Structure of the human respiratory complex II.

Human complex II is a key protein complex that links two essential energy-producing processes: the tricarboxylic acid cycle and oxidative phosphorylation. Deficiencies due to mutagenesis have been shown to cause mitochondrial disease and some types of cancers. However, the structure of this complex is yet to be resolved, hindering a comprehensive understanding of the functional aspects of this molecular machine. Here, we have determined the structure of human complex II in the presence of ubiquinone at 2.86 Å resolution by cryoelectron microscopy, showing it comprises two water-soluble subunits, SDHA and SDHB, and two membrane-spanning subunits, SDHC and SDHD. This structure allows us to propose a route for electron transfer. In addition, clinically relevant mutations are mapped onto the structure. This mapping provides a molecular understanding to explain why these variants have the potential to produce disease.

Genome-wide development of simple sequence repeats markers and genetic diversity analysis of chayote.

BACKGROUND: Chayote is a high economic crop in the Cucurbitaceae family, playing an important role in food production, disease treatment and the production of degradable materials in industries. Due to the harsh environment, such as high temperature, drought and frost, some chayote resources are gradually disappearing. It is crucial to collect, characterize, and conserve chayote resources. However, the genetic diversity of chayote resources in China has not been studied so far. RESULTS: In this study, we collected 35 individuals of chayote from 14 provinces in China. Subsequently, we found 363,156 SSR motifs from the chayote genome and designed 57 pairs of SSR primers for validation. Out of these, 48 primer pairs successfully amplified bands, with 42 of them showing polymorphism. These 42 primer pairs detected a total of 153 alleles, averaging 3.64 alleles per locus. The polymorphic information content ranged from 0.03 to 0.78, with an average value of 0.41, indicating a high level of polymorphism. Based on the analysis using STRUCTURE, PCoA, and UPGMA methods, the 35 chayote individuals were divided into two major clusters. Through further association analysis, 7 significantly associated SSR markers were identified, including four related to peel color and three related to spine. CONCLUSIONS: These molecular markers will contribute to the analysis of genetic diversity and genetic breeding improvement of chayote in the future.

Cryo-EM structure of Mycobacterium smegmatis DyP-loaded encapsulin.

Encapsulins containing dye-decolorizing peroxidase (DyP)-type peroxidases are ubiquitous among prokaryotes, protecting cells against oxidative stress. However, little is known about how they interact and function. Here, we have isolated a native cargo-packaging encapsulin from Mycobacterium smegmatis and determined its complete high-resolution structure by cryogenic electron microscopy (cryo-EM). This encapsulin comprises an icosahedral shell and a dodecameric DyP cargo. The dodecameric DyP consists of two hexamers with a twofold axis of symmetry and stretches across the interior of the encapsulin. Our results reveal that the encapsulin shell plays a role in stabilizing the dodecameric DyP. Furthermore, we have proposed a potential mechanism for removing the hydrogen peroxide based on the structural features. Our study also suggests that the DyP is the primary cargo protein of mycobacterial encapsulins and is a potential target for antituberculosis drug discovery.

Architecture of the mycobacterial succinate dehydrogenase with a membrane-embedded Rieske FeS cluster.

Complex II, also known as succinate dehydrogenase (SQR) or fumarate reductase (QFR), is an enzyme involved in both the Krebs cycle and oxidative phosphorylation. Mycobacterial Sdh1 has recently been identified as a new class of respiratory complex II (type F) but with an unknown electron transfer mechanism. Here, using cryoelectron microscopy, we have determined the structure of Mycobacterium smegmatis Sdh1 in the presence and absence of the substrate, ubiquinone-1, at 2.53-Å and 2.88-Å resolution, respectively. Sdh1 comprises three subunits, two that are water soluble, SdhA and SdhB, and one that is membrane spanning, SdhC. Within these subunits we identified a quinone-binding site and a rarely observed Rieske-type [2Fe-2S] cluster, the latter being embedded in the transmembrane region. A mutant, where two His ligands of the Rieske-type [2Fe-2S] were changed to alanine, abolished the quinone reduction activity of the Sdh1. Our structures allow the proposal of an electron transfer pathway that connects the substrate-binding and quinone-binding sites. Given the unique features of Sdh1 and its essential role in Mycobacteria, these structures will facilitate antituberculosis drug discovery efforts that specifically target this complex.

