Regulatory T cells for amyotrophic lateral sclerosis/motor neuron disease: A clinical and preclinical systematic review

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by neuronal degeneration and inflammation in the nerves. The role of the immune system has been concentrated by researchers in the etiopathogenesis of the disease. Given the inhibitory roles of regulatory T cells (Tregs), it is expected that increasing or activating their populations in patients with ALS can have significant therapeutic effects. Here we searched databases, including CENTRAL, MEDLINE, CINAHL Plus, clinicaltrials.gov , and ICTRP for randomized clinical trials (RCTs) and non-RCTs until March 2019. For preclinical studies, we searched PubMed, Scopus, and Google Scholar up to June 2019. We also included preclinical studies, due to the lack of clinical information available, which used Tregs (or directly targeting them) for treating mice models of ALS. We identified 29 records (CENTRAL 7, MEDLINE 4, CINAHL Plus 8, and clinicaltrials.gov 10) and removed 10 duplicated publications. After screening, we identified one RCT which had been published as an abstract, three non-RCTs, and four ongoing studies. We also identified 551 records (PubMed 446, Google Scholar 68, and Scopus 37) for preclinical studies and performed a meta-analysis. Finally, we found three papers that matched our inclusion criteria for preclinical studies. Results indicated the effectiveness of the application of Tregs in the treatment of ALS. Our meta-analysis on preclinical studies revealed that Tregs significantly prolonged survival in mice models of ALS. Overall, our analysis testified that exertion of Tregs in the treatment of ALS is a promising approach, that notwithstanding, requires further evaluations.     

Structure‐activity relationship studies of shortened analogues of the antimicrobial peptide EeCentrocin 1 from the sea urchin Echinus esculentus

EeCentrocin 1 is a potent antimicrobial peptide isolated from the marine sea urchin Echinus esculentus. The peptide has a hetero‐dimeric structure with the antimicrobial activity confined in its largest monomer, the heavy chain (HC), encompassing 30 amino acid residues. The aim of the present study was to develop a shorter drug lead peptide using the heavy chain of EeCentrocin 1 as a starting scaffold and to perform a structure‐activity relationship study with sequence modifications to optimize antimicrobial activity. The experiments consisted of 1) truncation of the heavy chain, 2) replacement of amino acids unfavourable for in vitro antimicrobial activity, and 3) an alanine scan experiment on the truncated and modified heavy chain sequence to identify essential residues for antimicrobial activity. The heavy chain of EeCentrocin 1 was truncated to less than half its initial size, retaining most of its original antimicrobial activity. The truncated and optimized lead peptide ( P6 ) consisted of the 12 N‐terminal amino acid residues from the original EeCentrocin 1 HC sequence and was modified by two amino acid replacements and a C‐terminal amidation. Results from the alanine scan indicated that the generated lead peptide ( P6 ) contained the optimal sequence for antibacterial activity, in which none of the alanine scan peptides could surpass its antimicrobial activity. The lead peptide ( P6 ) was also superior in antifungal activity compared to the other peptides prepared and showed minimal inhibitory concentrations (MICs) in the low micromolar range. In addition, the lead peptide ( P6 ) displayed minor haemolytic and no cytotoxic activity, making it a promising lead for further antimicrobial drug development.     

Genome‐wide association study identifies an NLR gene that confers partial resistance to Magnaporthe oryzae in rice

Because of the frequent breakdown of major resistance (R) genes, identification of new partial R genes against rice blast disease is an important goal of rice breeding. In this study, we used a core collection of the Rice Diversity Panel II (C‐RDP‐II), which contains 584 rice accessions and are genotyped with 700 000 single‐nucleotide polymorphism (SNP) markers. The C‐RDP‐II accessions were inoculated with three blast strains collected from different rice‐growing regions in China. Genome‐wide association study identified 27 loci associated with rice blast resistance (LABRs). Among them, 22 LABRs were not associated with any known blast R genes or QTLs. Interestingly, a nucleotide‐binding site leucine‐rich repeat (NLR) gene cluster exists in the LABR12 region on chromosome 4. One of the NLR genes is highly conserved in multiple partially resistant rice cultivars, and its expression is significantly up‐regulated at the early stages of rice blast infection. Knockout of this gene via CRISPR‐Cas9 in transgenic plants partially reduced blast resistance to four blast strains. The identification of this new non‐strain specific partial R gene, tentatively named rice blast Partial Resistance gene 1 (PiPR1), provides genetic material that will be useful for understanding the partial resistance mechanism and for breeding durably resistant cultivars against blast disease of rice.     

A Phenazine based colorimetric and fluorescent chemosensor for sequential detection of Ag+ and I− in aqueous media

A new colorimetric and fluorescent probe MNTPZ based on 1H‐imidazo[4,5‐b]phenazine derivative has been designed and synthesized for successive detection of Ag⁺ and I^?. The probe MNTPZ shows selective colorimetric response by a change in color from yellow to orange and “turn‐off” fluorometric response upon binding with Ag⁺ in DMSO: Water (pH = 7, 1:1, v/v) over other cations. The binding mode of probe MNTPZ to Ag⁺ was studied by Job's plot, ¹H NMR studies, FT‐IR spectroscopy and DFT calculations. Moreover, the situ generated probe MNTPZ + Ag⁺ complex acted as an efficient fluorometric “turn‐on” probe for I^? via Ag⁺ displacement approach. The detection limit of probe MNTPZ for Ag⁺ and the resultant complex probe MNTPZ + Ag⁺ for I^? were determined to be 1.36 μmol/L and 1.03 μmol/L respectively. Notably, the developed probe was successfully used for quantitative determination of I^? in real samples with satisfactory results.     

