[Clinical significance of IL-18 and IL-18-binding protein in bone marrow of patients with myelodysplastic syndrome].

Objective: To analyze the level and clinical significance of IL-18 and IL-18-binding protein (BP) in the bone marrow of patients with myelodysplastic syndrome (MDS) . Methods: A total of 43 newly diagnosed patients with MDS who were admitted to the Department of Hematology, Tianjin Medical University General Hospital, from July 2020 to February 2021 were randomly selected. The control group consisted of 14 patients with acute myeloid leukemia (AML) and 25 patients with iron-deficiency anemia (IDA). The levels of IL-18 and IL-18 BP in the bone marrow supernatant were measured, and their correlations with MDS severity, as well as the functionality of CD8(+) T cells and natural killer cells, was analyzed. Results: The levels of IL-18, IL-18 BP, and free IL-18 (fIL-18) in the bone marrow supernatant of patients with MDS were higher than in the IDA group. The level of fIL-18 was linearly and negatively correlated with the MDS-International Prognostic Scoring System (IPSS) score. IL-18 receptor (IL-18Rα) expression on CD8(+) T cells in the MDS group was lower than in the IDA group, and the levels of fIL-18 and IL-18Rα were positively correlated with CD8(+) T-cell function in the MDS group. Conclusion: IL-18 BP antagonizes IL-18, leading to a decrease in fIL-18 in the bone marrow microenvironment of patients with MDS, affecting CD8(+) T-cell function, which is closely related to MDS severity; therefore, it may become a new target for MDS treatment.

The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore.

MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.

Genetic improvement of wheat early vigor promote weed-competitiveness under Mediterranean climate.

Chemical weed-control is the most effective practice for wheat, however, rapid evolution of herbicide-resistant weeds threat food-security and calls for integration of non-chemical practices. We hypothesis that integration of alternative GA-responsive dwarfing genes into elite wheat cultivars can promote early vigor and weed-competitiveness under Mediterranean climate. We develop near-isogenic lines of bread wheat cultivars with GAR dwarfing genes and evaluate them for early vigor and weed-competitiveness under various environmental and management conditions to identify promising NIL for weed-competitiveness and grain yield. While all seven NILs responded to external gibberellic acid application, they exhibited differences in early vigor. Greenhouse and field evaluations highlighted NIL OC1 (Rht8andRht12) as a promising line, with significant advantage in canopy early vigor over its parental. To facilitate accurate and continuous early vigor data collection, we applied non-destructive image-based phenotyping approaches which offers non-expensive and end-user friendly solution for selection. NIL OC1 was tested under different weed density level, infestation waves, and temperatures and highlight the complex genotypic × environmental × management interactions. Our findings demonstrate the potential of genetic modification of dwarfing genes as promising approach to improve weed-competitiveness, and serve as basis for future breeding efforts to support sustainable wheat production under semi-arid Mediterranean climate.

Safety and efficacy of taurine as an add-on treatment for tics in youngsters.

BACKGROUND AND PURPOSE: The pathophysiological model of tics generally describes disruption of γ-aminobutyric acid transmission, and taurine is found to be an agonist of γ-aminobutyric acid receptors. The study aimed to evaluate the safety and efficacy of taurine as an add-on treatment for tics. METHODS: Four hundred and four youngsters with tic disorders were randomly assigned to 12 weeks of either oral taurine or placebo. The Yale Global Tic Severity Scale was used to measure tic severity. The primary outcome measure was global severity scores reduced by more than 60% compared with baseline scores. RESULTS: Three hundred and eighty-two patients were successfully treated. At week 4, no significant differences were found in the treatment effect and the total occurrence of adverse drug reactions between the taurine and placebo groups. At week 12, the proportion of significant improvement in tics was significantly higher in the taurine group than the placebo group (53.4% with taurine versus 34.5% without taurine; relative risk 1.546; P < 0.001), and no group differences were found in the total occurrence of adverse drug reactions. CONCLUSIONS: Taurine is safe and effective for tics.

Phenotypic analysis of atopic dermatitis in children aged 1-12 months: elaboration of novel diagnostic criteria for infants in China and estimation of prevalence.

