Selenium and nano-selenium ameliorations in two breeds of broiler chickens exposed to heat stress

The objective of this study was to compare the effects of synthesized nano-selenium (NS) and commercial inorganic selenium (Se) on immunity, behaviour, and performance of Arbor (AB) and Ross (RB) broilers that were exposed to heat stress of 40 °C for 6 - 8 hours daily over 38 days. Two hundred and ten one-day-old broilers of two breeds were supplemented with 0.5 mL/L of NS or Se in their drinking water. Two hundred sera, 200 intestinal swabs, and 1000 internal organ and tissue samples were collected. Weight gain, performance index, behavioral indices, total antioxidant capacity, malondialdehyde, superoxide dismutase, immunoglobulin G, immunoglobulin M, serum total protein, albumin, alanine aminotransferase, aspartate aminotransferase, and serum creatinine concentrations increased (P <0.01) in RB compared with AB when supplemented with NS. Meanwhile, NS supplementation decreased (P <0.01) water intake and the logarithmic bacterial counts of the intestine and breast in RB and AB, respectively. Histopathology revealed mild leukocytic infiltration and mild vacuolar degeneration in hepatocytes, and focal leukocytic infiltration, mild congestion, and cytoplasmic vacuolation in the myocardium of RB. Photomicrographs showed a mild lymphoid depletion in the spleen, while histopathology of the bursa of Fabricius revealed a normal follicular epithelium and normal lymphoid follicles with mild inter-follicular fibrosis in RB that were supplied with NS as opposed to AB, which expressed more severe pathological affections from heat stress. Thus, NS was more effective than Se in allowing broilers to respond to heat stress.Keywords: behaviour, immunity, growth traits, tissue architectur

Using bioinformatics tools for the discovery of Dengue RNA-dependent RNA polymerase inhibitors

Background Dengue fever has rapidly manifested into a serious global health concern. The emergence of various viral serotypes has prompted the urgent need for innovative drug design techniques. Of the viral non-structural enzymes, the NS5 RNA-dependent RNA polymerase has been established as a promising target due to its lack of an enzymatic counterpart in mammalian cells and its conserved structure amongst all serotypes. The onus is now on scientists to probe further into understanding this enzyme and its mechanism of action. The field of bioinformatics has evolved greatly over recent decades, with updated drug design tools now being publically available. Methods In this study, bioinformatics tools were used to provide a comprehensive sequence and structural analysis of the two most prominent serotypes of Dengue RNA-dependent RNA polymerase. A list of popular flavivirus inhibitors were also chosen to dock to the active site of the enzyme. The best docked compound was then used as a template to generate a pharmacophore model that may assist in the design of target-specific Dengue virus inhibitors. Results Comparative sequence alignment exhibited similarity between all three domains of serotype 2 and 3.Sequence analysis revealed highly conserved regions at residues Meth530, Thr543 Asp597, Glu616, Arg659 and Pro671. Mapping of the active site demonstrated two highly conserved residues: Ser710 and Arg729. Of the active site interacting residues, Ser796 was common amongst all ten docked compounds, indicating its importance in the drug design process. Of the ten docked flavivirus inhibitors, NITD-203 showed the best binding affinity to the active site. Further pharmacophore modeling of NITD-203 depicted significant pharmacophoric elements that are necessary for stable binding to the active site. Discussion This study utilized publically available bioinformatics tools to provide a comprehensive framework on Dengue RNA-dependent RNA polymerase. Based on docking studies, a pharmacophore model was also designed to unveil the crucial pharmacophoric elements that are required when constructing an efficacious DENV inhibitor. We believe that this study will be a cornerstone in paving the road toward the design of target-specific inhibitors against DENV RdRp

Diabetes mellitus caused by mutations in human insulin : analysis of impaired receptor binding of insulins Wakayama, Los Angeles and Chicago using pharmacoinformatics

