Malaria intervention scale-up in Africa : effectiveness predictions for health programme planning tools, based on dynamic transmission modelling

Scale-up of malaria prevention and treatment needs to continue to further important gains made in the past decade, but national strategies and budget allocations are not always evidence-based. Statistical models were developed summarizing dynamically simulated relations between increases in coverage and intervention impact, to inform a malaria module in the Spectrum health programme planning tool.; The dynamic Plasmodium falciparum transmission model OpenMalaria was used to simulate health effects of scale-up of insecticide-treated net (ITN) usage, indoor residual spraying (IRS), management of uncomplicated malaria cases (CM) and seasonal malaria chemoprophylaxis (SMC) over a 10-year horizon, over a range of settings with stable endemic malaria. Generalized linear regression models (GLMs) were used to summarize determinants of impact across a range of sub-Sahara African settings.; Selected (best) GLMs explained 94-97 % of variation in simulated post-intervention parasite infection prevalence, 86-97 % of variation in case incidence (three age groups, three 3-year horizons), and 74-95 % of variation in malaria mortality. For any given effective population coverage, CM and ITNs were predicted to avert most prevalent infections, cases and deaths, with lower impacts for IRS, and impacts of SMC limited to young children reached. Proportional impacts were larger at lower endemicity, and (except for SMC) largest in low-endemic settings with little seasonality. Incremental health impacts for a given coverage increase started to diminish noticeably at above ~40 % coverage, while in high-endemic settings, CM and ITNs acted in synergy by lowering endemicity. Vector control and CM, by reducing endemicity and acquired immunity, entail a partial rebound in malaria mortality among people above 5 years of age from around 5-7 years following scale-up. SMC does not reduce endemicity, but slightly shifts malaria to older ages by reducing immunity in child cohorts reached.; Health improvements following malaria intervention scale-up vary with endemicity, seasonality, age and time. Statistical models can emulate epidemiological dynamics and inform strategic planning and target setting for malaria control

COYOTES, SHEEP AND LITHIUM CHLORIDE

The use of LiCl-treated baits and carcasses has been advocated as a means of controlling coyote predation on sheep through a process known as aversive conditioning or taste aversion. While some investigators have made well publicized claims of damage reduction through the use of LiCl on sheep ranges, other researchers have experienced difficulty establishing prey aversion in captive coyotes. The conflicting results suggest a need for extensive, carefully controlled research in both pen and field situations before valid conclusions can be reached regarding aversive conditioning as a depredations control method

COYOTES, SHEEP AND LITHIUM CHLORIDE

The use of LiCl-treated baits and carcasses has been advocated as a means of controlling coyote predation on sheep through a process known as aversive conditioning or taste aversion. While some investigators have made well publicized claims of damage reduction through the use of LiCl on sheep ranges, other researchers have experienced difficulty establishing prey aversion in captive coyotes. The conflicting results suggest a need for extensive, carefully controlled research in both pen and field situations before valid conclusions can be reached regarding aversive conditioning as a depredations control method

Long-Term Potentiation in Isolated Dendritic Spines

BACKGROUND:In brain, N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation can induce long-lasting changes in synaptic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor (AMPAR) levels. These changes are believed to underlie the expression of several forms of synaptic plasticity, including long-term potentiation (LTP). Such plasticity is generally believed to reflect the regulated trafficking of AMPARs within dendritic spines. However, recent work suggests that the movement of molecules and organelles between the spine and the adjacent dendritic shaft can critically influence synaptic plasticity. To determine whether such movement is strictly required for plasticity, we have developed a novel system to examine AMPAR trafficking in brain synaptosomes, consisting of isolated and apposed pre- and postsynaptic elements. METHODOLOGY/PRINCIPAL FINDINGS:We report here that synaptosomes can undergo LTP-like plasticity in response to stimuli that mimic synaptic NMDAR activation. Indeed, KCl-evoked release of endogenous glutamate from presynaptic terminals, in the presence of the NMDAR co-agonist glycine, leads to a long-lasting increase in surface AMPAR levels, as measured by [(3)H]-AMPA binding; the increase is prevented by an NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5). Importantly, we observe an increase in the levels of GluR1 and GluR2 AMPAR subunits in the postsynaptic density (PSD) fraction, without changes in total AMPAR levels, consistent with the trafficking of AMPARs from internal synaptosomal compartments into synaptic sites. This plasticity is reversible, as the application of AMPA after LTP depotentiates synaptosomes. Moreover, depotentiation requires proteasome-dependent protein degradation. CONCLUSIONS/SIGNIFICANCE:Together, the results indicate that the minimal machinery required for LTP is present and functions locally within isolated dendritic spines