BACKGROUND: Atopic dermatitis (AD) is the most common skin disorder in infancy. However, the diagnosis and definite significance of infantile AD remains a debated issue. OBJECTIVE: To analyse the phenotypes of AD in infancy, to establish diagnostic criteria and to estimate the prevalence of this condition in China. METHODS: This is a multicentric study, in which 12 locations were chosen from different metropolitan areas of China. Following careful and complete history-taking and skin examination, the definite diagnosis of AD was made and the severity based on the SCORAD index was determined by local experienced dermatologists. Based on the detailed phenotyping, the major and representative clinical features of infantile AD were selected to establish the diagnostic criteria and evaluate their diagnostic efficacy. RESULTS: A total of 5967 infants were included in this study. The overall point prevalence of AD was 30.48%. The infantile AD developed as early as at the second month of life, and its incidence peaked in the third month of life at 40.81%. The proportion of mild, moderate and severe AD was 67.40%, 30.57% and 2.03%, respectively. The most commonly seen manifestations in the infantile AD were facial dermatitis (72.07%), xerosis (42.72%) and scalp dermatitis (27.93%). We established the novel diagnostic criteria of infants, which included: (i) onset after 2 weeks of birth; (ii) pruritus and/or irritability and sleeplessness comparable with lesions; and (iii) all two items above with one of the following items can reach a diagnosis of AD: (i) eczematous lesions distributed on cheeks and/or scalp and/or extensor limbs, and (ii) eczematous lesions on any other parts of body accompanied by xerosis. CONCLUSIONS: In China, the prevalence of AD in infancy is 30.48% according to clinical diagnosis of dermatologists. The novel Chinese diagnostic criteria for AD in infants show a higher sensitivity and comparable specificity.

An Improved Racetrack Structure for Transporting a Skyrmion.

Magnetic skyrmions are promising building blocks for next generation data storage due to their stability, small size and extremely low currents to drive them, which can be used instead of traditional magnetic domain walls to store information as data bits in metalic racetrack memories. However, skyrmions can drift from the direction of electron flow due to the Magnus force and thus may annihilate at the racetrack edges, resulting in the loss of information. Here we propose a new skyrmion-based racetrack structure by adding high-K materials (materials with high magnetic crystalline anisotropy) at the edges, which confines the skyrmions in the center region of the metalic racetrack efficiently. This design can overcome both the clogging and annihilation of skyrmions according to our micromagnetic simulation, which occur normally for skyrmions moving on a racetrack under small and large driving currents, respectively. Phase diagrams for skyrmion motion on the proposed racetrack with various values of current density and racetrack edge width have been calculated and given, showing that skyrmions can be driven at a high speed (about 300 m/s) in the racetrack under relatively smaller driving currents. This design offers the possiblity of building an ultrafast and energy-efficient skyrmion transport device.

MOAP-1 Mediates Fas-Induced Apoptosis in Liver by Facilitating tBid Recruitment to Mitochondria.

Fas apoptotic signaling regulates diverse physiological processes. Acute activation of Fas signaling triggers massive apoptosis in liver. Upon Fas receptor stimulation, the BH3-only protein Bid is cleaved into the active form, tBid. Subsequent tBid recruitment to mitochondria, which is facilitated by its receptor MTCH2 at the outer mitochondrial membrane (OMM), is a critical step for commitment to apoptosis via the effector proteins Bax or Bak. MOAP-1 is a Bax-binding protein enriched at the OMM. Here, we show that MOAP-1-deficient mice are resistant to Fas-induced hepatocellular apoptosis and lethality. In the absence of MOAP-1, mitochondrial accumulation of tBid is markedly impaired. MOAP-1 binds to MTCH2, and this interaction appears necessary for MTCH2 to engage tBid. These findings reveal a role for MOAP-1 in Fas signaling in the liver by promoting MTCH2-mediated tBid recruitment to mitochondria.

A Nanobody Activation Immunotherapeutic that Selectively Destroys HER2-Positive Breast Cancer Cells.

We report a rationally designed nanobody activation immunotherapeutic that selectively redirects anti-dinitrophenyl (anti-DNP) antibodies to the surface of HER2-positive breast cancer cells, resulting in their targeted destruction by antibody-dependent cellular cytotoxicity. As nanobodies are relatively easy to express, stable, can be humanized, and can be evolved to potently and selectively bind virtually any disease-relevant cell surface receptor, we anticipate broad utility of this therapeutic strategy.

Deterioration of the coercivity due to the diffusion induced interface layer in hard/soft multilayers.

Hard/soft permanent magnets have aroused many interests in the past two decades because of their potential in achieving giant energy products as well as their rich variety of magnetic behaviors. Nevertheless, the experimental energy products are much smaller than the theoretical ones due to the much smaller coercivity measured in the experiments. In this paper, the deterioration of the coercivity due to the interface atomic diffusion is demonstrated based on a three dimensional (3D) micromagnetic software (OOMMF) and a formula derived for the pinning field in a hard/soft multilayer, which can be applied to both permanent magnets and exchange-coupled-composite (ECC) media. It is found that the formation of the interface layer can decrease the coercivity by roughly 50%, which is responsible for the observed smaller coercivity in both composite and single-phased permanent magnets. A method to enhance the coercivity in these systems is proposed based on the discussions, consistent with recent experiments where excellent magnetic properties are achieved.

Illuminating HIV gp120-Ligand Recognition through Computationally-Driven Optimization of Antibody-Recruiting Molecules.