A Novel Ultrafiltrate Extract of Propolis Exerts Anti-inflammatory Activity through Metabolic Rewiring.

Thousands of years ago, humans started to use propolis because of its medicinal properties, and modern science has successfully identified several bioactive molecules within this resinous bee product. However, a natural propolis extract which has been removed the adhesive glue and preserved propolis bioactive compounds is urgently needed to maximise the therapeutic opportunities. In this study, a novel ultrafiltrate fraction from Brazilian green propolis, termed P30K, was demonstrated with anti-inflammatory properties, both in vitro and in vivo. Total flavonoids and total phenolic acids content in P30K were 244.6 mg/g and 275.8 mg/g respectively, while the IC50 value of inhibition of cyclooxygenase-2 (COX-2) was 8.30 µg/mL. The anti-inflammatory activity of P30K was furtherly corroborated in experimental models of lipopolysaccharides (LPS)-induced acute liver and lung injury. Mechanistically, integrated GC-MS and LC-MS based serum metabolomics analysis revealed that P30K modulated citrate cycle (TCA), pyruvate, glyoxylate and dicarboxylate metabolism pathways to inhibit secretion of pro-inflammatory cytokines. Results of network pharmacology and molecular docking suggested that P30K targeted catechol-O-methyltransferases (COMT), 11ß-hydroxysteroid dehydrogenases (HSD11B1), and monoamine oxidases (MAOA and MAOB) to promote cellular metabolomic rewiring. Collectively, our work reveals P30K as an efficient therapeutic agent against inflammatory conditions and its efficacy is related to metabolic rewiring.

Physiological, anatomical and quality indexes of root tuber formation and development in chayote (Sechium edule).

BACKGROUND: Chayote is an underutilized species of Cucurbitaceae. It is rich in nutrients such as protein, minerals, phenols and its extracts have anti-cardiovascular and anti-cancer effects, making it a versatile plant for both medicinal and culinary purposes. Although research on its root tuber is limited, they are rich in starch and have a structure similar to that of potatoes, cassava, and sweet potatoes. Therefore, they can serve as potential substitutes for potatoes and offer promising prospects as agricultural and industrial resources. However, the physiological and cellular mechanisms of chayote root tuber formation and development are still unclear. RESULTS: In this study, we observed the growth habit of 'Tuershao' (high yield of root tuber). The results revealed that the tuber enlargement period of 'Tuershao' lasts approximately 120 days, with the early enlargement phase occurring during 0-30 days, rapid enlargement phase during 30-90 days, and maturation phase during 90-120 days. Physiological indicators demonstrated a gradual increase in starch content as the tuber developed. The activities of sucrose synthase (SUS) and invertase (VIN) showed a consistent trend, reaching the highest level in the rapid expansion period, which was the key enzyme affecting tuber expansion. Moreover, the special petal like structure formed by the secondary phloem and secondary xylem of the tuber resulted in its enlargement, facilitating the accumulation of abundant starch within the thin-walled cells of this structure. Principal component analysis further confirmed that starch content, SUS and VIN activities, as well as the concentrations of calcium (Ca), iron (Fe), and selenium (Se), were the major factors influencing tuber development. Moreover, the low temperature environment not only promoted the growth of 'Tuershao' tubers but also enhanced the accumulation of nutritional substances. CONCLUSIONS: These findings contribute to a deeper understanding of the formation and developmental mechanisms of 'Tuershao' tubers, providing valuable guidance for cultivation practices aimed at improving crop yield.

Transcriptome Mechanisms of Tomato Seedlings Induced by Low-Red to Far-Red Light Ratio under Calcium Nitrate Stress.