Several naturally occuring mutations in the human insulin gene are associated with diabetes mellitus. The three known mutant molecules, Wakayama, Los Angeles and Chicago were evaluated using molecular docking and molecular dynamics (MD) to analyse mechanisms of deprived binding affinity for insulin receptor (IR). Insulin Wakayama, is a variant in which valine at position A3 is substituted by leucine, while in insulin Los Angeles and Chicago, phenylalanine at position B24 and B25 are replaced by serine and leucine respectively. These mutations show radical changes in binding affinity for insulin receptor. The ZDOCK server was used for molecular docking while AMBER 14 was used for the molecular dynamics study. The published crystal structure of insulin receptor bound to natural insulin was also used for molecular dynamics. The binding interactions and molecular dynamics trajectories clearly explained the critical factors for deprived binding to the insulin receptor. The surface area around position A3 was increased when valine was substituted by leucine, while at position B24 and B25 aromatic amino acid phenylalanine replaced by non-aromatic serine and leucine might be responsible for fewer binding interactions at the binding site of insulin receptor that leads to instability of the complex. In the MD simulation the normal mode analysis (NMA), rmsd trajectories and prediction of fluctuation indicated instability of complexes with mutant insulin in order of insulin native insulin < insulin Chicago < insulin Los Angeles < insulin Wakayama molecules which corresponds to the biological evidence of the differing affinities of the mutant insulins for the IR.The University of Pretoria Vice Chancellor’s postdoctoral fellowship and National Research Foundation (NRF), South Africa Innovation postdoctoral fellowship schemes.http://www.tandfonline.com/loi/tbsd202018-03-31hb2017Chemical Patholog

Management and outcomes in critically ill nonagenarian versus octogenarian patients.

BACKGROUND: Intensive care unit (ICU) patients age 90 years or older represent a growing subgroup and place a huge financial burden on health care resources despite the benefit being unclear. This leads to ethical problems. The present investigation assessed the differences in outcome between nonagenarian and octogenarian ICU patients. METHODS: We included 7900 acutely admitted older critically ill patients from two large, multinational studies. The primary outcome was 30-day-mortality, and the secondary outcome was ICU-mortality. Baseline characteristics consisted of frailty assessed by the Clinical Frailty Scale (CFS), ICU-management, and outcomes were compared between octogenarian (80-89.9 years) and nonagenarian (> 90 years) patients. We used multilevel logistic regression to evaluate differences between octogenarians and nonagenarians. RESULTS: The nonagenarians were 10% of the entire cohort. They experienced a higher percentage of frailty (58% vs 42%; p < 0.001), but lower SOFA scores at admission (6 + 5 vs. 7 + 6; p < 0.001). ICU-management strategies were different. Octogenarians required higher rates of organ support and nonagenarians received higher rates of life-sustaining treatment limitations (40% vs. 33%; p < 0.001). ICU mortality was comparable (27% vs. 27%; p = 0.973) but a higher 30-day-mortality (45% vs. 40%; p = 0.029) was seen in the nonagenarians. After multivariable adjustment nonagenarians had no significantly increased risk for 30-day-mortality (aOR 1.25 (95% CI 0.90-1.74; p = 0.19)). CONCLUSION: After adjustment for confounders, nonagenarians demonstrated no higher 30-day mortality than octogenarian patients. In this study, being age 90 years or more is no particular risk factor for an adverse outcome. This should be considered- together with illness severity and pre-existing functional capacity - to effectively guide triage decisions. TRIAL REGISTRATION: NCT03134807 and NCT03370692

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Does Size Really Matter? Probing the Efficacy of Structural Reduction in the Optimization of Bioderived Compounds – A Computational “Proof-of-Concept”

Over the years, numerous synthetic approaches have been utilized in drug design to improve the pharmacological properties of naturally derived compounds and most importantly, minimize toxic effects associated with their transition to drugs. The reduction of complex bioderived compounds to simpler bioactive fragments has been identified as a viable strategy to develop lead compounds with improved activities and minimal toxicities. Although this ‘reductive’ strategy has been widely exemplified, underlying biological events remain unresolved, hence the unanswered question remains how does the fragmentation of a natural compound improve its bioactivity and reduce toxicities? Herein, using a combinatorial approach, we initialize a computational “proof-of- concept” to expound the differential pharmacological and antagonistic activities of a natural compound, Anguinomycin D, and its synthetic fragment, SB640 towards Exportin Chromosome Region Maintenance 1 (CRM1). Interestingly, our findings revealed that in comparison with the parent compound, SB640 exhibited improved pharmacological attributes, while toxicities and off-target activities were relatively minimal. Moreover, we observed that the reduced size of SB640 allowed ‘deep access’ at the Nuclear Export Signals (NES) binding groove of CRM1, which favored optimal and proximal positioning towards crucial residues while the presence of the long polyketide tail in Anguinomycin D constrained its burial at the hydrophobic groove. Furthermore, with regards to their antagonistic functions, structural inactivation (rigidity) was more pronounced in CRM1 when bound by SB640 as compared to Anguinomycin D. These findings provide essential insights that portray synthetic fragmentation of natural compounds as a feasible approach towards the discovery of potential leads in disease treatment. Keywords: Chromosome region maintenance 1, Anguinomycin D, SB640, Structural reduction, NES-binding groove, Polyketide tai