Generalized Integer Partitions, Tilings of Zonotopes and Lattices

In this paper, we study two kinds of combinatorial objects, generalized integer partitions and tilings of two dimensional zonotopes, using dynamical systems and order theory. We show that the sets of partitions ordered with a simple dynamics, have the distributive lattice structure. Likewise, we show that the set of tilings of zonotopes, ordered with a simple and classical dynamics, is the disjoint union of distributive lattices which we describe. We also discuss the special case of linear integer partitions, for which other dynamical systems exist. These results give a better understanding of the behaviour of tilings of zonotopes with flips and dynamical systems involving partitions.Comment: See http://www.liafa.jussieu.fr/~latapy

Dihydropyrimidine-thiones and clioquinol synergize to target beta-amyloid cellular pathologies through a metal-dependent mechanism

The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by β-amyloid (Aβ), the peptide implicated in Alzheimer’s disease. Rescue of Aβ toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action. The bioactivity was distinct, however, from that of the 8-hydroxyquinoline clioquinol (CQ). These structurally dissimilar compounds strongly synergized at concentrations otherwise not competent to reduce toxicity. Cotreatment ameliorated Aβ toxicity by reducing Aβ levels and restoring functional vesicle trafficking. Notably, these low doses significantly reduced deleterious off-target effects caused by CQ on mitochondria at higher concentrations. Both single and combinatorial treatments also reduced death of neurons expressing Aβ in a nematode, indicating that DHPM-thiones target a conserved protective mechanism. Furthermore, this conserved activity suggests that expression of the Aβ peptide causes similar cellular pathologies from yeast to neurons. Our identification of a new cytoprotective scaffold that requires metal-binding underscores the critical role of metal phenomenology in mediating Aβ toxicity. Additionally, our findings demonstrate the valuable potential of synergistic compounds to enhance on-target activities, while mitigating deleterious off-target effects. The identification and prosecution of synergistic compounds could prove useful for developing AD therapeutics where combination therapies may be required to antagonize diverse pathologies.D.F.T was funded by NRSA Fellowship NIH 5F32NS061419. D.F.T. and S.L. were supported by WIBR funds in support of research on Regenerative Disease, the Picower/JPB Foundation, and the Edward N. and Della L. Thome Foundation. G.A.C. and S.L. were funded by a Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award. L.E.B., R.T., and S.E.S. were funded by NIH GM086180, NIH GM067041, and NIH GM111625. (5F32NS061419 - NRSA Fellowship NIH; WIBR funds in support of research on Regenerative Disease; Picower/JPB Foundation; Edward N. and Della L. Thome Foundation; Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award; GM086180 - NIH; NIH GM067041 - NIH; NIH GM111625 - NIH)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705239/Accepted manuscrip

Optimal (Randomized) Parallel Algorithms in the Binary-Forking Model

In this paper we develop optimal algorithms in the binary-forking model for a variety of fundamental problems, including sorting, semisorting, list ranking, tree contraction, range minima, and ordered set union, intersection and difference. In the binary-forking model, tasks can only fork into two child tasks, but can do so recursively and asynchronously. The tasks share memory, supporting reads, writes and test-and-sets. Costs are measured in terms of work (total number of instructions), and span (longest dependence chain). The binary-forking model is meant to capture both algorithm performance and algorithm-design considerations on many existing multithreaded languages, which are also asynchronous and rely on binary forks either explicitly or under the covers. In contrast to the widely studied PRAM model, it does not assume arbitrary-way forks nor synchronous operations, both of which are hard to implement in modern hardware. While optimal PRAM algorithms are known for the problems studied herein, it turns out that arbitrary-way forking and strict synchronization are powerful, if unrealistic, capabilities. Natural simulations of these PRAM algorithms in the binary-forking model (i.e., implementations in existing parallel languages) incur an $\Omega(\log n)$ overhead in span. This paper explores techniques for designing optimal algorithms when limited to binary forking and assuming asynchrony. All algorithms described in this paper are the first algorithms with optimal work and span in the binary-forking model. Most of the algorithms are simple. Many are randomized

Late Pleistocene vertebrate trace fossils in the Goukamma Nature Reserve, Cape South Coast, South Africa

More than 100 Late Pleistocene trace fossil sites have been identified in aeolianites along a 275 kilometer stretch of the Cape south coast. A zone of concentration of such sites exists within the Goukamma Nature Reserve, both along the coast and along the Goukamma River. These sites provide insight into the Pleistocene fauna along the Cape south coast. Features include lion trackways, multiple elephant tracksites, a long trackway most likely attributable to Long-horned Buffalo, medium-sized carnivore tracks, avian tracks, equid tracks attributable to the giant Cape horse, numerous artiodactyl tracks, and burrow traces. The ephemeral nature of the tracksites makes regular surveys of these areas desirable, along with site documentation and trackway replication and preservation initiatives. The protected status of the area offers opportunities for geoheritage appreciation.JN