In recent times, the excessive accumulation of nitrate has been one of the main reasons for the secondary salinization of greenhouse soils. Light plays a key role in a plant's growth, development, and response to stress. A low-red to far-red (R:FR) light ratio could enhance plant salinity tolerance, but the mechanism at a molecular level is unclear. Thus, we analyzed the transcriptome responses of tomato seedlings to calcium nitrate stress under either a low R:FR ratio (0.7) or normal light conditions. Under calcium nitrate stress, a low R:FR ratio enhanced both the antioxidant defense system and the rapid physiological accumulation of proline in tomato leaves, which promoted plant adaptability. Using weighted gene co-expression network analysis (WGCNA), three modules including 368 differentially expressed genes (DEGs) were determined to be significantly associated with these plant traits. Functional annotations showed that the responses of these DEGs to a low R:FR ratio under excessive nitrate stress were enriched in the areas of hormone signal transduction, amino acid biosynthesis, sulfide metabolism, and oxidoreductase activity. Furthermore, we identified important novel hub genes encoding certain proteins, including FBNs, SULTRs, and GATA-like transcription factor, which may play a vital role in low R:FR light-induced salt responses. These findings offer a new perspective on the mechanisms and environmental implications behind low R:FR ratio light-modulated tomato saline tolerance.

Genome-Wide Identification of the MADS-Box Gene Family during Male and Female Flower Development in Chayote (Sechium edule).

The MADS-box gene plays an important role in plant growth and development. As an important vegetable of Cucurbitaceae, chayote has great edible and medicinal value. So far, there is little molecular research on chayote, and there are no reports on the MADS-box transcription factor of chayote. In this study, the MADS-box gene family of chayote was analyzed for the first time, and a total of 70 MADS-box genes were identified, including 14 type I and 56 type II MICK MADS genes. They were randomly distributed on 13 chromosomes except for chromosome 11. The light response element, hormone response element and abiotic stress response element were found in the promoter region of 70 MADS genes, indicating that the MADS gene can regulate the growth and development of chayote, resist abiotic stress, and participate in hormone response; GO and KEGG enrichment analysis also found that SeMADS genes were mainly enriched in biological regulation and signal regulation, which further proved the important role of MADS-box gene in plant growth and development. The results of collinearity showed that segmental duplication was the main driving force of MADS gene expansion in chayote. RNA-seq showed that the expression levels of SeMADS06, SeMADS13, SeMADS26, SeMADS28, SeMADS36 and SeMADS37 gradually increased with the growth of chayote, indicating that these genes may be related to the development of root tubers of 'Tuershao'. The gene expression patterns showed that 12 SeMADS genes were specifically expressed in the male flower in 'Tuershao' and chayote. In addition, SeMADS03 and SeMADS52 may be involved in regulating the maturation of male flowers of 'Tuershao' and chayote. SeMADS21 may be the crucial gene in the development stage of the female flower of 'Tuershao'. This study laid a theoretical foundation for the further study of the function of the MADS gene in chayote in the future.

Potential of the Signal Peptide Derived from the PAS_chr3_0030 Gene Product for Secretory Expression of Valuable Enzymes in Pichia pastoris.

Pichia pastoris is widely used for the production of valuable recombinant proteins. An advantage of P. pastoris over other expression systems is that it secretes low levels of endogenous proteins, which facilitates the purification processes if the desired recombinant proteins are efficiently secreted into the culture medium. However, not all recombinant proteins can be successfully secreted by P. pastoris, especially enzymes that are located in intracellular compartments in their native hosts. Few studies have reported strategies for releasing recombinant proteins which cannot be secreted by standard protocols. Here, we investigated whether this challenge can be addressed using novel secretion leaders. Analysis of the secretome and transcriptome of P. pastoris indicated that the four genes with the highest protein-to-transcript ratios were EPX1, PAS_chr3_0030, SCW10, and UTH1, suggesting that their gene products contain efficient secretion leaders. Our data revealed that the signal peptide derived from the PAS_chr3_0030 gene product conferred secretion competence to certain industrial enzymes, e.g., a nitrilase of Alcaligenes faecalis ZJUTB10, a ribosylnicotinamide kinase of P. pastoris, and a glucose dehydrogenase of Exiguobacterium sibiricum. Therefore, the signal peptide derived from the PAS_chr3_0030 gene product represents a novel secretion sequence for the secretory expression of recombinant enzymes in P. pastoris. IMPORTANCE Although P. pastoris is widely used for the secretory production of pharmaceutical proteins, its successful applications in the secretory production of industrial enzymes are limited. The α-mating factor pre-pro leader is the most widely used secretion signal in P. pastoris, but numerous industrial enzymes cannot be secreted using it. The importance of this study is that we identified a signal peptide derived from the PAS_chr3_0030 gene product which conferred secretion competence to three-quarters of the enzymes tested. This signal peptide derived from the PAS_chr3_0030 gene product may facilitate the application of P. pastoris in industrial biocatalysis.

