Dual blockade of VEGFR1 and VEGFR2 by a novel peptide abrogates VEGF-driven angiogenesis,tumor growth,and metastasis through PI3K/AKT and MAPK/ERK1/2 pathway

Background

Neutralization of vascular endothelial growth factor receptor 1 (VEGFR1) and/or VEGFR2 is a widely used means of inhibiting tumor angiogenesis.

Webbing life type and behavioral response of the date palm mite, <Emphasis Type="Italic">Oligonychus afrasiaticus</Emphasis>, to webbing residues on leaves and fruits of date palm

The present study examined the webbing life type and behavioral response of date palm mite (DPM) Oligonychus afrasiaticus (McGregor) toward its webbing residues, in presence or absence of immature individuals, on leaves and fruits of date palm. DPM exhibited a complicated web life type on both the leaves and fruits of date palm, which is characterized by the following features: complicated irregular web structure; webbing density on the leaves is medium and on the fruits extremely high; eggs are always laid on the threads of web without web cover; fecal pellets are deposited on the substrate surface (both leaf and fruit); quiescent stages are on the silken web threads; and the preferred site for feeding and walking is under the web. Behavioral observation of DPM females revealed that the midrib of leaves and the base of fruits of date palm were the preferred sites for feeding and web construction. The number and development stage of DPM affected the behavioral response of females on date palm leaves but not on the fruits. DPM spent most time feeding under the web on both the leaves and fruits of date palm.     

GENETIC VARIABILITY AND MOLECULAR PHYLOGENY OF DINOPHYSIS SPECIES (DINOPHYCEAE) FROM NORWEGIAN WATERS INFERRED FROM SINGLE CELL ANALYSES OF rDNA1

The objectives of this study were to determine rDNA sequences of the most common Dinophysis species in Scandinavian waters and to resolve their phylogenetic relationships within the genus and to other dinoflagellates. A third aim was to examine the intraspecific variation in D. acuminata and D. norvegica, because these two species are highly variable in both morphology and toxicity. We obtained nucleotide sequences of coding (small subunit [SSU], partial large subunit [LSU], 5.8S) and noncoding (internal transcribed spacer [ITS]1, ITS2) parts of the rRNA operon by PCR amplification of one or two Dinophysis cells isolated from natural water samples. The three photosynthetic species D. acuminata, D. acuta, and D. norvegica differed in only 5 to 8 of 1802 base pairs (bp) within the SSU rRNA gene. The nonphotosynthetic D. rotundata (synonym Phalacroma rotundatum[Claparède et Lachmann] Kofoid et Michener), however, differed in approximately 55 bp compared with the three photosynthetic species. In the D1 and D2 domains of LSU rDNA, the phototrophic species differed among themselves by 3 to 12 of 733 bp, whereas they differed from D. rotundata by more than 100 bp. This supports the distinction between Dinophysis and Phalacroma. In the phylogenetic analyses based on SSU rDNA, all Dinophysis species were grouped into a common clade in which D. rotundata diverged first. The results indicate an early divergence of Dinophysis within the Dinophyta. The LSU phylogenetic analyses, including 4 new and 11 Dinophysis sequences from EMBL, identified two major clades within the phototrophic species. Little or no intraspecific genetic variation was found in the ITS1–ITS2 region of single cells of D. norvegica and D. acuminata from Norway, but the delineation between these two species was not always clear.     

