Synthesis and biological screening of some pyridine derivatives as anti-malarial agents

Two series of pyridine derivatives were synthesised and evaluated for their in vivo anti-malarial activity against Plasmodium berghei. The anti-malarial activity was determined in vivo by applying 4-day standard suppressive test using chloroquine (CQ)-sensitive P. berghei ANKA strain-infected mice. Compounds 2a, 2g and 2h showed inhibition of the parasite multiplication by 90, 91 and 80%, respectively, at a dose level of 50 μmol/kg. Moreover, The most active compounds (2a, 2g and 2h) were tested in vitro against CQ-resistant Plasmodium falciparum RKL9 strains where compound 2g showed promising activity with IC(50)?=?0.0402 μM. The compounds were non-toxic at 300 and 100?mg/kg through the oral and parenteral routes, respectively. The docking pose of the most active compounds (2a, 2g and 2h) in the active site of dihydrofolate reductase enzyme revealed several hydrogen and hydrophobic interactions that contribute to the observed anti-malarial activities.     

More gating charges are needed to open a Shaker K+ channel than are needed to open an rBIIA Na+ channel

This study presents what is, to our knowledge, a novel technique by means of which the ratio of the single gating charges of voltage-gated rat brain IIA (rBIIA) sodium and Shaker potassium ion channels was estimated. In the experiment, multiple tandems of enhanced green fluorescent protein were constructed and inserted into the C-terminals of Na⁺ and K⁺ ion channels. cRNA of Na⁺ and K⁺ ion channels was injected and expressed in Xenopus laevis oocytes. The two electrode voltage-clamp technique allowed us to determine the total gating charge of sodium and potassium ion channels, while a relative measure of the amount of expressed channels could be established on the basis of the quantification of the fluorescence intensity of membrane-bound channels marked by enhanced green fluorescent proteins. As a result, gating charge and fluorescence intensity were found to be positively correlated. A relative comparison of the single gating charges of voltage-gated sodium and potassium ion channels could thus be established: the ratio of the single gating charges of the Shaker potassium channel and the rBIIA sodium channel was found to be 2.5 ± 0.4. Assuming the single channel gating charge of the Shaker K⁺ channel to be ∼13 elementary charges (well supported by other studies), this leads to approximately six elementary charges for the rBIIA sodium channel, which includes a fraction of gating charge that is missed during inactivation.     

Azole antimicrobial pharmacophore-based tetrazoles: Synthesis and biological evaluation as potential antimicrobial and anticonvulsant agents

The azole pharmacophore is still considered a viable lead structure for the synthesis of more efficacious and broad spectrum antimicrobial agents. Potential antibacterial and antifungal activities are encountered with some tetrazoles. Therefore, this study presents the synthesis and antimicrobial evaluation of a new series of substituted tetrazoles that are structurally related to the famous antimicrobial azole pharmacophore. A detailed discussion of the structural elucidation of some of the newly synthesized compounds is also described. Antimicrobial evaluation revealed that twenty compounds were able to display variable growth inhibitory effects on the tested Gram positive and Gram negative bacteria with special efficacy against the Gram positive strains. Meanwhile, six compounds exhibited moderate antifungal activity against Candida albicans and Aspergillus fumigatus. Structurally, the antibacterial activity was encountered with tetrazoles containing a phenyl substituent, while the obtained antifungal activity was confined to the benzyl variants. Compounds 16, 18, 24 and 27 were proved to be the most active antibacterial members within this study with a considerable broad spectrum against all the Gram positive and negative strains tested. A distinctive anti-Gram positive activity was displayed by compound 18 against Staphylococcus aureus that was equipotent to ampicillin (MIC 6.25 μg/mL).On the other hand, twelve compounds were selected to be screened for their preliminary anticonvulsant activity against subcutaneous metrazole (ScMet) and maximal electroshock (MES) induced seizures in mice. The results revealed that five compounds namely; 3, 5, 13, 21, and 24 were able to display noticeable anticonvulsant activity in both tests at 100 mg/kg dose level. Compounds 5 and 21 were proved to be the most active anticonvulsant members in this study with special high activity in the ScMet assay (% protection: 100% and 80%, respectively).     

Surveillance and genotyping of Enterobacter sakazakii suggest its potential transmission from milk powder into imitation recombined soft cheese

Aims:  To examine the presence of Enterobacter sakazakii in milk and milk-related products produced/distributed under Egyptian conditions and to probe possible transmission routes of the pathogen during the preparation of dairy products.
Methods and Results:  One hundred and thirty-seven samples of milk and milk-related products were randomly collected from Egyptian markets and examined for the presence of Ent. sakazakii . The pathogen could be detected only in skimmed milk powder (SMP) and its related product, imitation recombined soft (IRS) cheese. Enterobacter sakazakii isolates recovered from these products were phenotypically similar and sensitive to all antibiotics examined in this study. They also showed indistinguishable banding patterns when subjected to macro-restriction profiling using pulsed-field gel electrophoresis (mrp-PFGE). One Ent. sakazakii isolate was inoculated into SMP that was used in the preparation of IRS cheese using two cheese making procedures. The pathogen could survive for up to 1 month in the IRS cheese prepared by either procedure.
Conclusions:  The simultaneous presence of Ent. sakazakii in SMP and IRS cheese samples collected within the same local market besides the phenotypic and genotypic similarities of isolates recovered from these samples suggested the possibility of Ent. sakazakii being transmitted from SMP into IRS cheese. This hypothesis was supported by the observation that the pathogen could survive in the IRS cheese prepared from contaminated SMP.
Significance and Impact of the Study:  The study highlights SMP and IRS cheese as potential transmission vehicles of Ent. sakazakii . It also raises concern on the microbiological safety of IRS cheese prepared from SMP.     