Zika virus NS5 protein potential inhibitors: an enhanced <i>in silico</i> approach in drug discovery

<p>The re-emerging Zika virus (ZIKV) is an arthropod-borne virus that has been described to have explosive potential as a worldwide pandemic. The initial transmission of the virus was through a mosquito vector, however, evolving modes of transmission has allowed the spread of the disease over continents. The virus has already been linked to irreversible chronic central nervous system conditions. The concerns of the scientific and clinical community are the consequences of Zika viral mutations, thus suggesting the urgent need for viral inhibitors. There have been large strides in vaccine development against the virus but there are still no FDA approved drugs available. Rapid rational drug design and discovery research is fundamental in the production of potent inhibitors against the virus that will not just mask the virus, but destroy it completely. <i>In silico</i> drug design allows for this prompt screening of potential leads, thus decreasing the consumption of precious time and resources. This study demonstrates an optimized and proven screening technique in the discovery of two potential small molecule inhibitors of ZIKV Methyltransferase and RNA dependent RNA polymerase. This <i>in silico</i> ‘per-residue energy decomposition pharmacophore’ virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents.</p

Dual anti-inflammatory and selective inhibition mechanism of leukotriene A₄ hydrolase/aminopeptidase: insights from comparative molecular dynamics and binding free energy analyses

<p>Human leukotriene A₄ hydrolase/aminopeptidase (LTA₄H) is a zinc metalloenzyme with a dual catalytic activity; conversion of LTA₄ into LTB₄ and degradation of chemotactic tripeptide Pro-Gly-Pro (PGP). Existing inhibitors, such as SC-57461A, block both catalytic activities of the enzyme, leading to drug failures. Recently, a novel compound, ARM1, was reported to selectively inhibit the hydrolase activity of LTA₄H while sparing its aminopeptidase activity. However, the molecular understanding of such preferential inhibitory mechanism remains obscure. The discovery of ARM1 prompted us to further explore its binding theme and provide more insight into the structural and dual mechanistic features of LTA₄H protein. To accomplish this, we embarked on wide range of computational tools, including comparative molecular dynamics (MDs) simulations and postdynamic analyses for LTA₄H and in complex with ARM1, PGP, ARM1-PGP, and SC-57461A. MD analysis reveals that the binding of ARM1 exhibits a more stable active site and overall stable protein conformation when compared to the nonselective inhibitor SC-57461A. In addition, MM/GBSA-binding free energy calculation also reveals that ARM1 exhibit a lower binding affinity, when compared to the nonselective inhibitor SC-57461A – which is in a great agreement with experimental data. Per residue energy decomposition analysis showed that Phe314, Val367, Tyr378, Trp311, Pro382, and Leu369 are key residues critical for the selective inhibition of the epoxide hydrolase activity of LTA₄H by ARM1. Findings from this report will not only provide more understanding into the structural, dynamic, and mechanistic features of LTA₄H but would also assist toward the rational design of novel and selective hydrolase inhibitors of LTA₄H as anti-inflammatory drugs.</p

