Deficiency of Transcription Factor Sp1 Contributes to Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disorder. However, the pathogenesis of HCM, especially its nongenetic mechanisms, remains largely unclear. Transcription factors are known to be involved in various biological processes including cell growth. We hypothesized that SP1 (specificity protein 1), the first purified TF in mammals, plays a role in the cardiomyocyte growth and cardiac hypertrophy of HCM. METHODS: Cardiac-specific conditional knockout of Sp1 mice were constructed to investigate the role of SP1 in the heart. The echocardiography, histochemical experiment, and transmission electron microscope were performed to analyze the cardiac phenotypes of cardiac-specific conditional knockout of Sp1 mice. RNA sequencing, chromatin immunoprecipitation sequencing, and adeno-associated virus experiments in vivo were performed to explore the downstream molecules of SP1. To examine the therapeutic effect of SP1 on HCM, an SP1 overexpression vector was constructed and injected into the mutant allele of Myh6 R404Q/+ (Myh6 c. 1211C>T) HCM mice. The human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with HCM were used to detect the potential therapeutic effects of SP1 in human HCM. RESULTS: The cardiac-specific conditional knockout of Sp1 mice developed a typical HCM phenotype, displaying overt myocardial hypertrophy, interstitial fibrosis, and disordered myofilament. In addition, Sp1 knockdown dramatically increased the cell area of hiPSC-CMs and caused intracellular myofibrillar disorganization, which was similar to the hypertrophic cardiomyocytes of HCM. Mechanistically, Tuft1 was identified as the key target gene of SP1. The hypertrophic phenotypes induced by Sp1 knockdown in both hiPSC-CMs and mice could be rescued by TUFT1 (tuftelin 1) overexpression. Furthermore, SP1 overexpression suppressed the development of HCM in the mutant allele of Myh6 R404Q/+ mice and also reversed the hypertrophic phenotype of HCM hiPSC-CMs. CONCLUSIONS: Our study demonstrates that SP1 deficiency leads to HCM. SP1 overexpression exhibits significant therapeutic effects on both HCM mice and HCM hiPSC-CMs, suggesting that SP1 could be a potential intervention target for HCM.

Development and validation of an artificial intelligence model for predicting de novo distant bone metastasis in breast cancer: a dual-center study.

OBJECTIVE: Breast cancer has become the most prevalent malignant tumor in women, and the occurrence of distant metastasis signifies a poor prognosis. Utilizing predictive models to forecast distant metastasis in breast cancer presents a novel approach. This study aims to utilize readily available clinical data and advanced machine learning algorithms to establish an accurate clinical prediction model. The overall objective is to provide effective decision support for clinicians. METHODS: Data from 239 patients from two centers were analyzed, focusing on clinical blood biomarkers (tumor markers, liver and kidney function, lipid profile, cardiovascular markers). Spearman correlation and the least absolute shrinkage and selection operator regression were employed for feature dimension reduction. A predictive model was built using LightGBM and validated in training, testing, and external validation cohorts. Feature importance correlation analysis was conducted on the clinical model and the comprehensive model, followed by univariate and multivariate regression analysis of these features. RESULTS: Through internal and external validation, we constructed a LightGBM model to predict de novo bone metastasis in newly diagnosed breast cancer patients. The area under the receiver operating characteristic curve values of this model in the training, internal validation test, and external validation test1 cohorts were 0.945, 0.892, and 0.908, respectively. Our validation results indicate that the model exhibits high sensitivity, specificity, and accuracy, making it the most accurate model for predicting bone metastasis in breast cancer patients. Carcinoembryonic Antigen, creatine kinase, albumin-globulin ratio, Apolipoprotein B, and Cancer Antigen 153 (CA153) play crucial roles in the model's predictions. Lipoprotein a, CA153, gamma-glutamyl transferase, α-Hydroxybutyrate dehydrogenase, alkaline phosphatase, and creatine kinase are positively correlated with breast cancer bone metastasis, while white blood cell ratio and total cholesterol are negatively correlated. CONCLUSION: This study successfully utilized clinical blood biomarkers to construct an artificial intelligence model for predicting distant metastasis in breast cancer, demonstrating high accuracy. This suggests potential clinical utility in predicting and identifying distant metastasis in breast cancer. These findings underscore the potential prospect of developing economically efficient and readily accessible predictive tools in clinical oncology.