The Chinese Parkinson's Disease Registry (CPDR): Study Design and Baseline Patient Characteristics.

BACKGROUND: There is a lack of large multicenter Parkinson's disease (PD) cohort studies and limited data on the natural history of PD in China. OBJECTIVES: The objective of this study was to launch the Chinese Parkinson's Disease Registry (CPDR) and to report its protocol, cross-sectional baseline data, and prospects for a comprehensive observational, longitudinal, multicenter study. METHODS: The CPDR recruited PD patients from 19 clinical sites across China between January 2018 and December 2020. Clinical data were collected prospectively using at least 17 core assessment scales. Patients were followed up for clinical outcomes through face-to-face interviews biennially. RESULTS: We launched the CPDR in China based on the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network (PD-MDCNC). A total of 3148 PD patients were enrolled comprising 1623 men (51.6%) and 1525 women (48.4%). The proportions of early-onset PD (EOPD, age at onset ≤50 years) and late-onset PD (LOPD) were 897 (28.5%) and 2251 (71.5%), respectively. Stratification by age at onset showed that EOPD manifested milder motor and nonmotor phenotypes and was related to increased probability of dyskinesia. Comparison across genders suggested a slightly older average age at PD onset, milder motor symptoms, and a higher rate of developing levodopa-induced dyskinesias in women. CONCLUSIONS: The CPDR is one of the largest multicenter, observational, longitudinal, and natural history studies of PD in China. It offers an opportunity to expand the understanding of clinical features, genetic, imaging, and biological markers of PD progression. © 2022 International Parkinson and Movement Disorder Society.

Topology on a new facet of bismuth.

Bismuth-based materials have been instrumental in the development of topological physics, even though bulk bismuth itself has been long thought to be topologically trivial. A recent study has, however, shown that bismuth is in fact a higher-order topological insulator featuring one-dimensional (1D) topological hinge states protected by threefold rotational and inversion symmetries. In this paper, we uncover another hidden facet of the band topology of bismuth by showing that bismuth is also a first-order topological crystalline insulator protected by a twofold rotational symmetry. As a result, its [Formula: see text] surface exhibits a pair of gapless Dirac surface states. Remarkably, these surface Dirac cones are "unpinned" in the sense that they are not restricted to locate at specific k points in the [Formula: see text] surface Brillouin zone. These unpinned 2D Dirac surface states could be probed directly via various spectroscopic techniques. Our analysis also reveals the presence of a distinct, previously uncharacterized set of 1D topological hinge states protected by the twofold rotational symmetry. Our study thus provides a comprehensive understanding of the topological band structure of bismuth.

Transcriptome and Metabolome Analysis Provide New Insights into the Process of Tuberization of Sechium edule Roots.

Chayote (Sechium edule) produces edible tubers with high starch content after 1 year of growth but the mechanism of chayote tuberization remains unknown. 'Tuershao', a chayote cultivar lacking edible fruits but showing higher tuber yield than traditional chayote cultivars, was used to study tuber formation through integrative analysis of the metabolome and transcriptome profiles at three tuber-growth stages. Starch biosynthesis- and galactose metabolism-related genes and metabolites were significantly upregulated during tuber bulking, whereas genes encoding sugars will eventually be exported transporter (SWEET) and sugar transporter (SUT) were highly expressed during tuber formation. Auxin precursor (indole-3-acetamide) and ethylene precursor, 1-aminocyclopropane-1-carboxylic acid, were upregulated, suggesting that both hormones play pivotal roles in tuber development and maturation. Our data revealed a similar tuber-formation signaling pathway in chayote as in potatoes, including complexes BEL1/KNOX and SP6A/14-3-3/FDL. Down-regulation of the BEL1/KNOX complex and upregulation of 14-3-3 protein implied that these two complexes might have distinct functions in tuber formation. Finally, gene expression and microscopic analysis indicated active cell division during the initial stages of tuber formation. Altogether, the integration of transcriptome and metabolome analyses unraveled an overall molecular network of chayote tuberization that might facilitate its utilization.

