Far-red light modulates grapevine growth by increasing leaf photosynthesis efficiency and triggering organ-specific transcriptome remodelling : Author.

BACKGROUND: Growing evidence demonstrates that the synergistic interaction of far-red light with shorter wavelength lights could evidently improve the photosynthesis efficiency of multiple species. However, whether/how far-red light affects sink organs and consequently modulates the source‒sink relationships are largely unknown. RESULTS: Here, equal intensities of white and far-red lights were added to natural light for grape plantlets to investigate the effects of far-red light supplementation on grapevine growth and carbon assimilate allocation, as well as to reveal the underlying mechanisms, through physiological and transcriptomic analysis. The results showed that additional far-red light increased stem length and carbohydrate contents in multiple organs and decreased leaf area, specific leaf weight and dry weight of leaves in comparison with their counterparts grown under white light. Compared to white light, the maximum net photosynthetic rate of the leaves was increased by 31.72% by far-red light supplementation, indicating that far-red light indeed elevated the photosynthesis efficiency of grapes. Transcriptome analysis revealed that leaves were most responsive to far-red light, followed by sink organs, including stems and roots. Genes related to light signaling and carbon metabolites were tightly correlated with variations in the aforementioned physiological traits. In particular, VvLHCB1 is involved in light harvesting and restoring the balance of photosystem I and photosystem II excitation, and VvCOP1 and VvPIF3, which regulate light signal transduction, were upregulated under far-red conditions. In addition, the transcript abundances of the sugar transporter-encoding genes VvSWEET1 and VvSWEET3 and the carbon metabolite-encoding genes VvG6PD, VvSUS7 and VvPGAM varied in line with the change in sugar content. CONCLUSIONS: This study showed that far-red light synergistically functioning with white light has a beneficial effect on grape photosystem activity and is able to differentially affect the growth of sink organs, providing evidence for the possible addition of far-red light to the wavelength range of photosynthetically active radiation (PAR).

EML4-ALK G1202R and EML4-ALK L1196M mutations induce crizotinib resistance in non-small cell lung cancer cells through activating epithelial-mesenchymal transition mediated by MDM2/MEK/ERK signal axis.

Crizotinib, as the first-generation of anaplastic lymphoma kinase (ALK) inhibitor, effectively improves the survival time of ALK-positive non-small cell lung cancer (NSCLC) patients. However, its efficacy is severely limited by drug resistance caused by secondary mutations. G1202R and L1196M are classical mutation sites located in ALK kinase domain. They may hinder the binding of ALK inhibitors to the target kinase domain, resulting in drug resistance in patients. However, the exact mechanism of drug resistance mediated by these mutations remains unclear. In this study, we aimed to evaluate how G1202R and L1196M mutations mediate crizotinib resistance. To explore the resistance mechanism, we constructed EML4-ALK G1202R and L1196M mutant cell lines with A549 cells. The results showed that the mutant cells exhibited significant epithelial-mesenchymal transition (EMT) and metastasis compared to control (A549-vector) or wild type (A549-EML4-ALK) cells. Subsequently, it was found that the occurrence of EMT was correlated to the high expression of murine double minute 2 (MDM2) protein and the activation of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway in mutant cells. Down-regulation of MDM2 inhibited the activation of MEK/ERK pathway, thus reversed the EMT process and markedly increased the inhibitory effect of crizotinib on the growth of mutant cells. Collectively, resistance of ALK-positive NSCLC cells to crizotinib is induced by G1202R and L1196M mutations through activation of the MDM2/MEK/ERK signalling axis, promoting EMT process and metastasis. These findings suggest that the combination of MDM2 inhibitors and crizotinib could be a potential therapeutic strategy.

The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells.

We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell-specific promoters and demonstrate that Pax4 forces endocrine precursor cells, as well as mature alpha cells, to adopt a beta cell destiny. This results in a glucagon deficiency that provokes a compensatory and continuous glucagon+ cell neogenesis requiring the re-expression of the proendocrine gene Ngn3. However, the newly formed alpha cells fail to correct the hypoglucagonemia since they subsequently acquire a beta cell phenotype upon Pax4 ectopic expression. Notably, this cycle of neogenesis and redifferentiation caused by ectopic expression of Pax4 in alpha cells is capable of restoring a functional beta cell mass and curing diabetes in animals that have been chemically depleted of beta cells.

High-Performance, Light-Stimulation Healable, and Closed-Loop Recyclable Lignin-Based Covalent Adaptable Networks.

