Unraveling the senses of Phytophthora; leads to novel control strategies?

Oomycetes cause devastating diseases on plants and animals. They cause major yield losses in many crop plants and their control heavily depends on agrochemicals. This is certainly true for the potato late blight pathogen Phytophthora infestans. Strong concerns about adverse effects of agrochemicals on food safety and environment are incentives for the development of novel, environmental friendly control strategies preferably based on natural products. Cyclic lipopeptides (CLPs) were recently discovered as a new class of natural compounds with strong activities against oomycetes including Phytophthora. CLPs lyse zoospores, inhibit mycelial growth and effectively reduce late blight disease. In order to unravel how Phytophthora senses CLPs and other environmental signals we follow two approaches. On the one hand, we monitor genome wide changes in gene expression induced by CLPs with the aim to identify the cellular pathways targeted by CLPs. On the other hand, we analyse components of ubiquitous signal transduction pathways with the aim to identify features that are unique for Phytophthora or oomycetes and, hence, could be suitable targets for novel anti-oomycete agents. Mining and comparing whole genome sequences have revealed that Phytophthora harbours many novel phospholipid modifying enzymes, unique for oomycetes. They have aberrant combinations of catalytic and regulatory domains occasionally combined with transmembrane domains. The latter resemble receptors that might be activated by extracellular ligands. Phospholipids, the substrates of these enzymes, are structural membrane components that also function in signalling. Together these findings open new avenues of research aimed at target-discovery in oomycetes

Dipolar triplet states of para-nitroaniline and N-alkyl; Derivatives with one-, two-, and three-fold symmetry

Photoexcitation of p-nitroaniline (PNA) and its N-alkyl derivs. results in the formation of triplet states with dipole moments considerably larger than that of the ground state, as monitored by time-resolved microwave cond. (TRMC). The triplet state lifetime, tT, is only 54 ns for PNA in benzene but increases to 1400 ns on N,N-di-Me substitution and to 275 ns in the more polar solvent p-dioxane. This sensitivity of tT is attributed to the close proximity of all of the lowest lying singlet and triplet np* and pp* states of PNA, which results in substantial S1 .tautm. T1 mixing. The dipole moment of the \"pure\" 3pp* state is estd. to be 11 D. Methylene-bridged arrays of PNA moieties with two- and three-fold Dn symmetry, 2-PNA and 3-PNA, are also found to have highly dipolar triplet states, indicating that symmetry breaking and exciton localization occur in T1. Flip-flop interchange between the resonant dipolar structures is estd. to take place on a time scale of tens of picoseconds. Collective interactions between the PNA moieties in the multichromophoric arrays results in a marked blue shift in the first absorption max. from 384 nm for 1-PNA to 375 nm for 2-PNA and to 354 nm for 3-PN

Studying the impact of presence of alpha acid glycoprotein and protein glycoprotein in chronic myeloid leukemia patients treated with imatinib mesylate in the State of Qatar

Despite the efficacy of imatinib mesylate (IM) in treating chronic myeloid leukemia (CML), there is a high degree of resistance. Alpha- 1-acid glycoprotein may reduce drug efficacy through its ability to interact with IM and blocks it from reaching its target, while protein glycoprotein (PGP) may reduce the intracellular concentration of the drug via an active pump mechanism. We thus investigated the correlation between AGP and PGP levels and the resistance/response to treatment. A total of 26 CML patients were investigated for AGP and PGP levels at diagnosis and during treatment. There was no significant difference or correlation between AGP levels and the different groups of patients. There was also no significant difference in the fluorescence intensities of PGP levels among the different patient groups. The resistance observed in our CML patient population could not be correlated with AGP and PGP levels. There was no significant pattern of AGP and PGP expression, irrespective of the response or resistance to treatment