Engineering laboratory/factory-specific phage-resistant strains of Escherichia coli by mutagenesis and screening.

The Escherichia coli (E. coli) has been widely employed in biotechnology industry and academia. However, the bioproduct manufacturing driven by E. coli is prone to the phage contamination. Good laboratory/factory hygiene may decrease but not avoid completely the chances of the phage contamination. The present study aims to resolve this problem by engineering laboratory/factory-specific phage-resistant E. coli strains. By adding a laboratory or factory derived phage into the atmospheric and room temperature plasma mutagenized E. coli, a phage-resistant strain could be generated. Interestingly, the resistant strain exhibited cross-resistance to unencountered phages. When operating the resistant strain in a polluted environment, the phage contamination was largely prevented. There was no significant difference in heterogeneous protein production between the parental strain and the phage-resistant strain. Importantly, it requires only one day to generate the phage-resistant strain. This practical method for engineering laboratory/factory-specific phage-resistant strains may have great potential in resuming E. coli operation in laboratories and factories during phage contamination outbreaks.

The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.

This study aimed to determine the mutational spectrum of familial Parkinson's disease and sporadic early-onset Parkinson's disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson's disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson's disease, 242 probands from families with autosomal-dominant Parkinson's disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson's disease-associated genes occurred more frequently in the autosomal-recessive Parkinson's disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson's disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson's disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson's disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson's disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson's disease-associated genes. Our data highlight the importance of genetic testing in Parkinson's disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

Identification of a novel promoter for driving antibiotic-resistant genes to reduce the metabolic burden during protein expression and effectively select multiple integrations in Pichia Pastoris.

Routine approaches for the efficient expression of heterogenous proteins in Pichia pastoris include using the strong methanol-regulated alcohol oxidase (AOX1) promoter and multiple inserts of expression cassettes. To screen the transformants harboring multiple integrations, antibiotic-resistant genes such as the Streptoalloteichus hindustanus bleomycin gene are constructed into expression vectors, given that higher numbers of insertions of antibiotic-resistant genes on the expression vector confer resistance to higher concentrations of the antibiotic for transformants. The antibiotic-resistant genes are normally driven by the strong constitutive translational elongation factor 1a promoter (PTEF1). However, antibiotic-resistant proteins are necessary only for the selection process. Their production during the heterogenous protein expression process may increase the burden in cells, especially for the high-copy strains which harbor multiple copies of the expression cassette of antibiotic-resistant genes. Besides, a high concentration of the expensive antibiotic is required for the selection of multiple inserts because of the effective expression of the antibiotic-resistant gene by the TEF1 promoter. To address these limitations, we replaced the TEF1 promoter with a weaker promoter (PDog2p300) derived from the potential promoter region of 2-deoxyglucose-6-phosphate phosphatase gene for driving the antibiotic-resistant gene expression. Importantly, the PDog2p300 has even lower activity under carbon sources (glycerol and methanol) used for the AOX1 promoter-based production of recombinant proteins compared with glucose that is usually used for the selection process. This strategy has proven to be successful in screening of transformants harboring more than 3 copies of the gene of interest by using plates containing 100 µg/ml of Zeocin. Meanwhile, levels of Zeocin resistance protein were undetectable by immunoblotting in these multiple-copy strains during expression of heterogenous proteins.Key points• PDog2p300 was identified as a novel glucose-regulated promoter.• The expression of antibiotic-resistant gene driven by PDog2p300 was suppressed during the recombinant protein expression, resulting in reducing the metabolic burden.• The transformants harboring multiple integrations were cost-effectively selected by using the PDog2p300 for driving antibiotic-resistant genes.

Expression and diagnostic value of circulating miRNA-190 and miRNA-197 in patients with pulmonary thromboembolism.