Here we report on the structure-based optimization of antibody-recruiting molecules targeting HIV gp120 (ARM-H). These studies have leveraged a combination of medicinal chemistry, biochemical and cellular assay analysis, and computation. Our findings have afforded an optimized analog of ARM-H, which is ~1000 fold more potent in gp120-binding and MT-2 antiviral assays than our previously reported derivative. Furthermore, computational analysis, taken together with experimental data, provides evidence that azaindole- and indole-based attachment inhibitors bind gp120 at an accessory hydrophobic pocket beneath the CD4-binding site and can also adopt multiple unique binding modes in interacting with gp120. These results are likely to prove highly enabling in the development of novel HIV attachment inhibitors, and more broadly, they suggest novel applications for ARMs as probes of conformationally flexible systems.

Accurate GM atrophy quantification in MS using lesion-filling with co-registered 2D lesion masks.

BACKGROUND: In multiple sclerosis (MS), brain atrophy quantification is affected by white matter lesions. LEAP and FSL-lesion_filling, replace lesion voxels with white matter intensities; however, they require precise lesion identification on 3DT1-images. AIM: To determine whether 2DT2 lesion masks co-registered to 3DT1 images, yield grey and white matter volumes comparable to precise lesion masks. METHODS: 2DT2 lesion masks were linearly co-registered to 20 3DT1-images of MS patients, with nearest-neighbor (NNI), and tri-linear interpolation. As gold-standard, lesion masks were manually outlined on 3DT1-images. LEAP and FSL-lesion_filling were applied with each lesion mask. Grey (GM) and white matter (WM) volumes were quantified with FSL-FAST, and deep gray matter (DGM) volumes using FSL-FIRST. Volumes were compared between lesion mask types using paired Wilcoxon tests. RESULTS: Lesion-filling with gold-standard lesion masks compared to native images reduced GM overestimation by 1.93 mL (p < .001) for LEAP, and 1.21 mL (p = .002) for FSL-lesion_filling. Similar effects were achieved with NNI lesion masks from 2DT2. Global WM underestimation was not significantly influenced. GM and WM volumes from NNI, did not differ significantly from gold-standard. GM segmentation differed between lesion masks in the lesion area, and also elsewhere. Using the gold-standard, FSL-FAST quantified as GM on average 0.4% of the lesion area with LEAP and 24.5% with FSL-lesion_filling. Lesion-filling did not influence DGM volumes from FSL-FIRST. DISCUSSION: These results demonstrate that for global GM volumetry, precise lesion masks on 3DT1 images can be replaced by co-registered 2DT2 lesion masks. This makes lesion-filling a feasible method for GM atrophy measurements in MS.

Using genetically modified tomato crop plants with purple leaves for absolute weed/crop classification.

BACKGROUND: Weed/crop classification is considered the main problem in developing precise weed-management methodologies, because both crops and weeds share similar hues. Great effort has been invested in the development of classification models, most based on expensive sensors and complicated algorithms. However, satisfactory results are not consistently obtained due to imaging conditions in the field. RESULTS: We report on an innovative approach that combines advances in genetic engineering and robust image-processing methods to detect weeds and distinguish them from crop plants by manipulating the crop's leaf color. We demonstrate this on genetically modified tomato (germplasm AN-113) which expresses a purple leaf color. An autonomous weed/crop classification is performed using an invariant-hue transformation that is applied to images acquired by a standard consumer camera (visible wavelength) and handles variations in illumination intensities. CONCLUSION: The integration of these methodologies is simple and effective, and classification results were accurate and stable under a wide range of imaging conditions. Using this approach, we simplify the most complicated stage in image-based weed/crop classification models.

Exploring binding and effector functions of natural human antibodies using synthetic immunomodulators.

The ability to profile the prevalence and functional activity of endogenous antibodies is of vast clinical and diagnostic importance. Serum antibodies are an important class of biomarkers and are also crucial elements of immune responses elicited by natural disease-causing agents as well as vaccines. In particular, materials for manipulating and/or enhancing immune responses toward disease-causing cells or viruses have exhibited significant promise for therapeutic applications. Antibody-recruiting molecules (ARMs), bifunctional organic molecules that redirect endogenous antibodies to pathological targets, thereby increasing their recognition and clearance by the immune system, have proven particularly interesting. Notably, although ARMs capable of hijacking antibodies against oligosaccharides and electron-poor aromatics have proven efficacious, systematic comparisons of the prevalence and effectiveness of natural anti-hapten antibody populations have not appeared in the literature. Herein we report head-to-head comparisons of three chemically simple antigens, which are known ligands for endogenous antibodies. Thus, we have chemically synthesized bifunctional molecules containing 2,4-dinitrophenyl (DNP), phosphorylcholine (PC), and rhamnose. We have then used a combination of ELISA, flow cytometry, and cell-viability assays to compare these antigens in terms of their abilities both to recruit natural antibody from human serum and also to direct serum-dependent cytotoxicity against target cells. These studies have revealed rhamnose to be the most efficacious of the synthetic antigens examined. Furthermore, analysis of 122 individual serum samples has afforded comprehensive insights into population-wide prevalence and isotype distributions of distinct anti-hapten antibody populations. In addition to providing a general platform for comparing and studying anti-hapten antibodies, these studies serve as a useful starting point for the optimization of antibody-recruiting molecules and other synthetic strategies for modulating human immunity.

