Adaptive mutation using statistics mechanism for genetic algorithms

Copyright @ 2004 Springer-Verla

On the statistical mechanics of prion diseases

We simulate a two-dimensional, lattice based, protein-level statistical mechanical model for prion diseases (e.g., Mad Cow disease) with concommitant prion protein misfolding and aggregation. Our simulations lead us to the hypothesis that the observed broad incubation time distribution in epidemiological data reflect fluctuation dominated growth seeded by a few nanometer scale aggregates, while much narrower incubation time distributions for innoculated lab animals arise from statistical self averaging. We model `species barriers' to prion infection and assess a related treatment protocol.Comment: 5 Pages, 3 eps figures (submitted to Physical Review Letters

A Comparative Study on the In Vivo and In Situ Degradability of Napier (Pennisetum purpureum), Guinea (Megathyrsus maximus), and Paspalum (Paspalum conjugatum) as Forage Grasess

This study evaluated the in vivo and in situ degradability of 3 local forage grasses: Napier sp., Guinea sp., and Paspalum sp. Three (3) rumen-cannulated cattle of similar age were used for the degradability assessments. The in vivo experiment followed a 3×3×3 Latin Square Design (LSD), while the in situ degradability study employed a 3×5 factorial in a randomized complete block design (RCBD). Dietary treatments consisted of A–Napier sp., B – Guinea sp., and C – Paspalum sp. In the in vivo digestibility trial, no differences were observed except for GE and NDF digestibility. As for the test diets, in vivo digestibility was comparable using local forages in the feed and nutrient digestibility assays (p>0.05). In contrast, no significant interactions were observed in the in situ ruminal degradability in feed, DMD, CPD, NDFD, and ADFD (p>0.05). However, main effects for Forage (factor A) showed a significant effect for both DMD (p<0.0028) and NDFD (p<0.0385). In addition, feed degradability was significant (p<0.0189). For the incubation time (Factor B), feed disappearance, DMD, and ADFD showed strong quadratic effects (p<0.0018, p<0.0001, and p<0.0095, respectively), suggesting that the breakdown process began rapidly but gradually slowed over time. In contrast, CPD and NDFD displayed a linear increase (p<0.0001)

Physico-Chemical Characteristics and In Vitro Rumen Degradability of Insect Frass as NPN Source for Mineral Blocks in Goats

The study was conducted to determine the potential of superworm (Zophobas morio) larvae (SWL) and black soldier fly (Hermetia illucens) larvae (BSFL) frass at 10% inclusion as non-protein nitrogen (NPN) source in formulating mineral blocks for goats, with emphasis on the physico-chemical properties of the mineral blocks, and to assess the extent of feed degradation in goats supplemented with insect frass-based mineral block through an in vitro degradability trial. A total of 16 post-weaned goats were used to determine the effects of supplementing insect frass-based mineral blocks on the feed degradation in goats. The goats were arranged in a randomized complete block design (RCBD) with four (4) treatments and four (4) blocks with initial body weight (BW) as the blocking factor. Treatment A (control), Treatment B (urea molasses mineral block) (UMMB), Treatment C (superworm larvae frass mineral block) (SWLFMB), and Treatment D (black soldier fly larvae frass mineral block) (BSFLFMB) served as treatments. Based on the results, insect frass-based mineral blocks showed potential as a good nutritional supplement for goats. These mineral blocks offer valuable sources of protein, non-protein nitrogen (NPN), and minerals. Evaluation of hardness and solubility indicated that the SWLFMB showed better hardness and compactness, but demonstrated the highest solubility among formulations. In contrast, the UMMB displayed relatively low hardness and compactness, yet was the least soluble of all the mineral block variants. Moreover, in vitro studies showed no significant difference among treatments. Therefore, insect frass-based mineral blocks are a viable alternative source of minerals and NPN for goats, which can be utilized to optimize ruminant feed resources

In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in Escherichia coli as Leishmania amazonensis Arginase Inhibitors

Arginase is a metalloenzyme that plays a central role in Leishmania infections. Previously, rosmarinic and caffeic acids were described as antileishmanial agents and as Leishmania amazonensis arginase inhibitors. Here, we describe the inhibition of arginase in L. amazonensis by rosmarinic acid analogs (1–7) and new caffeic acid-derived amides (8–10). Caffeic acid esters and amides were produced by means of an engineered synthesis in E. coli and tested against L. amazonensis arginase. New amides (8–10) were biosynthesized in E. coli cultured with 2 mM of different combinations of feeding substrates. The most potent arginase inhibitors showed Ki(s) ranging from 2 to 5.7 μM. Compounds 2–4 and 7 inhibited L. amazonensis arginase (L-ARG) through a noncompetitive mechanism whilst compound 9 showed a competitive inhibition. By applying an in silico protocol, we determined the binding mode of compound 9. The competitive inhibitor of L-ARG targeted the key residues within the binding site of the enzyme, establishing a metal coordination bond with the metal ions and a series of hydrophobic and polar contacts supporting its micromolar inhibition of L-ARG. These results highlight that dihydroxycinnamic-derived compounds can be used as the basis for developing new drugs using a powerful tool based on the biosynthesis of arginase inhibitors

Cinnamides Target Leishmania amazonensis Arginase Selectively

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 ± 7.8 μM) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 ± 0.7 μM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3-17.8 μM, and where the most active was compound 15 (IC50 = 1.3 ± 0.1 μM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 μM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors

CIP2A expression is increased in prostate cancer

Abstract Background The CIP2A protein is a recently characterized oncoprotein which inhibits protein phosphatase 2A activity. Expression of CIP2A has been detected in several carcinomas, but its expression and significance in prostate cancer has not been examined so far. Methods Expression of the CIP2A protein was studied using immunohistochemistry in prostate cancer (n = 59) and in benign prostatic hyperplasia (n = 20) specimens. The CIP2A staining scores were compared with several clinicopathological parameters. Results Expression of CIP2A was increased in prostate cancer epithelium as compared with the benign hyperplastic epithelium (p Conclusions Expression of the CIP2A protein is increased in prostate cancer specimens and its expression is associated with poorly differentiated and high-risk tumors.</p

Neuroprotective effects of the multitarget agent AVCRI104P3 in brain of middle-aged mice

Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Aβ aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3β, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3β in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementia

Overexpression and Small Molecule-Triggered Downregulation of CIP2A in Lung Cancer

Lung cancer is the leading cause of cancer deaths worldwide, with a five-year overall survival rate of only 15%. Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein inhibiting PP2A in many human malignancies. However, whether CIP2A can be a new drug target for lung cancer is largely unclear.Normal and malignant lung tissues were derived from 60 lung cancer patients from southern China. RT-PCR, Western blotting and immunohistochemistry were used to evaluate the expression of CIP2A. We found that among the 60 patients, CIP2A was undetectable or very low in paratumor normal tissues, but was dramatically elevated in tumor samples in 38 (63.3%) patients. CIP2A overexpression was associated with cigarette smoking. Silencing CIP2A by siRNA inhibited the proliferation and clonogenic activity of lung cancer cells. Intriguingly, we found a natural compound, rabdocoetsin B which is extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce down-regulation of CIP2A and inactivation of Akt pathway, and inhibit proliferation and induce apoptosis in a variety of lung cancer cells.Our findings strongly indicate that CIP2A could be an effective target for lung cancer drug development, and the therapeutic potentials of CIP2A-targeting agents warrant further investigation