Episodic outbreaks of small mammals influence predator community dynamics in an east African savanna ecosystem

Little is known about the dynamics of small mammals in tropical savanna: a critical gap in our understanding of Africa's best known ecosystems. Historical evidence suggested small mammals peak in abundance (outbreak) in Serengeti National Park (SNP), as in agricultural systems. We asked 1) what are bottom–up drivers of small mammals and 2) do predators have top–down effects? We documented dynamics of small mammals, birds of prey, and mammalian carnivores in SNP and agricultural areas. We used climatic fluctuations and differences between unmodified and agricultural systems as perturbations to examine trophic processes, key to understanding responses to climate change and increasing human pressures. Data were derived from intermittent measures of abundance collected 1968–1999, combined with systematic sampling 2000–2010 to construct a 42‐year time series. Data on abundance of black‐shouldered kites (1968–2010), eight other species of rodent‐eating birds (1997–2010), and 10 carnivore species (1993–2010) were also collated. Outbreaks occurred every 3–5 years in SNP, with low or zero abundance between peaks. There was a positive relationship between rainfall in the wet season and 1) small mammal abundance and 2) the probability of an outbreak, both of which increased with negative Southern Oscillation Index values. Rodent‐eating birds and carnivores peaked 6–12 months after small mammals. In agricultural areas, abundance remained higher than in natural habitats. Abundances of birds of prey and mammalian carnivores were extremely low in these areas and not related to small mammal abundance. Small mammals are an important food resource for higher trophic levels in the Serengeti ecosystem. Changes in climate and land use may alter their future dynamics, with cascading consequences for higher trophic levels, including threatened carnivores. Although outbreaks cause substantial damage to crops in agricultural areas, small mammals also play a vital role in maintaining some of the diversity and complexity found in African savanna ecosystems.     

The impact of host species and vector control measures on the fitness of African malaria vectors

Many malaria vector mosquitoes in Africa have an extreme preference for feeding on humans. This specialization allows them to sustain much higher levels of transmission than elsewhere, but there is little understanding of the evolutionary forces that drive this behaviour. In Tanzania, we used a semi-field system to test whether the well-documented preferences of the vectors, Anopheles arabiensis and Anopheles gambiae sensu stricto (s.s.) for cattle and humans, respectively, are predicted by the fitness they obtain from host-seeking on these species relative to other available hosts. Mosquito fitness was contrasted, when humans were fully exposed and when they were protected by a typical bednet. The fitness of both vectors varied between host species. The predicted relationship between host preference and fitness was confirmed in An. arabiensis, but not in An. gambiae s.s., whose fitness was similar on humans and other mammals. Use of typical, imperfect bednets generated only minor reductions in An. gambiae s.s. feeding success and fitness on humans, but was predicted to generate a significant reduction in the lifetime reproductive success of An. arabiensis on humans relative to cows. This supports the hypothesis that such human-protective measures could additionally benefit malaria control by increasing selection for zoophily in vectors.     

Alcohol Metabolic Inefficiency: Structural Characterization of Polymorphism-Induced ALDH2 Dysfunctionality and Allosteric Site Identification for Design of Potential Wildtype Reactivators

Liver mitochondrial aldehyde dehydrogenase 2 (ALDH2) enzyme is responsible for the rapid conversion of acetaldehyde to acetic acid. ALDH2 (E487K) polymorphism results in an inactive allele (ALDH2*2) which cause dysfunctional acetaldehyde metabolism. The 3D structure of an enzyme is crucial to its functionality and a disruption in its structural integrity could result in its metabolic inefficiency and dysfunctionality. Allosteric targeting of polymorphs could facilitate the restoration of wildtype functionalities in ALDH2 polymorphs and serve as an advancement in the treatment of associated diseases. Therefore, structural insights into ALDH2*2 polymorph could reveal the varying degree of alterations which occur at its critical domains and accounts for enzymatic dysfunctionality. In this study, we report the structural characterization of ALDH2*2 polymorph and its critical domains using computational tools. Our findings revealed that the polymorph exhibited significant alterations in stability and flexibility at the catalytic and co-enzyme-binding domain. Moreover, there was an increase in the solvent-exposed surface residues and this indicates structural perturbations. Analysis of the interaction network at ALDH2*2 catalytic domain revealed residual displacement and interaction loss when compared to the wildtype thereby providing insight into the catalytic inefficiency of the polymorph. Interestingly, perturbations induced by ALDH2 polymorphism involves the re-orientation of surface residues, which resulted in the formation of surface exposed pockets. These identified pockets could be potential sites for allosteric targeting. The findings from this study will aid the design of novel site-specific small molecule reactivators with the propensity of restoring wildtype activities for treatment of polymorphic ALDH2 related diseases.     

Insight into the Therapeutic Potential of a Bicyclic Hydroxypyridone Compound 2-[(2,4-Dichlorophenyl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one as COMT Inhibitor in the Treatment of Parkinson's Disease: A Molecular Dynamic Simulation Approach

Parkinson's disease (PD) is one of the most targeted neurodegenerative diseases in clinical research. Awareness of research is due to its increasing number of affected people worldwide. The pathology of PD has been linked to several key proteins upregulation such as the catechol O-Methyltransferase (COMT). Hence, the synthesis of compounds possessing inhibitory capacity has been the frontline of research in recent years. Several compounds have been synthesized among which is the nitrocatechol. However, major limitations associated with the nitrocatechol scaffold include the inability to possess adequate CNS penetration properties and hepatic toxicity associated with the compounds. However, a series of bicyclic hydroxypyridones compounds were synthesized to evaluate their inhibitory potentials on COMT protein with compound 38 (c38) 2-[(2,4-dichlorophenyl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one shown to have a 40 fold increase level coverage in its IC₅₀ over brain exposure when compared to the other synthesized compound. The molecular dynamics method was employed to understand the nature of interaction exhibited by c38. Molecular mechanics of c38 revealed a disruptive effect on the secondary structure of COMT protein. Per residue decomposition analysis revealed similar crucial residues involved in the favorable binding of c38 and tolcapone implicated its increased inhibitory capacity on COMT in preventing PD. Free binding energy (ΔG_bind) of c38 further revealed the inhibitory capacity towards COMT protein in comparison to the FDA approved tolcapone. Ligand mobility analysis of both compounds showed a timewise different mobility pattern across the simulation time frame at the active site pocket of the protein connoting the different inhibitory potency exhibited by c38 and tolcapone. Findings from this study revealed optimization of c38 could facilitate the discovery of new compounds with enhanced inhibitory properties towards COMT in treating PD.     