Droplet-based assembly of magnetic superballs

The self-assembly of materials driven by the inherent directionality of the constituent particles is of both practical and fundamental interest because it enables the fabrication of complex and hierarchical structures with tailored functionalities. By employing evaporation assisted self-assembly, we form opal-like structures with micro-sized magnetic superball particles. We study the structure formation of different superball shapes during evaporation of a dispersion droplet with in-situ small angle x-ray scattering with microradian resolution in the absence and presence of an external magnetic field. In the absence of a magnetic field, strong shape-dependent structures form as the water evaporates from the system. Applying a magnetic field to the droplet has a unique effect on the system; strong magnetic fields inhibit the growth of well-ordered assemblies due to the formation of out-of-equilibrium dipolar structures while lower magnetic fields allow particles to rearrange and orient without inhibition. In this work, we show how the superball assembly inside a droplet can be controlled by the magnetic field strength and the superball shape. The tunability of these parameters not only enables the controllable formation of macroscopic colloidal assemblies but also opens up possibilities for the development of functional materials with tailored properties on a macro-scale.</p

Етнополітична партія як специфічний суб’єкт міжетнічних взаємин

Характер міжетнічних відносин зумовлений нерівністю прав і можливостей людей, які належать до різних етнічних спільнот, унаслідок чого між ними виникають конфлікти. У процесі їх врегулювання важлива роль покладається на політичні інститути (державу, партії, міжнародні організації), що мають гарантувати рівну участь етнічних суб’єктів у всіх сферах життєдіяльності соціуму. У статті зосереджено увагу на феномені етнополітичної партії, яка покликана забезпечувати політичне представництво конкретного народу-етносу в органах влади.The character of interethnic relationships is stipulated by inequality of rights and abilities of people that belong to different ethnic communities, which results in conflicts. Political institutions (the state, political parties, international organizations) are to play significant role in their settlement. They have to assure equal participation of ethnical entities in all areas of social life. In the article we focus on such phenomena as ethnopolitical party, which goal is to provide political representation of a given nation-ethnos in power institutions

Increased PXR and Suppressed T-Cell Signaling Are Associated With Malignant Degeneration of Barrett's Esophagus

Background and Aims: Barrett's esophagus (BE) is the precursor lesion for esophageal adenocarcinoma (EAC). To detect EAC in early stage, patients with BE undergo endoscopic surveillance. Surveillance cohorts largely consist of nondysplastic BE (NDBE) patients with a low annual progression risk (&lt;0.5%). Predictive biomarkers for malignant progression of NDBE could improve efficacy of surveillance. Biomarker research has mostly focused on aberrant protein expression on BE epithelial cells. Moreover, insight in cell signaling driving malignant transformation is unknown. This study uses a data-driven approach to analyze tumor-stroma interaction in NDBE which progressed to high-grade dysplasia or EAC. Methods: In this case-control study, we performed RNA sequencing analysis on index NDBE biopsies from 6 patients who, during long-term follow-up, progressed and 7 who did not progress to high-grade dysplasia/EAC. For control samples, squamous and duodenum tissues from BE patients were analyzed. For validation, we used quantitative PCR. Results: Significant differences in BE transcriptomic profiles between progressors and nonprogressors were found by principal component and differential expression analyses. Ingenuity pathway analysis indicated that 8 cell signaling pathways were significantly upregulated in the progressors, and 14 pathways were significantly downregulated. The most interesting finding was the upregulation of the xenobiotic metabolism pregnane X receptor signaling pathway in the progressor cohort, while of the downregulated pathways in progressors, several were related to the immune system. Conclusion: These novel transcriptomic insights are fundamental for developing (chemo-)preventive therapies. These could be therapies, which protect against toxins, including biles, responsible for pregnane X receptor activation or which enhance protective immune mechanisms. The identified RNA markers are promising biomarkers for improving risk stratification in surveillance programs.</p

