Poly(A) RNA and Paip2 act as allosteric regulators of poly(A)-binding protein

When bound to the 30 poly(A) tail of mRNA, poly(A)binding protein (PABP) modulates mRNA translation and stability through its association with various proteins. By visualizing individual PABP molecules in real time, we found that PABP, containing four RNA recognition motifs (RRMs), adopts a conformation on poly(A) binding in which RRM1 is in proximity to RRM4. This conformational change is due to the bending of the region between RRM2 and RRM3. PABP-interacting protein 2 actively disrupts the bent structure of PABP to the extended structure, resulting in the inhibition of PABP-poly(A) binding. These results suggest that the changes in the configuration of PABP induced by interactions with various effector molecules, such as poly(A) and PABP-interacting protein 2, play pivotal roles in its function.X1143sciescopu

A review on the economic feasibility of composting for organic waste management in Asian countries

The rising rate of population growth and industrial development mainly in urban areas have led to significant increase in municipal solid waste (MSW) production. It has been a challenge to materialise a sustainable solid waste management notably in many developing countries. Organic portion represents a significant component in the municipal solid waste across countries with different level of income, ranging from about 25 to 70 %. Composting can be a viable option to manage waste sustainably by transforming waste into value-added fertiliser. Large-scale operation of composting is confronted with concern over feasible economic performance, which varied following different mode of operation. This study aims to review the economic feasibility (EF) on two different composting systems, which are the in-vessel and windrow system, implemented in several developed and developing countries. The review considered the cost factors for both composting systems, including the capital cost and operating cost. The return on investment (ROI) is estimated for both composting systems based on the potential cost benefits from the compost sale and the saving of waste tipping fee. This review provides a better insight into the desirability and applicability of both composting systems as an alternative to the landfilling practice. It is expected that the review of the various composting system could be very useful for improving the sustainable composting technology in the developing countries

Solid lipid nanoparticles self-assembled from spray dried microparticles

We report the self-assembly of anti-cancer drug-loaded solid lipid nanoparticles (SLNs) from spray dried microparticles comprising poly(vinylpyrrolidone) (PVP) loaded with glyceryl tristearate (GTS) and either indomethacin (IMC) or 5-fluorouracil (5-FU). When the spray dried microparticles are added to water, the PVP matrix dissolves and the GTS and drug self-assemble into SLNs. The SLNs provide a non-toxic delivery platform for both hydrophobic (indomethacin) and hydrophilic (5-fluorouracil) drugs. They show extended release profiles over more than 24 h, and in permeation studies the drug cargo is seen to accumulate inside cancer cells. This overcomes major issues with achieving local intestinal delivery of these active ingredients, in that IMC permeates well and thus will enter the systemic circulation and potentially lead to side effects, while 5-FU remains in the lumen of the small intestine and will be secreted without having any therapeutic benefit. The SLN formulations are as effective as the pure drugs in terms of their ability to induce cell death. Our approach represents a new and simple route to the fabrication of SLNs: by assembling these from spray-dried microparticles on demand, we can circumvent the low storage stability which plagues SLN formulations

Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome.

In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of an NS-associated allele PTPN11(D61G) in adult mouse hippocampus results in increased baseline excitatory synaptic function and deficits in LTP and spatial learning, which can be reversed by a mitogen-activated protein kinase kinase (MEK) inhibitor. Furthermore, brief treatment with lovastatin reduces activation of the GTPase Ras-extracellular signal-related kinase (Erk) pathway in the brain and normalizes deficits in LTP and learning in adult Ptpn11(D61G/+) mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS

In vitro anticancer properties and biological evaluation of novel natural alkaloid jerantinine B

Natural products play a pivotal role in medicine especially in the cancer arena. Many drugs that are currently used in cancer chemotherapy originated from or were inspired by nature. Jerantinine B (JB) is one of seven novel Aspidosperma indole alkaloids isolated from the leaf extract of Tabernaemontana corymbosa. Preliminary antiproliferative assays revealed that JB and JB acetate significantly inhibited growth and colony formation, accompanied by time- and dose-dependent apoptosis induction in human cancer cell lines. JB significantly arrested cells at the G2/M cell cycle phase, potently inhibiting tubulin polymerisation. Polo-like kinase 1 (PLK1; an early trigger for the G2/M transition) was also dose-dependently inhibited by JB (IC50 1.5 µM). Furthermore, JB provoked significant increases in reactive oxygen species (ROS). Annexin V+ cell populations, dose-dependent accumulation of cleaved-PARP and caspase 3/7 activation, and reduced Bcl-2 and Mcl-1 expression confirm apoptosis induction. Preclinical in silico biopharmaceutical assessment of JB calculated rapid absorption and bioavailability >70%. Doses of 8–16 mg/kg JB were predicted to maintain unbound plasma concentrations >GI50 values in mice during efficacy studies. These findings advocate continued development of JB as a potential chemotherapeutic agent

Codrug Approach for the Potential Treatment of EML4-ALK Positive Lung Cancer

We report on the synergistic effect of PI3K inhibition with ALK inhibition for the possible treatment of EML4-ALK positive lung cancer. We have brought together ceritinib (ALK inhibitor) and pictilisib (PI3K inhibitor) into a single bivalent molecule (a codrug) with the aim of designing a molecule for slow release drug delivery that targets EML4-ALK positive lung cancer. We have joined the two drugs through a new, pH-sensitive linker where the resulting codrugs are hydrolytically stable at lower pH (pH 6.4) but rapidly cleaved at higher pH (pH 7.4). Compound (19), which was designed for optimal lung retention, demonstrated clean liberation of the drug payloads in vitro and represents a novel approach to targeted lung delivery

Genotyping of Sarawak rice cultivars using microsatellite markers

Genetic diversity of 53 Sarawak rice cultivars, originating from Southern Sarawak, was assessed using 54 microsatellite markers. Initial polymorphism detection was conducted using 54 primer pairs distributed on 12 rice chromosomes. Polymorphic markers were chosen from the initial screening results in order to obtain microsatellite marker panels that can differentiate the rice cultivars undertaken in the study. The chosen microsatellite marker panel consisted of RM1, RM240, RM489, RM252, RM413, RM204, RM11, RM404, RM316, RM271, RM206, and RM19, with one representative from each chromosome. A total of 43 alleles were detected with an average of 3.58 alleles per locus. The polymorphism information content (PIC) values obtained from the microsatellite marker panels ranged from 0.306 to 0.730, with an average of 0.622. The Unweighted Pair Group Method with Arithmetic Mean (UPGMA) dendrogram (r = 0.789) revealed 2 major groups with 6 sub-clusters and the wide range of similarity values (0.24-1.0) obtained showed a high degree of diversity among the cultivars. The results suggest microsatellite markers as a useful tool for the estimation of genetic diversity and cultivar differentiation and present invaluable genetic information for future breeding and association mapping efforts