A Dutch guideline for the treatment of scoliosis in neuromuscular disorders

Background

Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.

Methods

The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.

Results

For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.

Conclusion

In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.     

Arabidopsis GNARLED encodes a NAP125 homolog that positively regulates ARP2/3

In migrating cells, the actin filament nucleation activity of ARP2/3 is an essential component of dynamic cell shape change and motility. In response to signals from the small GTPase Rac1, alterations in the composition and/or subcellular localization of the WAVE complex lead to ARP2/3 activation. The human WAVE complex subunit, WAVE1/SCAR1, was first identified in Dictyostelium and is a direct ARP2/3 activator. In the absence of an intact WAVE complex, SCAR/WAVE protein is destabilized. Although the composition of the five-subunit WAVE complex is well characterized, the means by which individual subunits and fully assembled WAVE complexes regulate ARP2/3 in vivo are unclear. The molecular genetics of trichome distortion in Arabidopsis is a powerful system to understand how signaling pathways and ARP2/3 control multicellular development. In this paper we prove that the GNARLED gene encodes a homolog of the WAVE subunit NAP125. Despite the moderate level of amino acid identity between Arabidopsis and human NAP125, both homologs were functionally interchangeable in vivo and interacted physically with the putative Arabidopsis WAVE subunit ATSRA1. gnarled trichomes had nearly identical cell shape and actin cytoskeleton phenotypes when compared to ARP2/3 subunit mutants, suggesting that GRL positively regulates ARP2/3.     

Synaptic strength regulated by palmitate cycling on PSD-95

Dynamic regulation of AMPA-type glutamate receptors represents a primary mechanism for controlling synaptic strength, though mechanisms for this process are poorly understood. The palmitoylated postsynaptic density protein, PSD-95, regulates synaptic plasticity and associates with the AMPA receptor trafficking protein, stargazin. Here, we identify palmitate cycling on PSD-95 at the synapse and find that palmitate turnover on PSD-95 is regulated by glutamate receptor activity. Acutely blocking palmitoylation disperses synaptic clusters of PSD-95 and causes a selective loss of synaptic AMPA receptors. We also find that rapid glutamate-mediated AMPA receptor internalization requires depalmitoylation of PSD-95. In a nonneuronal model system, clustering of PSD-95, stargazin, and AMPA receptors is also regulated by ongoing palmitoylation of PSD-95 at the plasma membrane. These studies suggest that palmitate cycling on PSD-95 can regulate synaptic strength and regulates aspects of activity-dependent plasticity.     

Next-Generation Pyrosequencing Analysis of Microbial Biofilm Communities on Granular Activated Carbon in Treatment of Oil Sands Process-Affected Water

The development of biodegradation treatment processes for oil sands process-affected water (OSPW) has been progressing in recent years with the promising potential of biofilm reactors. Previously, the granular activated carbon (GAC) biofilm process was successfully employed for treatment of a large variety of recalcitrant organic compounds in domestic and industrial wastewaters. In this study, GAC biofilm microbial development and degradation efficiency were investigated for OSPW treatment by monitoring the biofilm growth on the GAC surface in raw and ozonated OSPW in batch bioreactors. The GAC biofilm community was characterized using a next-generation 16S rRNA gene pyrosequencing technique that revealed that the phylum Proteobacteria was dominant in both OSPW and biofilms, with further in-depth analysis showing higher abundances of Alpha- and Gammaproteobacteria sequences. Interestingly, many known polyaromatic hydrocarbon degraders, namely, Burkholderiales, Pseudomonadales, Bdellovibrionales, and Sphingomonadales, were observed in the GAC biofilm. Ozonation decreased the microbial diversity in planktonic OSPW but increased the microbial diversity in the GAC biofilms. Quantitative real-time PCR revealed similar bacterial gene copy numbers (>10⁹ gene copies/g of GAC) for both raw and ozonated OSPW GAC biofilms. The observed rates of removal of naphthenic acids (NAs) over the 2-day experiments for the GAC biofilm treatments of raw and ozonated OSPW were 31% and 66%, respectively. Overall, a relatively low ozone dose (30 mg of O₃/liter utilized) combined with GAC biofilm treatment significantly increased NA removal rates. The treatment of OSPW in bioreactors using GAC biofilms is a promising technology for the reduction of recalcitrant OSPW organic compounds.     

产β—葡萄糖苷酶真菌诱变菌株快速筛选方法

报道了一种快速筛选产β-葡萄糖管酶真菌诱变菌株的方法。该法利用ρNPG经β-葡萄糖苷酶水解,水解产物ρNP在碱性条件下显色的原理。采用自制的特殊初筛平皿.经一年多的实践应用表明此法具有简便、灵敏、筛子消耗量小、筛选效率高等优点。