BACKGROUND: Diagnosing pulmonary thromboembolism (PTE) remains challenging due to the lack of specific clinical symptoms and biomarkers. Circulating microRNAs (miRNAs) have proved to be potential biomarkers for numerous cardiovascular diseases. The aims of this study were to quantitatively analyze the expression of plasma miRNA-190 and miRNA-197 in patients with PTE and to evaluate the diagnostic value for PTE. METHODS: Thirty patients diagnosed with PTE by computed tomographic pulmonary angiography at the emergency department were enrolled in this study, and plasma was collected immediately. For comparison, myocardial infarction (MI, n = 45) and healthy participants (NC, n = 45) were recruited as the control groups. Quantitative reverse transcription PCR (qRT-PCR) was conducted to reveal the relative expression levels of miRNA-190 and miRNA-197 in each group. The plasma concentrations of D-dimer were measured by immunoturbidimetric assay. The diagnostic value was evaluated by analyzing the area under the receiver operating characteristic curve (AUC). RESULTS: The relative expression levels of miRNA-190 and miRNA-197 in the PTE group were both significantly higher than in the MI group (t = 3.602 t = 4.791, P < .05, respectively) and the healthy control group (t = 5.814, t = 5.886, P < .05, respectively). As diagnostic indicator, the sensitivity and specificity of miRNA-190 were 75.56% and 80%, respectively, with an AUC of 0.7844 (95%CI: 0.6858-0.8831, P < .001). The sensitivity and specificity of miRNA-197 were 73.33% and 86.67%, respectively, with an AUC value of 0.7931 (95%CI: 0.6870-0.8991, P < .001). Combining miRNA-190 and miRNA-197 with D-dimer levels significantly increased the diagnostic power, improving the AUC to 0.9536 (95% CI: 0.9083-0.9989, P < .001). CONCLUSIONS: The relative expression levels of miRNA-190 and miRNA-197 in PTE patients were significantly higher than in the MI and healthy control groups, indicating that (a) both may be involved in the pathophysiological process of PTE and (b) both may serve as potential noninvasive diagnostic markers for PTE. The combination of miRNA-190, miRNA-197, and D-dimer levels showed better sensitivity and specificity, which is more conducive to the diagnosis of PTE.

Network response of two cherry tomato (Lycopersicon esculentum) cultivars to Cadmium stress as revealed by transcriptome analysis.

Soil cadmium (Cd) contamination severely threatens human health. Therefore, screening and breeding low-Cd absorption cultivars of cherry tomato (Solanum lycopersicum L.) is essential to restrict human Cd intake. In this study, a hydroponic experiment was conducted to perform a comparative transcriptome analysis of the leaves of two cherry tomato cultivars with different Cd contents under different Cd stress (0, 10, and 50 µM), for the purpose of exploring the differences in the transcriptional responses to Cd stress between the two cultivars. Our results revealed that the Cd content in the leaves of HLZ (Hanluzhe; a low-Cd accumulation cultivar) was significantly lower than that in the leaves of LFC (Lvfeicui; a high-Cd accumulation cultivar). Transcriptome analysis showed that the different expression genes (DEGs) were mainly involved in plant hormone signal transduction, antioxidant enzymes, cell wall biosynthesis, and metal transportation. In the LFC leaves, DEGs in the IAA signal transduction and antioxidant enzymes exhibited higher transcription levels. However, the DEGs in the ETH signal transduction demonstrated a lower transcription level compared to that of HLZ. Over-expressed genes in the pectin biosynthesis and pectin methylesterase (PME) of the LFC leaves might result in the trapping of Cd by increased levels of low-methylated pectin around the cell wall. Furthermore, Cd transporter genes, such as HMA5, NRAMP6, CAX3, ABCC3, and PDR1, were up-regulated in the HLZ leaves, indicating that the HLZ cultivar comprised an active Cd transport capacity from apoplast to vacuolar. This may contribute to the low Cd concentration observed in the HLZ leaves. Overall, our study provides a molecular basis for tomato screening and breeding.

PK/PD modeling based on NO-ET homeostasis for improving management of sunitinib-induced hypertension in rats.