Verrucophora farcimen gen. et sp. nov. (Dictyochophyceae,Heterokonta)—a bloom‐forming ichthyotoxic flagellate from the Skagerrak,Norway1

Since 1998, a heterokont flagellate initially named Chattonella aff. verruculosa has formed recurrent extensive blooms in the North Sea and the Skagerrak, causing fish mortalities. Cells were isolated from the 2001 bloom off the south coast of Norway, and monoalgal cultures were established and compared with the Chattonella verruculosa Y. Hara et Chihara reference strain NIES 670 from Japan. The cells in Norwegian cultured isolates were very variable in size and form, being large oblong (up to 34 μm long) to small rounded (5–9 μm in diameter) with two unequal flagella, numerous chloroplasts, and mucocysts. The SSU and partial LSU rDNA sequences of strains from Norway and Japan were compared and differed by 0.4% (SSU) and 1.3% (LSU), respectively. Five strains from Norway were identical in the LSU rDNA region. Phylogenetic analyses based on heterokont SSU and concatenated SSU + LSU rDNA sequences placed C. aff. verruculosa and the Japanese C. verruculosa within the clade of Dictyochophyceae, with the picoflagellate Florenciella parvula Eikrem as the closest relative. Ultrastructure, morphology, and pigment composition supported this affinity. We propose the name Verrucophora farcimen sp. et gen. nov. for this flagellate and systematically place it within the class Dictyochophyceae. Our studies also show that C. verruculosa from Japan is genetically and morphologically different but closely related to V. farcimen. The species is transferred from the class Raphidophyceae to the class Dictyochophyceae and renamed Verrucophora verruculosa. We propose a new order, Florenciellales, to accommodate V. farcimen, V. verruculosa, and F. parvula.     

Campylobacter jejuni adenosine triphosphate phosphoribosyltransferase is an active hexamer that is allosterically controlled by the twisting of a regulatory tail

Adenosine triphosphate phosphoribosyltransferase (ATP‐PRT) catalyzes the first committed step of the histidine biosynthesis in plants and microorganisms. Here, we present the functional and structural characterization of the ATP‐PRT from the pathogenic ε‐proteobacteria Campylobacter jejuni (CjeATP‐PRT). This enzyme is a member of the long form (HisG_L) ATP‐PRT and is allosterically inhibited by histidine, which binds to a remote regulatory domain, and competitively inhibited by AMP. In the crystalline form, CjeATP‐PRT was found to adopt two distinctly different hexameric conformations, with an open homohexameric structure observed in the presence of substrate ATP, and a more compact closed form present when inhibitor histidine is bound. CjeATP‐PRT was observed to adopt only a hexameric quaternary structure in solution, contradicting previous hypotheses favoring an allosteric mechanism driven by an oligomer equilibrium. Instead, this study supports the conclusion that the ATP‐PRT long form hexamer is the active species; the tightening of this structure in response to remote histidine binding results in an inhibited enzyme.     

Prevalence and determinants of healthcare avoidance during the COVID-19 pandemic: A population-based cross-sectional study

BackgroundDuring the Coronavirus Disease 2019 (COVID-19) pandemic, the number of consultations and diagnoses in primary care and referrals to specialist care declined substantially compared to prepandemic levels. Beyond deferral of elective non-COVID-19 care by healthcare providers, it is unclear to what extent healthcare avoidance by community-dwelling individuals contributed to this decline in routine healthcare utilisation. Moreover, it is uncertain which specific symptoms were left unheeded by patients and which determinants predispose to healthcare avoidance in the general population. In this cross-sectional study, we assessed prevalence of healthcare avoidance during the pandemic from a patient perspective, including symptoms that were left unheeded, as well as determinants of healthcare avoidance.Methods and findingsOn April 20, 2020, a paper COVID-19 survey addressing healthcare utilisation, socioeconomic factors, mental and physical health, medication use, and COVID-19–specific symptoms was sent out to 8,732 participants from the population-based Rotterdam Study (response rate 73%). All questionnaires were returned before July 10, 2020. By hand, prevalence of healthcare avoidance was subsequently verified through free text analysis of medical records of general practitioners. Odds ratios (ORs) for avoidance were determined using logistic regression models, adjusted for age, sex, and history of chronic diseases. We found that 1,142 of 5,656 included participants (20.2%) reported having avoided healthcare. Of those, 414 participants (36.3%) reported symptoms that potentially warranted urgent evaluation, including limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). Determinants related to avoidance were older age (adjusted OR 1.14 [95% confidence interval (CI) 1.08 to 1.21]), female sex (1.58 [1.38 to 1.82]), low educational level (primary education versus higher vocational/university 1.21 [1.01 to 1.46), poor self-appreciated health (per level decrease 2.00 [1.80 to 2.22]), unemployment (versus employed 2.29 [1.54 to 3.39]), smoking (1.34 [1.08 to 1.65]), concern about contracting COVID-19 (per level increase 1.28 [1.19 to 1.38]) and symptoms of depression (per point increase 1.13 [1.11 to 1.14]) and anxiety (per point increase 1.16 [1.14 to 1.18]). Study limitations included uncertainty about (perceived) severity of the reported symptoms and potentially limited generalisability given the ethnically homogeneous study population.ConclusionsIn this population-based cross-sectional study, 1 in 5 individuals avoided healthcare during lockdown in the COVID-19 pandemic, often for potentially urgent symptoms. Healthcare avoidance was strongly associated with female sex, fragile self-appreciated health, and high levels of depression and anxiety. These results emphasise the need for targeted public education urging these vulnerable patients to timely seek medical care for their symptoms to mitigate major health consequences.