Evidence of Microplastics in Bronchoalveolar Lavage Fluid among Never-Smokers: A Prospective Case Series.

Microplastics (MPs) are abundant in air, but evidence of their deposition in the respiratory tract is limited. We conducted a prospective case series to investigate the deposition of microplastics in bronchoalveolar lavage fluid (BALF) and determine the internal dose of MPs via inhalation. Eighteen never-smokers aged 32-74 years who underwent fiberoptic bronchoscopy with BALF were recruited from Zhuhai, China. Control samples were obtained by performing the same procedure using isotonic saline instead of BALF. Laser direct infrared spectroscopy combined with scanning electron microscopy detected the presence and characteristics of MPs and quantitatively analyzed the microplastic in BALF and control samples. Concentrations of total and specific MPs in BALF and control samples were compared using the Wilcox test. Thirteen types of MPs were observed in 18 BALF samples. Polyethylene (PE, 86.1%) was the most abundant in BALF, followed by poly(ethylene terephthalate) (PET, 7.5%) and polypropylene (PP, 1.9%). Compared with the control samples, BALF had significantly higher concentrations of PE (median [IQR] of BALF: 0.38 [8.05] N/g), PET (0.26 [0.54] N/g), polyurethane (0.16 [0.24] N/g), PP (0.16 [0.11] N/g), and total MPs (0.91 [6.58] N/g). The presence of MPs in BALF provides novel evidence that MPs penetrate deep into the respiratory tract.

Genome-wide association study of eigenvectors provides genetic insights into selective breeding for tomato metabolites.

BACKGROUND: Long-term domestication and intensive breeding of crop plants aim to establish traits desirable for human needs, and characteristics related to yield, disease resistance, and postharvest storage have traditionally received considerable attention. These processes have led also to negative consequences, as is the case of loss of variants controlling fruit quality, for instance in tomato. Tomato fruit quality is directly associated to metabolite content profiles; however, a full understanding of the genetics affecting metabolite content during tomato domestication and improvement has not been reached due to limitations of the single detection methods previously employed. Here, we aim to reach a broad understanding of changes in metabolite content using a genome-wide association study (GWAS) with eigenvector decomposition (EigenGWAS) on tomato accessions. RESULTS: An EigenGWAS was performed on 331 tomato accessions using the first eigenvector generated from the genomic data as a "phenotype" to understand the changes in fruit metabolite content during breeding. Two independent gene sets were identified that affected fruit metabolites during domestication and improvement in consumer-preferred tomatoes. Furthermore, 57 candidate genes related to polyphenol and polyamine biosynthesis were discovered, and a major candidate gene chlorogenate: glucarate caffeoyltransferase (SlCGT) was identified, which affected the quality and diseases resistance of tomato fruit, revealing the domestication mechanism of polyphenols. CONCLUSIONS: We identified gene sets that contributed to consumer liking during domestication and improvement of tomato. Our study reports novel evidence of selective sweeps and key metabolites controlled by multiple genes, increasing our understanding of the mechanisms of metabolites variation during those processes. It also supports a polygenic selection model for the application of tomato breeding.

LRP5 regulates cardiomyocyte proliferation and neonatal heart regeneration by the AKT/P21 pathway.