In this work, high-performance, light-stimulation healable, and closed-loop recyclable covalent adaptable networks are successfully synthesized from natural lignin-based polyurethane (LPU) Zn2+ coordination structures (LPUxZy). Using an optimized LPU (LPU-20 with a tensile strength of 28.4 ± 3.5 MPa) as the matrix for Zn2+ coordination, LPUs with covalent adaptable coordination networks are obtained that have different amounts of Zn. When the feed amount of ZnCl2 is 9 wt%, the strength of LPU-20Z9 reaches 37.3 ± 3.1 MPa with a toughness of 175.4 ± 4.6 MJ m-3 , which is 1.7 times of that of LPU-20. In addition, Zn2+ has a crucial catalytic effect on "dissociation mechanism" in the exchange reaction of LPU. Moreover, the Zn2+ -based coordination bonds significantly enhance the photothermal conversion capability of lignin. The maximum surface temperature of LPU-20Z9 reaches 118 °C under the near-infrared illumination of 0.8 W m-2 . This allows the LPU-20Z9 to self-heal within 10 min. Due to the catalytic effect of Zn2+ , LPU-20Z9 can be degraded and recovered in ethanol completely. Through the investigation of the mechanisms for exchange reaction and the design of the closed-loop recycling method, this work is expected to provide insight into the development of novel LPUs with high-performance, light-stimulated heal ability, and closed-loop recyclability; which can be applied toward the expanded development of intelligent elastomers.

Synthesis of pyrazoles from sulfonyl hydrazone and benzyl acrylate under transition-metal-free conditions.

Pyrazoles as an important class of heterocyclic compounds, are widely found in pharmaceuticals and bioactive natural products. Herein we report a [3 + 2] cycloaddition reaction for the synthesis of a series of pyrazoles, with the yield up to 77%. This approach exhibits many notable features, such as convenient operating conditions, excellent functional group compatibility and readily accessible raw materials, providing an alternative route for the construction of pyrazole derivatives.

Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas.

Novel strategies in diabetes therapy would obviously benefit from the use of beta (beta) cell stem/progenitor cells. However, whether or not adult beta cell progenitors exist is one of the most controversial issues in today's diabetes research. Guided by the expression of Neurogenin 3 (Ngn3), the earliest islet cell-specific transcription factor in embryonic development, we show that beta cell progenitors can be activated in injured adult mouse pancreas and are located in the ductal lining. Differentiation of the adult progenitors is Ngn3 dependent and gives rise to all islet cell types, including glucose responsive beta cells that subsequently proliferate, both in situ and when cultured in embryonic pancreas explants. Multipotent progenitor cells thus exist in the pancreas of adult mice and can be activated cell autonomously to increase the functional beta cell mass by differentiation and proliferation rather than by self-duplication of pre-existing beta cells only.

Effect of platelet-rich plasma on the attachment of periodontal ligament fibroblasts to the diseased root surface and the attendant collagen formation.

OBJECTIVE: To investigate the effect of different concentrations of platelet-rich plasma (PRP) on collagen formation via periodontal ligament fibroblasts (PDLFs) on the surface of demineralised diseased tooth roots. METHODS: Various PDLFs were grown from tissue explants, with the cells between the fifth and eighth passage in the culture used. Human whole blood obtained from healthy subjects was collected in tubes containing an anticoagulant (acid-citrate-dextrose) and centrifuged (1300 rpm for 10 min) before the supernatant PRP layer was removed. A second spin at (2000 rpm for 10 min) produced the PRP fraction. The effect of PRP of various concentrations on the attachment of PDLFs on the diseased root surface of human teeth demineralised with ethylenediaminetetraacetic acid (EDTA) and treated with the PRP was then investigated in terms of PRP collagen formation, with the formation observed using the Sirius red staining method. RESULTS: The optical density values of the experimental groups were statistically significantly higher than those of the control groups (P < 0.05), while the Sirius red staining returned positive results for both the experimental group (A) and the control group (B). The images were analysed using a histogram, and a statistically significant difference was found (P < 0.05). CONCLUSION: While PRP could promote the attachment and collagen formation of PDLFs on the diseased root surface of human teeth demineralised with EDTA and treated with PRP, the effect is potentially reduced when the dose exceeds 20%.

Adsorption Thermodynamic and Kinetic Mechanism of Substrate-Induced Molecular Geometry Orientation.