Wharton-fragmentation-based approach to the carbocyclic core of the phomoidrides.

The carbocyclic core of the phomoidrides has been synthesized efficiently and in high yield. Key steps include a phenolic oxidation/intramolecular Diels-Alder sequence, tandem radical cyclization, and a late-stage Wharton fragmentation of a densely functionalized isotwistane skeleton.

Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition.

Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O-H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition.

Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin.

Loss of the E3 ubiquitin ligase Parkin causes early onset Parkinson's disease, a neurodegenerative disorder of unknown etiology. Parkin has been linked to multiple cellular processes including protein degradation, mitochondrial homeostasis, and autophagy; however, its precise role in pathogenesis is unclear. Recent evidence suggests that Parkin is recruited to damaged mitochondria, possibly affecting mitochondrial fission and/or fusion, to mediate their autophagic turnover. The precise mechanism of recruitment and the ubiquitination target are unclear. Here we show in Drosophila cells that PINK1 is required to recruit Parkin to dysfunctional mitochondria and promote their degradation. Furthermore, PINK1 and Parkin mediate the ubiquitination of the profusion factor Mfn on the outer surface of mitochondria. Loss of Drosophila PINK1 or parkin causes an increase in Mfn abundance in vivo and concomitant elongation of mitochondria. These findings provide a molecular mechanism by which the PINK1/Parkin pathway affects mitochondrial fission/fusion as suggested by previous genetic interaction studies. We hypothesize that Mfn ubiquitination may provide a mechanism by which terminally damaged mitochondria are labeled and sequestered for degradation by autophagy.

Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss.

Mutations in PINK1 and PARK2 cause autosomal recessive parkinsonism, a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons. To discover potential therapeutic pathways, we identified factors that genetically interact with Drosophila park and Pink1. We found that overexpression of the translation inhibitor Thor (4E-BP) can suppress all of the pathologic phenotypes, including degeneration of dopaminergic neurons in Drosophila. 4E-BP is activated in vivo by the TOR inhibitor rapamycin, which could potently suppress pathology in Pink1 and park mutants. Rapamycin also ameliorated mitochondrial defects in cells from individuals with PARK2 mutations. Recently, 4E-BP was shown to be inhibited by the most common cause of parkinsonism, dominant mutations in LRRK2. We also found that loss of the Drosophila LRRK2 homolog activated 4E-BP and was also able to suppress Pink1 and park pathology. Thus, in conjunction with recent findings, our results suggest that pharmacologic stimulation of 4E-BP activity may represent a viable therapeutic approach for multiple forms of parkinsonism.

Benzene-free synthesis of hydroquinone.

All current routes for the synthesis of hydroquinone utilize benzene as the starting material. An alternate route to hydroquinone has now been elaborated from glucose. While benzene is a volatile carcinogen derived from nonrenewable fossil fuel feedstocks, glucose is nonvolatile, nontoxic, and derived from renewable plant polysacharrides. Glucose is first converted into quinic acid using microbial catalysis. Quinic acid is then chemically converted into hydroquinone. Under fermentor-controlled conditions, Escherichia coli QP1.1/pKD12.138 synthesizes 49 g/L of quinic acid from glucose in 20% (mol/mol) yield. Oxidative decarboxylation of quinic acid in clarified, decolorized, ammonium ion-free fermentation broth with NaOCl and subsequent dehydration of the intermediate 3(R),5(R)-trihydroxycyclohexanone afforded purified hydroquinone in 87% yield. Halide-free, oxidative decarboxylation of quinic acid in fermentation broth with stoichiometric quantities of (NH(4))(2)Ce(SO(4))(3) and V(2)O(5) afforded hydroquinone in 91% and 85% yield, respectively. Conditions suitable for oxidative decarboxylation of quinic acid with catalytic amounts of metal oxidant were also identified. Ag(3)PO(4) at 2 mol % relative to quinic acid in fermentation broth catalyzed the formation of hydroquinone in 74% yield with K(2)S(2)O(8) serving as the cooxidant. Beyond establishing a fundamentally new route to an important chemical building block, oxidation of microbe-synthesized quinic acid provides an example of how the toxicity of aromatics toward microbes can be circumvented by interfacing chemical catalysis with biocatalysis.