The neonatal heart can efficiently regenerate within a short period after birth, whereas the adult mammalian heart has extremely limited capacity to regenerate. The molecular mechanisms underlying neonatal heart regeneration remain elusive. Here, we revealed that as a coreceptor of Wnt signalling, low-density lipoprotein receptor-related protein 5 (LRP5) is required for neonatal heart regeneration by regulating cardiomyocyte proliferation. The expression of LRP5 in the mouse heart gradually decreased after birth, consistent with the time window during which cardiomyocytes withdrew from the cell cycle. LRP5 downregulation reduced the proliferation of neonatal cardiomyocytes, while LRP5 overexpression promoted cardiomyocyte proliferation. The cardiac-specific deletion of Lrp5 disrupted myocardial regeneration after injury, exhibiting extensive fibrotic scars and cardiac dysfunction. Mechanistically, the decreased heart regeneration ability induced by LRP5 deficiency was mainly due to reduced cardiomyocyte proliferation. Further study identified AKT/P21 signalling as the key pathway accounting for the regulation of cardiomyocyte proliferation mediated by LRP5. LRP5 downregulation accelerated the degradation of AKT, leading to increased expression of the cyclin-dependent kinase inhibitor P21. Our study revealed that LRP5 is necessary for cardiomyocyte proliferation and neonatal heart regeneration, providing a potential strategy to repair myocardial injury.

Role of low molecular additives in the myofibrillar protein gelation: underlying mechanisms and recent applications.

Understanding mechanisms of myofibrillar protein gelation is important for development of gel-type muscle foods. The protein-protein interactions are largely responsible for the heat-induced gelation. Exogenous additives have been extensively applied to improve gelling properties of myofibrillar proteins. Research has been carried out to investigate effects of different additives on protein gelation, among which low molecular substances as one of the most abundant additives have been recently implicated in the modifications of intermolecular interactions. In this review, the processes of myosin dissociation under salt and the subsequent interaction via intermolecular forces are elaborated. The underlying mechanisms focusing on the role of low molecular additives in myofibrillar protein interactions during gelation particularly in relation to modifications of the intermolecular forces are comprehensively discussed, and six different additives i.e. metal ions, phosphates, amino acids, hydrolysates, phenols and edible oils are involved. The promoting effect of low molecular additives on protein interactions is highly attributed to the strengthened hydrophobic interactions providing explanations for improved gelation. Other intermolecular forces i.e. covalent bonds, ionic and hydrogen bonds could also be influenced depending on varieties of additives. This review can hopefully be used as a reference for the development of gel-type muscle foods in the future.

Functional characterization of a special dicistronic transcription unit encoding histone methyltransferase su(var)3-9 and translation regulator eIF2γ in Tribolium castaneum.

Operons are rare in eukaryotes, where they often allow concerted expression of functionally related genes. While a dicistronic transcription unit encoding two unrelated genes, the suppressor of position-effect variegation su(var)3-9 and the gamma subunit of eukaryotic translation initiation factor 2 (eIF2γ) has been found in insecta, and its significance is not well understood. Here, we analyzed the evolutionary history of this transcription unit in arthropods and its functions by using model Coleoptera insect Tribolium castaneum. In T. castaneum, Tcsu(var)3-9 fused into the 80 N-terminal amino acids of TceIF2γ, the transcription of these two genes are resolved by alternative splicing. Phylogenetic analysis supports the natural gene fusion of su(var)3-9 and eIF2γ occurred in the ancestral line of winged insects and silverfish, but with frequent re-fission during the evolution of insects. Functional analysis by using RNAi for these two genes revealed that gene fusion did not invoke novel functions for the gene products. As a histone methyltransferase, Tcsu(var)3-9 is primarily responsible for H3K9 di-, and tri-methylation and plays important roles in metamorphosis and embryogenesis in T. castaneum. While TceIF2γ plays essential roles in T. castaneum by positively regulating protein translation mediated ecdysteroid biosynthesis. The vulnerability of the gene fusion and totally different role of su(var)3-9 and eIF2γ in T. castaneum confirm this gene fusion is a non-selected, constructive neutral evolution event in insect. Moreover, the positive relationship between protein translation and ecdysteroid biosynthesis gives new insights into correlations between translation regulation and hormonal signaling.