Sunitinib is an oral small molecule multitargeted tyrosine kinase inhibitor, which is currently used to treat severe cancers. Clinical research has shown that patients treated with sunitinib develop hypertension. As soon as sunitinib-induced hypertension appears, it is usual to administer anti-hypertension agent. But this treatment may cause acute blood pressure fluctuation which may lead to additional cardiovascular risk. The aim of this study is to establish a mathematical model for managing sunitinib-induced hypertension and blood pressure fluctuation. A mechanism-based PK/PD model was developed based on animal experiments. Then this model was used to perform simulations, thus to propose an anti-hypertension indication, according to which the anti-hypertension treatment might yield relative low-level AUC and fluctuation of blood pressure. The simulation results suggest that the anti-hypertension agent may yield low-level AUC and fluctuation of blood pressure when relative ET-1 level ranges from -15% to 5% and relative NO level is more than 10% compared to control group. Finally, animal experiments were conducted to verify the simulation results. Macitentan (30 mg/kg) was administered based on the above anti-hypertension indication. Compared with the untreated group, the optimized treatment significantly reduced the AUC of blood pressure; meanwhile the fluctuation of blood pressure in optimized treatment group was 70% less than that in immediate treatment group. This work provides a novel model with potential translational value for managing sunitinib-induced hypertension.

Histopathologic study of extraocular muscles in thyroid-associated ophthalmopathy coexisting with ocular myasthenia gravis: a case report.

BACKGROUND: Coexistence of thyroid-associated ophthalmopathy (TAO) and ocular myasthenia gravis (OMG) is very rare. Little is known about the orbital histopathology associated with this condition. The authors reported a case of TAO coexisting with OMG and explored the histopathologic changes in extraocular muscles. CASE PRESENTATION: A 32-year-old man complaint of bilateral proptosis for 2 years. The patient was documented with a history of OMG and was treated with blepharoplasty to correct ptosis 3 years prior to presentation. Physical examination revealed right upper eyelid retraction resulting from the eyelid surgery. Computed tomographic scan demonstrated bilateral enlargement of the extraocular muscles. Thyroid function test confirmed hyperthyroid status. The patient was diagnosed with TAO (clinical activity score = 2/7) coexisting with OMG. Orbital decompression surgery reduced proptosis but resulted in new onset of left upper eyelid retraction because of the increased motor impulses to sustain eyelid elevation. Extraocular muscles were sampled during surgery and subjected to histopathologic stain. The stain results were analyzed against samples from age-, gender- matched TAO and control (non-TAO non-OMG) subjects. The measurement of myofiber size and glycosaminoglycan/collagen-occupied area was repeated in 3 randomly chosen fields of each slide. The variation of myofiber size was larger in the TAO + OMG (289.9 ± 142.5 µm2) samples than the TAO (544.1 ± 160.6 µm2) and control (157.0 ± 47.7 µm2) samples. Glycosaminoglycan was more abundant in the TAO + OMG (48.8 ± 12.2%) samples than the TAO (28.4 ± 3.6%) and control (3.3 ± 0.8%) samples. Collagen fibers accumulated in the TAO (60.5 ± 6.4%) samples but not in the TAO + OMG (36.1 ± 4.3%) and control (33.9 ± 2.7%) samples. Typical OMG changes were observed in the TAO + OMG samples but not in the TAO and control samples. These changes included central nuclei, aggregation of mitochondria and fiber type grouping. The histopathologic findings of TAO + OMG were summarized as inhomogeneously enlarged muscle fibers and predominantly endomysial accumulation of glycosaminoglycan. CONCLUSION: This study highlights the possibility of TAO coexisting with OMG and demonstrates the histopathologic features in this rare condition.

[Research Progress of Polyvinyl Alcohol (PVA) Based on Hydrogel Dressings].

This review introduces a brief description on the featured properties of polyvinyl alcohol based on hydrogel dressings. During past ten years many new artificial polymeric dressings have been developed, which meet requirements of wound healing. This review mainly focuses on one representative of ideal polymeric wound dressing membranes, polyvinyl alcohol based hydrogel dressings. But as the hydrogels with single component have low mechanical strength, recent trends have offered composite hydrogel membranes to achieve the ideal wound dressing requirements.