A Mechanistic Probe into the Dual Inhibition of T. cruzi Glucokinase and Hexokinase in Chagas Disease Treatment – A Stone Killing Two Birds?

Glucokinase (GLK) and Hexokinase (HK) have been characterized as essential targets in Trypanosoma cruzi (Tc)-mediated infection. A recent study reported the propensity of the concomitant inhibition of TcGLK and TcHK by compounds GLK2-003 and GLK2-004, thereby presenting an efficient approach in Chagas disease treatment. We investigated this possibility using atomic and molecular scaling methods. Sequence alignment of TcGLK and TcHK revealed that both proteins shared approximately 33.3 % homology in their glucose/inhibitor binding sites. The total binding free energies of GLK2-003 and GLK2-004 were favorable in both proteins. PRO92 and THR185 were pivotal to the binding and stabilization of the ligands in TcGLK, likewise their conserved counterparts, PRO163 and THR237 in TcHK. Both compounds also induced a similar pattern of perturbations in both TcGLK and TcHK secondary structure. Findings from this study therefore provide insights into the underlying mechanisms of dual inhibition exhibited by the compounds. These results can pave way to discover and optimize novel dual Tc inhibitors with favorable pharmacokinetics properties eventuating in the mitigation of Chagas disease.     

A Mathematical Model of the Tuberculosis Epidemic

Acta Biotheoretica - Tuberculosis has continued to retain its title as “the captain among these men of death”. This is evident as it is the leading cause of death globally from a single...     

Quinacrine is a prostaglandin antagonist

Quinacrine, an anti-malarial with local anaesthetic properties, because of its fluorescence characteristics and its ability to combine with chromosomes and biological membranes has been widely used as a “probe”. The sites with which it combines in $\text{Torpedo marmorata}$ electric organs have many of the characteristics of specific receptors. Using rat vascular and gastric smooth muscle we have shown that quinacrine can competitively antagonise the actions of prostaglandin E2. We suggest that the biological sites to which quinacrine binds can normally be occupied by prostaglandins.     

Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum

A parallel synthetic strategy to the 9-aminoacridine scaffold of the classical anti-malarial drug quinacrine (2) is presented. The method features a new route to 9-chloroacridines that utilizes triflates of salicylic acid derivatives, which are commercially available in a variety of substitution patterns. The route allows ready variation of the two diversity elements present in this class of molecules: the tricyclic aromatic heterocyclic core, and the disubstituted diamine sidechain. In this study, a library of 175 compounds was designed, although only 93 of the final products had purities acceptable for screening. Impurity was generally due to incomplete removal of 9-acridones (18), a degradation product of the 9-chloroacridine synthetic intermediates. The library was screened against two strains of Plasmodium falciparum, including a model of the drug-resistant parasite, and six novel compounds were found to have IC(50) values in the low nanomolar range.     

Host Handling Time in a Polyembryonic Wasp is Affected both by Previous Experience and by Host State (Parasitized or Not)

Foraging behavior for hosts in parasitoids resembles that of predators with respect to finding, evaluating and manipulating of the prey. Host handling time may depend on the life history of the parasitoid and can be affected by oviposition experience. Additionally, handling time can be affected by host aggregation, species, size and state (parasitized or not). We studied handling times in the egg-larval parasitoid wasp Copidosoma koehleri. We allowed naïve female wasps to oviposit into three consecutive unparasitized hosts, and measured time until oviposition, and the duration of ovipositor insertion. We recorded the same data for naïve females ovipositing into already parasitized hosts. We found that both previous experience by females and previous parasitism of hosts reduced handling time. The results suggest that host handling durations reflect the interplay between host state and parasitoid internal state.     

Oogenesis in the date stone beetle, Coccotrypes dactyliperda, depends on symbiotic bacteria

Abstract.  It has been suggested that sex ratio distorting symbionts are involved in the sex determination and female-biased sex ratios observed in strongly inbred scolytid beetles. Coccotrypes dactyliperda (Coleoptera: Scolytinae) is a species in which mother-son- and sib-mating occur inside the date seeds it inhabits, and the sex ratios produced are highly skewed toward females. In the present study, polymerase chain reaction (PCR) techniques and antibiotic treatments are applied to determine the possible role of Bacteria in this system. PCR with primers specifically designed to target the 16S rDNA gene in all Bacteria reveals the presence of Wolbachia and Rickettsia in control beetles, but not in antibiotic-treated individuals. Virgin females fed with antibiotics lay no eggs, and no sign of oogenesis is detected compared with all-male progeny of virgin control females. Mated females fed with antibiotics lay significantly fewer eggs than control females, with a strong effect of female age at the time of antibiotic feeding on the number of eggs laid. The study suggests that symbiotic bacteria are not involved in female-biased sex ratios but are required for oogenesis in C. dactyliperda . The specific role each of the bacteria ( Wolbachia and Rickettsia ) plays in the oogenesis remains to be determined.