Identification and functional characterization of methyl-CpG binding domain protein from Tribolium castaneum.

Methyl-CpG binding domain proteins (MBD) can specifically bind to methylated CpG sites and play important roles in epigenetic gene regulation. Here, we identified and functionally characterized the MBD protein in Tribolium castaneum. T. castaneum genome encodes only one MBD protein: TcMBD2/3. RNA interference targeting this gene at different developmental stages caused lethal phenotypes including metamorphosis deficiency in larvae and pupae, gastrointestinal system problems and fecundity deficiency in adult. Moreover, Tcmbd2/3 knockdown adult showed progressive reduced locomoter activity, a typical neurodegeneration phenotype. This is a common feature of DNA methylation in mammals and has not been found in other insects. However, band shift assays demonstrated that TcMBD2/3 could not bind to methylated DNA, indicating the essential roles of TcMBD2/3 is independent of DNA methylation. Our study provides Tcmbd2/3 plays important roles in T. castaneum and gives new insights into the potential mechanism of action of MBD proteins in insect.

Targeting Enteropeptidase with Reversible Covalent Inhibitors To Achieve Metabolic Benefits.

Inhibition of the serine protease enteropeptidase (EP) opens a new avenue to the discovery of chemotherapeutics for the treatment of metabolic diseases. Camostat has been used clinically for treating chronic pancreatitis in Japan; however, the mechanistic basis of the observed clinical efficacy has not been fully elucidated. We demonstrate that camostat is a potent reversible covalent inhibitor of EP, with an inhibition potency (k inact/KI) of 1.5 × 104 M-1s-1 High-resolution liquid chromatography-mass spectrometry (LC-MS) showed addition of 161.6 Da to EP after the reaction with camostat, consistent with insertion of the carboxyphenylguanidine moiety of camostat. Covalent inhibition of EP by camostat is reversible, with an enzyme reactivation half-life of 14.3 hours. Formation of a covalent adduct was further supported by a crystal structure resolved to 2.19 Å, showing modification of the catalytic serine of EP by a close analog of camostat, leading to formation of the carboxyphenylguanidine acyl enzyme identical to that expected for the reaction with camostat. Of particular note, minor structural modifications of camostat led to changes in the mechanism of inhibition. We observed from other studies that sustained inhibition of EP is required to effect a reduction in cumulative food intake and body weight, with concomitant improved blood glucose levels in obese and diabetic leptin-deficient mice. Thus, the structure-activity relationship needs to be driven by not only the inhibition potency but also the mechanistic and kinetic characterization. Our findings support EP as a target for the treatment of metabolic diseases and demonstrate that reversible covalent EP inhibitors show clinically relevant efficacy. SIGNIFICANCE STATEMENT: Interest in targeted covalent drugs has expanded in recent years, particularly so for kinase targets, but also more broadly. This study demonstrates that reversible covalent inhibition of the serine protease enteropeptidase is a therapeutically viable approach to the treatment of metabolic diseases and that mechanistic details of inhibition are relevant to clinical efficacy. Our mechanistic and kinetic studies outline a framework for detailed inhibitor characterization that is proving essential in guiding discovery efforts in this area.

A Delicate Balance between Antiferromagnetism and Ferromagnetism: Theoretical and Experimental Studies of A2 MRu5 B2 (A=Zr, Hf; M=Fe, Mn) Metal Borides.