A simple and rapid spectrofluorometric determination of pomalidomide in spiked plasma and urine. Application to degradation studies

A rapid and accurate spectrofluorimetric method for the determination of pomalidomide was developed and validated based on the measurement of its native fluorescence without the need for any derivatization and separation for the first time. The fluorescence intensity of the drug in acetonitrile solution allowed precise detection at 460 nm after excitation at 296 nm. The calibration curve was linear in the concentration range 31.0–500.0 ng/ml. Limit of detection and limit of quantification were found to be 8.04 and 24.36 ng/ml, respectively. Sensitive results allowed the drug to be detected with good recovery (75.46–109.72%) in human plasma and urine using the developed method. The proposed method was validated in terms of linearity, sensitivity, precision, accuracy, recovery, and stability parameters. Pomalidomide was subjected to degradation under various stress conditions (hydrolytic, oxidative and thermal) to demonstrate that the method was stable, indicating and identifying possible degradation products. In addition, the drug was exposed to electrochemical degradation using the chronoamperometry technique for the first time. Characterization of pomalidomide degradation products obtained because of oxidative degradation and electrochemical degradation was carried out using attenuated total reflection Fourier transform infrared spectroscopy, mass spectrometry and high performance liquid chromatography ? mass spectrometry methods and possible structures were proposed.     

CartograTree: connecting tree genomes,phenotypes and environment

Today, researchers spend a tremendous amount of time gathering, formatting, filtering and visualizing data collected from disparate sources. Under the umbrella of forest tree biology, we seek to provide a platform and leverage modern technologies to connect biotic and abiotic data. Our goal is to provide an integrated web‐based workspace that connects environmental, genomic and phenotypic data via geo‐referenced coordinates. Here, we connect the genomic query web‐based workspace, DiversiTree and a novel geographical interface called CartograTree to data housed on the TreeGenes database. To accomplish this goal, we implemented Simple Semantic Web Architecture and Protocol to enable the primary genomics database, TreeGenes, to communicate with semantic web services regardless of platform or back‐end technologies. The novelty of CartograTree lies in the interactive workspace that allows for geographical visualization and engagement of high performance computing (HPC) resources. The application provides a unique tool set to facilitate research on the ecology, physiology and evolution of forest tree species. CartograTree can be accessed at: http://dendrome.ucdavis.edu/cartogratree .     

Association between putative functional variants in the PSMB9 gene and risk of melanoma – re‐analysis of published melanoma genome‐wide association studies

To mine possibly hidden causal single‐nucleotide polymorphisms (SNPs) of melanoma, we investigated the association of SNPs in 76 M/G1 transition genes with melanoma risk using our published genome‐wide association study (GWAS) data set with 1804 melanoma cases and 1026 cancer‐free controls. We found multiple SNPs with P < 0.01 and performed validation studies for 18 putative functional SNPs in PSMB9 in two other GWAS data sets. Two SNPs (rs1351383 and rs2127675) were associated with melanoma risk in the GenoMEL data set (P = 0.013 and 0.004, respectively), but failed in validation using the Australian data set. Genotype–phenotype analysis revealed these two SNPs were significantly correlated with mRNA expression level of PSMB9. Further experiments revealed that SNP rs2071480, which is in high LD with rs1351383 and rs2127675, may have a weak effect on the promoter activity of PSMB9. Taken together, our data suggested that functional variants in PSMB9 may contribute to melanoma susceptibility.     

Synthesis of Theaspirone

β-Ionone (I) was oxidized to 2,3-epoxy-/β-ionone (II), which was converted to 2,3-dihydroxy-β-ionone (III) by acid treatment. III was reduced to 4-(1,2-dihydroxy-2,6,6-trimethylcyclohexan-1-yl)-2-butanol (V), which was converted, by oxidation, to cis- and trans-theaspirone (1-oxa-8-oxo-2,6,10,10-tetramethyl spiro-(4,5)-6-decene) (VII-A), (VII-B) and dihydroactinidiolide (2-hydroxy-2,6,6-trimethylcyclohexyliden-1-acetic acid lactone) (IX).     

Synthesis and antifungal activities of cyclic octa-lipopeptide burkholdine analogues

Synthesis and antifungal activity of cyclic octapeptide derivatives of burkholdines are described. To construct cyclic octapeptides, the combination of Fmoc-SPPS and cyclization with DIC/HOBt in the solution phase was employed. Synthesized peptides were evaluated for antifungal activity with MIC values against Saccharomyces cerevisiae, Aspergillus oryzae, and Candida viswanathii. As a result, the lipid side chain and the stereochemistry of each amino acid of Bk-1097 analogues significantly affected antifungal activity.