.
The combination of photothermal therapy (PTT) with immunotherapy can achieve an inherently synergistic anti-tumor effect. Here we integrated low-temperature PTT, PDL1 antibody and TGF-β inhibitor in hollow gold nanocage nanocomposites (GNC-Gal@CMaP) that selectively targeted colon cancer cells and accumulated in the tumor microenvironment. The GNC-Gal@CMaP nanocomposites achieved low-temperature PTT and immunogenic cell death, which subsequently enhanced the anti-tumor efficacy of anti-PDL1 antibody and galunisertib via activation of antigen-presenting cells that primed tumor-specific effector T cells. This study provides experimental proof for a combination of immunotherapy and PTT against CRC.
The clinical outcomes and therapeutic strategies for infiltrating ductal carcinoma (IDC) and infiltrating lobular carcinoma (ILC) are not uniform. The primary objectives of this study were to ...identify the differences in the clinical characteristics and prognoses between ILC and IDC, and identify the high-risk population based on the hormone receptor status and metastasis sites. The Surveillance, Epidemiology, and End Results Program database was searched and patients diagnosed with ILC or IDC from 1990 to 2013 were identified. In total,796,335 patients were analyzed, including 85,048 withILC (10.7%) and 711,287 withIDC (89.3%). The ILC group was correlatedwith older age, larger tumor size, later stage, lower grade, metastasis disease(M1) disease, and greater counts ofpositive lymph nodesandestrogen-receptor-positive (ER)/progesterone receptor-positive (PR) positive nodes. The overall survival showed an early advantage for ILC but a worse outcome after 5 years. Regarding the disease-specific survival, the IDC cohort had advantages over the ILC group, both during the early years and long-term. In hormone status and metastasis site subgroup analyses, the ER+/PR+ subgroup had the best survival, while the ER+/PR- subgroup had the worst outcome, especially the ILC cohort. ILC and IDC had different metastasis patterns. The proportion of bone metastasis was higher in the ILC group (91.52%) than that in the IDC (76.04%), and the ILC group was more likely to have multiple metastasis sites. Survival analyses showed patients with ILC had a higher risk of liver metastasis (disease-specific survivalDSS; P = 0.046), but had a better overall survival than the bone metastasis group (P<0.0001). We concluded that the long-term prognosis for ILC was poorer than that for IDC, and the ER+/PR- subgroup had the worst outcome. Therefore, the metastasis pattern and prognosis must be seriously evaluated, and a combination of endocrine therapy and chemotherapy should be considered.
Poor seed quality of soybean is often associated with Phomopsis seed decay (PSD), which is one of the most economically important seed diseases. Diaporthe longicolla (syn. Phomopsis longicolla) is ...the primary cause of PSD. Control of PSD is best accomplished by planting PSD-resistant cultivars. Sixteen exotic soybean accessions from the USDA soybean germplasm collection were screened for reaction to PSD at Stoneville, Mississippi. They consisted of maturity groups (MG) II, III and IV. Seeds from inoculated and non-inoculated plots harvested either promptly at maturity, or after a two-week delay in harvest, were assessed for infection by D. longicolla. Seed infection ranged from 0 to 36.7%. Overall, PI 417050 (MG II), PI 417017 (MG III), and PI 594692 (MG IV) had significantly (P ≤ 0.05) lower percentages of seed infected by D. longicolla and higher seed germinations than other genotypes in the same maturity groups. PI 587982A also performed well. As a result of these findings, these resistant accessions were used over multiple cycles of breeding to develop improved breeding lines with resistance to PSD and low seed damage. Breeding line 11043-225-72, with combined resistance from both PIs 417050 and 587982A, had low scores for PSD (6.7%) and seed damage (3.4%), while DS65-1, deriving resistance from PI 587982A, had the lowest seed damage score (1.1%) and the highest seed germination (85.6%) among all lines tested in 2017. DS65-1 and 11043-225-72, along with five other improved breeding lines, were provided to public soybean breeders for developing improved cultivars and germplasm lines. DS31-243 (PI 700941), derived from PI 587982A, was publicly released by the USDA in 2022. This research will lead to future releases of improved germplasm lines and cultivars with PSD resistance and high seed quality. It will also aid in disease management and be a benefit to soybean producers and the industry at large.
A charge control model for the transient analysis of the bipolar transistor laser in forward active mode is developed to describe the dynamics of electron, photon and charge densities. From three ...coupled-rate equations, analytical expressions are obtained for the threshold base current density, the steady-state electron and photon densities, and small-signal frequency response. We find that the threshold current density decreases with increasing spontaneous emission lifetime of electrons in the quantum well as well as a linear dependence of the photon density on the base current. By optimizing the model parameters in their physical range, we show that a -3-dB bandwidth of 55 GHz can be achieved for small-signal modulation of the laser. By numerically solving the rate equations, we investigate the -3-dB bandwidth under large-signal modulation to show that it remains nearly unchanged from the small-signal case. We further perform analysis of laser switching and find that the turn-on time is reduced by increasing the base current or decreasing the spontaneous emission lifetime of electrons in the quantum well.
We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the ...Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% 76 mmol/mol and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.3% 56 mmol/mol and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.
Diabetic kidney disease (DKD) is a common complication of diabetes that is clinically characterized by progressive albuminuria due to glomerular destruction. The etiology of DKD is multifactorial, ...and numerous studies have demonstrated that cellular senescence plays a significant role in its pathogenesis, but the specific mechanism requires further investigation.
This study utilized 5 datasets comprising 144 renal samples from the Gene Expression Omnibus (GEO) database. We obtained cellular senescence-related pathways from the Molecular Signatures Database and evaluated the activity of senescence pathways in DKD patients using the Gene Set Enrichment Analysis (GSEA) algorithm. Furthermore, we identified module genes related to cellular senescence pathways through Weighted Gene Co-Expression Network Analysis (WGCNA) algorithm and used machine learning algorithms to screen for hub genes related to senescence. Subsequently, we constructed a cellular senescence-related signature (SRS) risk score based on hub genes using the Least Absolute Shrinkage and Selection Operator (LASSO), and verified mRNA levels of hub genes by RT-PCR in vivo. Finally, we validated the relationship between the SRS risk score and kidney function, as well as their association with mitochondrial function and immune infiltration.
The activity of cellular senescence-related pathways was found to be elevated among DKD patients. Based on 5 hub genes (LIMA1, ZFP36, FOS, IGFBP6, CKB), a cellular senescence-related signature (SRS) was constructed and validated as a risk factor for renal function decline in DKD patients. Notably, patients with high SRS risk scores exhibited extensive inhibition of mitochondrial pathways and upregulation of immune cell infiltration.
Collectively, our findings demonstrated that cellular senescence is involved in the process of DKD, providing a novel strategy for treating DKD.
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