Metal-rich borides with the Ti3 Co5 B2 -type structure represent an ideal playground for tuning magnetic interactions through chemical substitutions. In this work, density functional theory (DFT) and experimental studies of Ru-rich quaternary borides with the general composition A2 MRu5 B2 (A=Zr, Hf, M=Fe, Mn) are presented. Total energy calculations show that the phases Zr2 FeRu5 B2 and Hf2 FeRu5 B2 prefer ground states with strong antiferromagnetic (AFM) interactions between ferromagnetic (FM) M-chains. Manganese substitution for iron lowers these antiferromagnetic interchain interactions dramatically and creates a strong competition between FM and AFM states with a slight preference for AFM in Zr2 MnRu5 B2 and for FM in Hf2 MnRu5 B2 . Magnetic property measurements show a field dependence of the AFM transition (TN ): TN is found at 0.1 T for all phases with predicted AFM states whereas for the predicted FM phase it is found at a much lower magnetic field (0.005 T). Furthermore, TN is lowest for a Hf-based phase (20 K) and highest for a Zr-based one (28 K), in accordance with DFT predictions of weaker AFM interactions in the Hf-based phases. Interestingly, the AFM transitions vanish in all compounds at higher fields (>1 T) in favor of FM transitions, indicating metamagnetic behaviors for these Ru-rich phases.

The discovery of azetidine-piperazine di-amides as potent, selective and reversible monoacylglycerol lipase (MAGL) inhibitors.

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.

Photodynamic therapy for cutaneous squamous cell carcinoma in situ: Impact of anatomic location, tumor diameter, and incubation time on effectiveness.

BACKGROUND: Photodynamic therapy (PDT) has been reported as a treatment for cutaneous squamous cell carcinoma in situ (SCCis), but only limited data are available on the effectiveness of PDT with aminolevulinic acid (ALA-PDT). OBJECTIVE: To review the outcomes of SCCis treated with ALA-PDT and examine factors associated with response. METHODS: A retrospective review identified 58 patients with 68 primary SCCis lesions treated with ALA-PDT and blue light illumination. Patient demographics, lesion features, treatment details, clinical response, and subsequent recurrence were extracted from medical record reviews. RESULTS: On completion of PDT the initial complete response rate was 77.9% and was not associated with the number of PDT treatments. On multivariate analysis factors associated with response were location on the face, tumor diameter <2 cm, and longer ALA incubation time. Lesions treated with a maximum incubation time of <3 hours had a 53.3% response compared with 84.9% for longer incubation. Subsequent recurrence of SCCis was noted in 7 of 53 cases (13.2%) at a median time of 11.7 months. LIMITATIONS: This was a retrospective study performed at a single institution without systematic follow-up. CONCLUSIONS: ALA-PDT may be an effective treatment for selected cases of SCCis. Effectiveness is impacted by anatomic location, tumor diameter, and ALA incubation time.

From 3D to 2D: Structural, Spectroscopic and Theoretical Investigations of the Dimensionality Reduction in the [PtAl2 ]δ- Polyanions of the Isotypic MPtAl2 Series (M=Ca-Ba, Eu).

Four new MPtAl2 (M=Ca, Sr, Ba, Eu) compounds, adopting the orthorhombic MgCuAl2 -type structure, have been synthesized from the elements using tantalum ampoules. All compounds are obtained as platelet-shaped crystallites and exhibit an increasing moisture sensitivity with increasing size of the formal M cation. Structural investigations indicate a pronounced elongation of the crystallographic b-axis, which results in a significant distortion of the [PtAl2 ]δ- polyanion. Within the polyanion, layer-like arrangements can be found with bonding Pt-Al interactions within the slab; the increase of the b-axis can be attributed to increasing Al-Al distances and therefore decreasing interactions between the slabs, caused by the differently-sized formal M cations. While the alkaline earth (M=Ca, Sr) representatives exhibit Pauli paramagnetism, BaPtAl2 shows diamagnetic behavior, finally EuPtAl2 is ferromagnetic with TC =54.0(5) K. The effective magnetic moment indicates that the Eu atoms are in a divalent oxidation state, which is confirmed by 151 Eu Mössbauer spectroscopic investigations. Measurements below the Curie-temperature show a full magnetic hyperfine field splitting with Bhf =21.7(1) T. 27 Al and 195 Pt magic-angle spinning NMR spectroscopy corroborates the presence of single crystallographic sites for the Pt and Al atoms. The large 27 Al nuclear electric quadrupolar coupling constants confirm unusually strong electric field gradients, in agreement with the structural distortions and the respective theoretical calculations. X-ray photoelectron spectroscopy has been utilized to investigate the charge transfer within the polyanion. The Pt 4f binding energy decreases with decreasing electronegativity / ionization energy of the alkaline earth elements, suggesting an increasing electron density at the Pt atoms. Theoretical investigations underline the platinide character of the investigated compounds by Bader charge calculations. The analysis of the integrated crystal orbital Hamilton population (ICOHP) values, electron localization function (ELF) and isosurface analyses lead to a consistent structural picture, indicating stable layer-like arrangements of the [PtAl2 ]δ- polyanion.