N719 dye (cis-[Ru(4-carboxy-4'-carboxylate-2,2'-bipyridine)2(NCS)2]) contains two carboxylic acid/carboxylate groups and two isothiocyanato (NCS) ligands and exhibit different spatial adsorption orientations during adsorption on different substrate surfaces. However, the effect of spatially adsorption orientations on the adsorption process has been rarely reported. This paper presents a detailed study of the adsorption kinetics and thermodynamics of N719 molecules based on a quartz crystal microbalance under variable temperature conditions using TiO2 or Au substrate surfaces to induce changes in the geometrical orientation molecules. This work also reveals the adsorption properties of carboxylate groups and NCS ligands acting as anchoring groups. Research results have shown that the surface N719 molecular density of the TiO2 substrate is higher than that of the Au substrate. Adsorption kinetics have shown that the adsorption rate of N719 molecules on the Au substrate surface with NCS ligands as anchor groups is slightly higher than that of carboxylate as the anchor groups on the TiO2 substrate surface, and in the case of the former adsorption mode, the desorption is more pronounced. Under two different spatial orientation adsorption modes, both exhibit physical adsorption. The thermodynamics of molecular adsorption with different spatial orientations show that all adsorption processes are spontaneous and endothermic. This work is beneficial for understanding the mechanism of adsorption of dye molecules, dye molecule synthesis method, ligand selection, and improvement of device efficiency.

Rhodium(III)-catalyzed cascade C-H functionalization/annulation of sulfoximines with iodonium ylides for the synthesis of cyclohexanone-1,2-benzothiazines.

A highly efficient Rh(III)-catalyzed cascade C-H activation/annulation of sulfoximines with iodonium ylides under metal-oxidant-free conditions has been reported. The fused cyclohexanone-1,2-benzothiazine scaffold is readily achieved with a one-pot process in this reaction. This protocol exhibits good functional group tolerance and moderate to excellent yields. Additionally, the olefination of the target product illustrates the promising usefulness of this strategy.

Metal-free visible-light-driven cascade cyclization reaction to synthesize 2-oxindoles via benzoyl and phenylsulfinyl radicals with acrylamide derivatives.

A metal-free visible-light-driven cascade cyclization reaction to synthesize 3-methyl-3-acetophenone-2-oxindoles and 3-methyl-3-(methylsulfonyl)benzene-2-oxindoles in yields up to 96% and 99%, via benzoyl and phenylsulfinyl radicals with acrylamide derivatives is reported, respectively. Extensive studies, including gram-scale, radical capture and isotope experiments, were performed to indicate that the reaction may involve a radical process.

Proteomic Analysis of Exudates from Chronic Ulcer of Diabetic Foot Treated with Scorpion Antimicrobial Peptide.

Scorpion peptides have good therapeutic effect on chronic ulcer of diabetic foot, but the related pharmacological mechanism has remained unclear. The different proteins and bacteria present in ulcer exudates from chronic diabetic foot patients, treated with scorpion antimicrobial peptide at different stages, were analyzed using isobaric tags for quantification-labeled proteomics and bacteriological methods. According to the mass spectrometry data, a total of 1865 proteins were identified qualitatively, and the number of the different proteins was 130 (mid/early), 401 (late/early), and 310 (mid, late/early). In addition, functional annotation, cluster analysis of effects and the analysis of signal pathway, transcription regulation, and protein-protein interaction network were carried out. The results showed that the biochemical changes of wound microenvironment during the treatment involved activated biological functions such as protein synthesis, cell proliferation, differentiation, migration, movement, and survival. Inhibited biological functions such as cell death, inflammatory response, immune diseases, and bacterial growth were also involved. Bacteriological analysis showed that Burkholderia cepacia was the main bacteria in the early and middle stage of ulcer exudate and Staphylococcus epidermidis in the late stage. This study provides basic data for further elucidation of the molecular mechanism of diabetic foot.

Isolated anti-HBc is an independent risk factor for tumor recurrence in intrahepatic cholangiocarcinoma after curative resection.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a poorly understood and aggressive malignancy with increasing incidence and mortality. Hepatitis B virus (HBV) infection is recognized as one of the important risk factors of ICC. There are few reports focusing on whether isolated antibody to hepatitis B core antigen (isolated anti-HBc, IAHBc) have prognostic role in ICC, while positive hepatitis B surface antigen (HBsAg) has been reported to be associated with the prognosis of ICC. The aim of this study was to investigate the prognostic value of IAHBc in ICC patients after curative resection, in order to identify those who have the high risk of ICC recurrence in the early stage. METHODS: We divided 209 ICC patients who underwent curative resection into 4 groups: group I (n = 40), HBsAg (-)/antibody to hepatitis B surface antigen (anti-HBs) (-)/anti-HBc (+); group II (n = 70), HBsAg (+)/anti-HBc (-); group III (n = 55), HBsAg (-)/anti-HBs (+)/anti-HBc (+); and group IV (n = 44), HBsAg (-)/anti-HBc (-). We compared the recurrence-free survival (RFS) and overall survival (OS) among these four groups. RESULTS: The median follow-up time was 16.93 months (range 1-34.6 months). The 1- and 2-year RFS and OS rates were 60% and 42%, and 78% and 63% respectively in all patients. Compared to the whole non-IAHBc patients (group II + group III + group IV), IAHBc patients (group I) showed significantly lower RFS at 1 year (39.8% vs. 64.4%, P = 0.001) and 2 years (20.7% vs. 46.7%, P = 0.001). When compared to other three individual groups, IAHBc patients (group I) also had the lowest RFS. We did not find significant difference in OS among the four groups. Further multivariate analysis revealed that IAHBc was an independent risk factor of RFS. CONCLUSIONS: IAHBc is an independent poor prognostic factor for tumor recurrence in ICC patients after curative resection.