CASSAVA AS NEW ANIMAL FEED IN EGYPT 3 - PELLETED COMPLETE CASSAVA FEED FOR GROWING RABBITS

[EN] Forty New Zealand White rabbits (20 males and 20 females) aged 5 weeks, of 735g in average weight, were divided into two groups on basis of weight and sex. A pelleted complete rabbit feed containing 45 % cassava products (CCF diet) as 30 % root meal + 15 % leaf meal, was formulated to be fed in comparison with a commercial feed (AF diet ; Atmida Cº) during the 15 weeks of experiment, divided in 3 stages of 5 weeks. 1 % urea was added to the CCF diet in arder to increase the N-content. The results indicated that CP digestibility and N-balance of CCF were significantly (P<0.05) lower than that in AF diet in the first 5 weeks after weaning (1st stage). But the CP digestibility and N-balance were not significantly different between two Qroups fed CCF and AF diets at 15 weeks after weaning (3rá stage). The CF digestibility was not significantly affected by type of feed and it was improved by advance in age of rabbits fed CCF or AF diets. In contrast N-balance was decreased with advancing of age of two groups of growing rabbits. No significant effect of sex was observed on digestibility or N-balance. The feed intake was significantly (P<0.01) lower with CCF diet than that with AF diet in 1 st and 2nd stages. Daily body gain was significantly (P<0.01) lower with rabbits fed CCF than those fed AF diets in 1 st stage but it was nearly similar between two groups at 2nd and 3rd stages. Feed conversion (feed/gain) was more efficient with rabbits fed AF than those fed CCF diets at 1 st stage but opposite trend was observed in 2nd and 3rd stages of growth. Slaughter and carcass traits showed no significant differences between the two groups fed CCF and AF diets. There were no significant differences in feed intake, feed conversion and daily body gain between male and female rabbits. Conclusively, it could be appear that cassava products (roots and leaves) can be used satisfactorily as the partial substitute for traditional energy and protein supplements to formulating pelleted diet for growing rabbits.[FR] Quarante lapins Néo-zélandais Blancs (20 males et 20 feme/les) agés de 5 semaines, pesant en moyenne 735g ont été divisés en deux groupes compte tenu de leur sexe et de leur poids. lis ont rer;u au cours des 15 semaines d'expérience, soit un aliment granulé complet (CCF) contenant 45 % de manioc (30 % de farine de racines et 15 % de farine de feuilles) soit un aliment complet (Atmida CJe) du commerce (AF). 1 % d'urée a été ajouté au régime CCF afin d'augmenter la teneur en azote. Les résultats indiquent que la digestibilité des PB et le bilan azoté du régime CCF etaient significativement plus bas que ceux du régime AF dans les 5 premiares semaines apres le sevrage (1 ere période). Mais la digestibilité des PB et le bilan azoté n'étaient pas significativement différents entre les deux groupes (CCF et AF) 15 semaines apres le sevrage (3eme période). La digestibilité de la cellulose brute n'était pas affectée par le régime, par contre, elle s'est améliorée avec l'age. A l'inverse, le bilan azoté s'est dégradé avec l'age, au sein des deux lots. Aucun effet de sexe n'a été observé pour la digestibilité ou le bilan azoté. La consommation était significativement plus basse (P<0.01) avec le régime CCF qu'avec le régime AF au cours des 1 ere et 2eme périodes. Le gain de poids journalier était significativement plus bas avec l'aliment CCF qu'avec l'aliment AF au cours de la premiare période mais il était presque identique dans les deux groupes au cours des 2eme et 3eme périodes. L'efficacité alimentaire était supérieure avec l'aliment AF comparé a l'aliment CCF pendant la premiare période, mais une tendance contraire a été observée durant la 2eme et 3eme périodes de croissance. Les caractéristiques d'abattage et de carcasse ne présentaient pas de différences significatives entre les deux groupes. 11 n'y avait pas de différences significatives entre males et feme/les concernant la consommation, /'indice de consommation et le gain de poids journalier. En conclusion il apparait que le manioc (feuilles et racines) peut etre utilisé de maniere satisfaisante comme substitut partiel des composants traditionnels énergétiques et azotés dans des formules d'aliments granulés pour lapins en croissance.Abd El-Baki, S.; Nowar, M.; Bassuny, S.; Hassona, E.; Soliman, E. (1993). CASSAVA AS NEW ANIMAL FEED IN EGYPT 3 - PELLETED COMPLETE CASSAVA FEED FOR GROWING RABBITS. World Rabbit Science. 1(4). doi:10.4995/wrs.1993.207SWORD1