Marije J. Splinter and colleagues assess the prevalence of healthcare avoidance during the COIVD-19 pandemic and investigate related determinants     

Docking of tryptophanyl [corrected tryptophan] analogs to trytophanyl-tRNA synthetase: implications for non-canonical amino acid incorporations

Abstract Non-canonical amino acids (N(AA)), as building blocks for peptides and proteins during ribosomal translation, represent a nearly infinite supply of novel functions. The specific selection, activation and tRNA-charging of amino acids by aminoacyl-tRNA synthetases (AARS) in the aminoacylation reaction are essential steps. In most cases, aminoacylation of N(AA) is a good indication that the related amino acid will participate in ribosomal translation as well. However, testing the translational capacity of amino acid analogs has technical limitations. Therefore, a rapid and reliable in silico test for N(AA) recognition by AARS would be advantageous in experimental design. We chose tryptophanyl-tRNA synthetase from Escherichia coli as a model system for docking studies with various tryptophan analogs using the FlexX-Pharm strategy. We were able to calculate relative binding energies for Trp analogs in TrpRS that correlate well with their translational activities in E. coli. In particular, FlexX-Pharm predicted the binding sites of fluoro-, amino-, hydroxyl- and aza-containing Trp analogs within 1.5 A of Trp in the homology model of E. coli TrpRS. Therefore, the use of ligand docking prior to N(AA) incorporation experiments might provide a straightforward means for determining N(AA) that can be efficiently incorporated into a protein.     

Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase

Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).     

4-(1,1-Dioxo-1,4-dihydro-1lambda6-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-ones as potent inhibitors of HCV NS5B polymerase

4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).     

A new two-dimensional thallium(I) coordination polymer with 4-hydroxybenzylidene-4-aminobenzoate: Thermal, structural, solution and solvatochromic studies

A new one-dimensional thallium(I) coordination polymer with a Schiff base ligand, {[Tl(L)(HL)](H₂O)_0.77}_n (1) [HL = 4-hydroxybenzylidene-4-aminobenzoic acid], has been synthesized and characterized. The single-crystal X-ray data of compound 1 show the coordination number of the Tl^I ions to be seven. The thermal stability of 1 was studied by thermal gravimetric (TG) and differential thermal analyses (DTA). The overall stoichiometry in the solid state is 1:2, but both spectrophotometric and conductometric methods did not support formation of a complex with this stoichiometry in solution. The solvatochromic behaviour of 4-hydroxybenzylidene-4-aminobenzoic acid was also investigated by studying its spectra in a selection of different organic solvents. The observed bands are assigned to electronic transitions.