The Effects of Astragalus Polysaccharide on Bone Marrow-Derived Mesenchymal Stem Cell Proliferation and Morphology Induced by A549 Lung Cancer Cells.

BACKGROUND The tumor microenvironment in lung cancer plays an important role in tumor progression and metastasis. Bone marrow-derived mesenchymal stem cells (MSCs) co-cultured with A549 lung cancer cells show changes in morphology, increase cell proliferation, and cell migration. This study aimed to investigate the effects of Astragalus polysaccharide (APS), a traditional Chinese herbal medicine, on the changes induced in bone marrow-derived MSCs by A549 lung cancer cells in vitro. MATERIAL AND METHODS Bone marrow-derived MSCs were co-cultured with A549 cells (Co-BMSCs). Co-cultured bone marrow-derived MSCs and A549 cells treated with 50 µg/ml of APS (Co-BMSCs + APS) were compared with untreated Co-BMSCs. Cell proliferation was measured using the cell counting kit-8 (CCK-8) assay. Flow cytometry evaluated the cell cycle. Microarray assays for mRNA expression and Western blot for protein expression were used. RESULTS Compared with untreated Co-BMSCs, APS treatment of Co-BMSCs improved cell morphology, reduced cell proliferation, and inhibited cell cycle arrest. The mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-kappaB) pathway, TP53, caspase-3, acetylated H4K5, acetylated H4K8, and acetylated H3K9 were involved in the regulatory process. CONCLUSIONS APS treatment reduced cell proliferation and morphological changes in bone marrow-derived MSCs that were co-cultured with A549 lung cancer cells in vitro.

An Old Dog with New Tricks - Additions to the Cesium Lithium Chloride System: Cs3Li2Cl5 and the Hydrated Cs3LiCl4 · 4H2O.

The CsCl/LiCl system has been studied for over a century now. Numerous phases have been predicted - only three have hitherto been found. We present the synthesis and single-crystal structure of the cesium lithium pentachloride Cs3Li2Cl5, predicted earlier but with a different structure. The anhydrous new phase readily reacts to Cs3LiCl4 · 4H2O in air. The tetrahydrate can also be obtained through the simplest, most inexpensive and green synthesis possible: an immediate, room-temperature mechanosynthesis from only CsCl and LiCl (3 : 1) in air. Differential scanning calorimetry (DSC) and thermogravimetric analyses (TGA), as well as in situ temperature-dependent powder X-ray diffraction studies on this second ever reported ternary alkali chloride hydrate allowed for a revision of the CsCl/LiCl phase diagram. Density of states and total energy calculations further elucidate the new alkali chlorides and update the relative stability of previous structure predictions.

The Protective Roles of Folic Acid in Preventing Diabetic Retinopathy Are Potentially Associated with Suppressions on Angiogenesis, Inflammation, and Oxidative Stress.