Conjunctive Analyses of BSA-Seq and BSR-Seq Unveil the Msß-GAL and MsJMT as Key Candidate Genes for Cytoplasmic Male Sterility in Alfalfa (Medicago sativa L.).

Knowing the molecular mechanism of male sterility in alfalfa is important to utilize the heterosis more effectively. However, the molecular mechanisms of male sterility in alfalfa are still unclear. In this study, the bulked segregant analysis (BSA) and bulked segregant RNA-seq (BSR) were performed with F2 separation progeny to study the molecular mechanism of male sterility in alfalfa. The BSA-seq analysis was located in a candidate region on chromosome 5 containing 626 candidate genes which were associated with male sterility in alfalfa, while the BSR-seq analysis filtered seven candidate DEGs related to male sterility, and these candidate genes including EF-Tu, ß-GAL, CESA, PHGDH, and JMT. The conjunctive analyses of BSR and BSA methods revealed that the genes of Msß-GAL and MsJMT are the common detected candidate genes involved in male sterility in alfalfa. Our research provides a theory basis for further study of the molecular mechanism of male sterility in alfalfa and significant information for the genetic breeding of Medicago sativa.

Andrographolide Inhibits Biofilm and Virulence in Listeria monocytogenes as a Quorum-Sensing Inhibitor.

Listeria monocytogenes is a major foodborne pathogen that can cause listeriosis in humans and animals. Andrographolide is known as a natural antibiotic and exhibits good antibacterial activity. We aimed to investigate the effect of andrographolide on two quorum-sensing (QS) systems, LuxS/AI-2 and Agr/AIP of L. monocytogenes, as well as QS-controlled phenotypes in this study. Our results showed that neither luxS expression nor AI-2 production was affected by andrographolide. Nevertheless, andrographolide significantly reduced the expression levels of the agr genes and the activity of the agr promoter P2. Results from the crystal violet staining method, confocal laser scanning microscopy (CLSM), and field emission scanning electron microscopy (FE-SEM) demonstrated that andrographolide remarkably inhibited the biofilm-forming ability of L. monocytogenes 10403S. The preformed biofilms were eradicated when exposed to andrographolide, and reduced surviving cells were also observed in treated biofilms. L. monocytogenes treated with andrographolide exhibited decreased ability to secrete LLO and adhere to and invade Caco-2 cells. Therefore, andrographolide is a potential QS inhibitor by targeting the Agr QS system to reduce biofilm formation and virulence of L. monocytogenes.

Na2S-Mediated One-Pot Selective Deoxygenation of α-Hydroxyl Carbonyl Compounds including Natural Products.

A practical method for the deoxygenation of α-hydroxyl carbonyl compounds under mild reaction conditions is reported here. The use of cheap and easy-to-handle Na2S·9H2O as the reductant in the presence of PPh3 and N-chlorosuccinimide (NCS) enables the selective dehydroxylation of α-hydroxyl carbonyl compounds, including ketones, esters, amides, imides and nitrile groups. The synthetic utility is demonstrated by the late-stage deoxygenation of bioactive molecule and complex natural products.

A Reactivity-Tunable Self-Immolative Design Enables Histone Deacetylase-Targeted Imaging and Prodrug Activation.