Tuning magnetic chirality by dipolar interactions

Chiral magnetism has gained enormous interest in recent years because of the anticipated wealth of applications in nanoelectronics. The demonstrated stabilization of chiral magnetic domain walls and skyrmions has been attributed to the actively investigated Dzyaloshinskii-Moriya interaction. Recently, however, predictions were made that suggest dipolar interactions can also stabilize chiral domain walls and skyrmions, but direct experimental evidence has been lacking. Here we show that dipolar interactions can indeed stabilize chiral domain walls by directly imaging the magnetic domain walls using scanning electron microscopy with polarization analysis. We further show that the competition between the Dzyaloshinskii-Moriya and dipolar interactions can reverse the domain-wall chirality. Finally, we suggest that this competition can be tailored by a Ruderman-Kittel-Kasuya-Yosida interaction. Our work therefore reveals that dipolar interactions play a key role in the stabilization of chiral spin textures. This insight will open up new routes towards balancing interactions for the stabilization of chiral magnetism

Inhibition of NF-κB-mediated signaling by the cyclin-dependent kinase inhibitor CR8 overcomes pro-survival stimuli to induce apoptosis in chronic lymphocytic leukemia cells

Purpose: Chronic lymphocytic leukemia (CLL) is currently incurable with standard chemotherapeutic agents, highlighting the need for novel therapies. Overcoming proliferative and cytoprotective signals generated within the microenvironment of lymphoid organs is essential for limiting CLL progression and ultimately developing a cure. Experimental Design: We assessed the potency of cyclin-dependent kinase (CDK) inhibitor CR8, a roscovitine analog, to induce apoptosis in primary CLL from distinct prognostic subsets using flow cytometry–based assays. CLL cells were cultured in in vitro prosurvival and proproliferative conditions to mimic microenvironmental signals in the lymphoid organs, to elucidate the mechanism of action of CR8 in quiescent and proliferating CLL cells using flow cytometry, Western blotting, and quantitative real-time PCR. Results: CR8 was 100-fold more potent at inducing apoptosis in primary CLL cells than roscovitine, both in isolated culture and stromal-coculture conditions. Importantly, CR8 induced apoptosis in CD40-ligated CLL cells and preferentially targeted actively proliferating cells within these cultures. CR8 treatment induced downregulation of the antiapoptotic proteins Mcl-1 and XIAP, through inhibition of RNA polymerase II, and inhibition of NF-κB signaling at the transcriptional level and through inhibition of the inhibitor of IκB kinase (IKK) complex, resulting in stabilization of IκBα expression. Conclusions: CR8 is a potent CDK inhibitor that subverts pivotal prosurvival and proproliferative signals present in the tumor microenvironment of CLL patient lymphoid organs. Our data support the clinical development of selective CDK inhibitors as novel therapies for CLL

The effect of propofol on effective brain networks

Objective: We compared the effective networks derived from Single Pulse Electrical Stimulation (SPES) in intracranial electrocorticography (ECoG) of awake epilepsy patients and while under general propofol-anesthesia to investigate the effect of propofol on these brain networks. Methods: We included nine patients who underwent ECoG for epilepsy surgery evaluation. We performed SPES when the patient was awake (SPES-clinical) and repeated this under propofol-anesthesia during the surgery in which the ECoG grids were removed (SPES-propofol). We detected the cortico-cortical evoked potentials (CCEPs) with an automatic detector. We constructed two effective networks derived from SPES-clinical and SPES-propofol. We compared three network measures (indegree, outdegree and betweenness centrality), the N1-peak-latency and amplitude of CCEPs between the two effective networks. Results: Fewer CCEPs were observed during SPES-propofol (median: 6.0, range: 0–29) compared to SPES-clinical (median: 10.0, range: 0–36). We found a significant correlation for the indegree, outdegree and betweenness centrality between SPES-clinical and SPES-propofol (respectively r s = 0.77, r s = 0.70, r s = 0.55, p &lt; 0.001). The median N1-peak-latency increased from 22.0 ms during SPES-clinical to 26.4 ms during SPES-propofol. Conclusions: Our findings suggest that the number of effective network connections decreases, but network measures are only marginally affected. Significance: The primary network topology is preserved under propofol.</p