This study aimed to evaluate the therapeutic effect of folic acid (FA) on diabetic retinopathy (DR) in a genetic mouse model of obese type 2 diabetes mellitus (T2D). C57BL/KsJ-db/db (db/db) T2D mice were divided into control, FA, metformin (MET), and FA plus MET groups (n = 10/group). Serum levels of glucose, glycated hemoglobin, and insulin were determined weekly. The retinal thickness was measured using optical coherence tomography (OCT) at 4 weeks after treatments. The retinal expression and serum levels of vascular formation, inflammation, and oxidative stress-associated molecules were examined. Our results demonstrated that FA, but not MET, played a protective role against retinal thinning in the early stage of DR in db/db mice, although FA did not exhibit antihyperglycemic effect. In addition, retinal expression and serum levels of a panel of molecules associated with angiogenesis (CD31 and VEGFR), inflammation (IL-1ß and NLRP3), and oxidative stress (3-NT, 4-HNE, Vav2, and NOX4) were significantly downregulated in FA-treated diabetic mice compared with those in saline-treated controls. Furthermore, the serum level of homocysteine was also markedly decreased following FA treatments. These findings suggest that through potential suppressions on angiogenesis, inflammation, and oxidative stress, FA may serve as a potential therapeutic agent against DR.

Overexpression of Transglutaminase from Cucumber in Tobacco Increases Salt Tolerance through Regulation of Photosynthesis.

Transglutaminase (TGase) is a regulator of posttranslational modification of protein that provides physiological protection against diverse environmental stresses in plants. Nonetheless, the mechanisms of TGase-mediated salt tolerance remain largely unknown. Here, we found that the transcription of cucumber TGase (CsTGase) was induced in response to light and during leaf development, and the CsTGase protein was expressed in the chloroplast and the cell wall. The overexpression of the CsTGase gene effectively ameliorated salt-induced photoinhibition in tobacco plants, increased the levels of chloroplast polyamines (PAs) and enhanced the abundance of D1 and D2 proteins. TGase also induced the expression of photosynthesis related genes and remodeling of thylakoids under normal conditions. However, salt stress treatment reduced the photosynthesis rate, PSII and PSI related genes expression, D1 and D2 proteins in wild-type (WT) plants, while these effects were alleviated in CsTGase overexpression plants. Taken together, our results indicate that TGase-dependent PA signaling protects the proteins of thylakoids, which plays a critical role in plant response to salt stress. Thus, overexpression of TGase may be an effective strategy for enhancing resistance to salt stress of salt-sensitive crops in agricultural production.

Improving the Stability of Oil Body Emulsions from Diverse Plant Seeds Using Sodium Alginate.

In this study, peanut, sesame, and rapeseed oil bodies (OBs) were extracted by the aqueous medium method. The surface protein composition, microstructure, average particle size d 4 ,   3 , ζ-potential of the extracted OBs in aqueous emulsion were characterized. The stability of the OB emulsions was investigated. It was found that different OB emulsions contained different types and contents of endogenous and exogenous proteins. Aggregation at low pHs (<6) and creaming at high pHs (7 and 8) both occurred for all of three OB emulsions. Sodium alginate (ALG) was used to solve the instability of OB emulsions under different conditions-low concentration of ALG improved the stability of OB emulsions below and near the isoelectric point of the OBs, through electrostatic interaction. While a high concentration of ALG improved the OB emulsion stability through the viscosity effect at pH 7. The OB emulsions stabilized by ALG were salt-tolerant and freeze-thaw resistant.

Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation.

Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability of this therapeutic approach. This discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets.

Magnetic ordering and metal-atom site preference in tetragonal CrMnAs: Electronic correlation effects.

The electronic and magnetic structures of tetragonal, Cu2 Sb-type CrMnAs were examined using density functional theory. To obtain reasonable agreement with reported atomic and low-temperature magnetic ordering in this compound, the intra-atomic electron-electron correlation in term of Hubbard U on Mn atoms are necessary. Using GGA + U, calculations identify four low-energy antiferromagnetically ordered structures, all of which adopt a magnetic unit cell that contains the same direct CrCr and CrMn magnetic interaction, as well as the same indirect Mn⋅⋅⋅Mn magnetic interaction across the Cr planes. One of these low-energy configurations corresponds to the reported case. Effective exchange parameters for metal-metal contacts obtained from SPRKKR calculations indicate both direct and indirect exchange couplings play important roles in tetragonal CrMnAs. © 2018 Wiley Periodicals, Inc.