Histone deacetylase (HDAC)-targeted probes and prodrugs are crucial for cancer theranostics. We developed a self-immolative design that enables in vivo activatable near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging and prodrug release in response to HDAC. This design comprises a phenyl ester linker with tunable reactivity, facilitating efficient release of caged fluorophores/drugs upon deacetylation. We engineered a new fluorophore using a spirocyclic xanthene scaffold with ring-open property, affording NIRF/PA detection with high contrast. We showed that a nitro-substituted self-immolative linker allows sensitive NIRF/PA in vivo imaging of HDAC with minimal interference. A highly efficient prodrug system was further developed for targeted therapy in HDAC-overexpressed triple negative breast tumors in mice. Our study provides a valuable paradigm for HDAC-targeted NIRF/PA imaging and prodrug release in vivo, highlighting its potential for bioimaging and drug development.

Palladium-Catalyzed ß-C(sp3)-H Arylation of Aliphatic Ketones Enabled by a Transient Directing Group.

The direct arylation of aliphatic ketones has been developed via Pd-catalyzed ß-C(sp3)-H bond functionalization with 2-(aminooxy)-N,N-dimethylacetamide as a novel transient directing group (TDG), which showed remarkable directing ability to generate arylated products in moderate to good yields. Furthermore, the reaction can tolerate abundant substrate of ketones and aryl iodides. This study expands the scope of applications for TDGs.

Selective synthesis of sulfoxides and sulfones via controllable oxidation of sulfides with N-fluorobenzenesulfonimide.

A practical and mild method for the switchable synthesis of sulfoxides or sulfones via selective oxidation of sulfides using cheap N-fluorobenzenesulfonimide (NFSI) as the oxidant has been developed. These highly chemoselective transformations were simply achieved by varying the NFSI loading with H2O as the green solvent and oxygen source without any additives. The good functional group tolerance makes the strategy valuable.

Exploring the binding mechanism of positive allosteric modulators in human metabotropic glutamate receptor 2 using molecular dynamics simulations.

Positive allosteric modulators (PAMs) of human metabotropic glutamate receptor 2 (hmGlu2) are well-known in the treatment of psychiatric disorders for their higher selectivity and lower tolerance risk. A variety of PAMs have been reported over the last decade and two compounds were in Phase II clinical trials for schizophrenia and anxiety. These trials were discontinued on account of the unsatisfactory therapeutic efficacy, but PAMs were explored as novel treatments for addiction and epilepsy. Thus, it is still important to explore novel hmGlu2 PAMs in the near future. Nowadays, the challenges in optimizing drug potency and improving scaffold diversity for PAMs are the noncomprehensive character analyses of multiple scaffolds; the exploration of the binding modes of PAMs in the allosteric binding site have been proposed to reduce this difficulty. However, there has been no comprehensive research about the binding profiles of PAMs in the hmGlu2 receptor. To address this issue, this work explores the binding characters of eight PAMs representing five chemical series by multiple computational methods. As a result, the shared binding modes of the eight studied PAMs interacting with 15 residues in the allosteric binding site were defined. In addition, the reduced hydrophobicity with low electronegativity of R1, increased hydrophobicity with low negative electron density of R2 and the electronegativity of the linker were identified as indicators that regulate the affinity of PAMs. This finding agrees well with the physicochemical properties of reported multiple series PAMs. This comprehensive work sheds additional light on the binding mechanism and physicochemical regularity underlining PAMs affinity and could be further utilized as a structural and energetic blueprint for discovering and assessing novel PAMs for hmGlu2.

The novel ALK inhibitor ZX-29 induces apoptosis through inhibiting ALK and inducing ROS-mediated endoplasmic reticulum stress in Karpas299 cells.

It is a well-known fact that 60%-85% of anaplastic large cell lymphoma (ALCL) is mainly driven by the anaplastic lymphoma kinase (ALK) fusion protein. Although ALK-positive ALCL patients respond significantly to ALK inhibitors, the development of resistance is inevitable, which requires the development of new therapeutic strategies for ALK-positive ALCL. Here, we investigated the anticancer activities of N-(2((5-chloro-2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (ZX-29), a newly synthesized ALK inhibitor, against nucleophosmin-ALK-positive cell line Karpas299. We demonstrated that ZX-29 decreased Karpas299 cells growth and had better cytotoxicity than ceritinib, which was mediated through downregulating the expression of ALK and related proteins, inducing cell cycle arrest, and promoting cell apoptosis. Moreover, ZX-29-induced cell apoptosis by inducing endoplasmic reticulum stress (ERS). In addition, ZX-29 increased the generation of reactive oxygen species (ROS), and cells pretreatment with N-acetyl- l-cysteine could attenuate ZX-29-induced cell apoptosis and ERS. Taken together, ZX-29 inhibited Karpas299 cell proliferation and induced apoptosis through inhibiting ALK and its downstream protein expression and inducing ROS-mediated ERS. Therefore, our results provide evidence for a novel antitumor candidate for the further investigation.