Costs of mass drug administration for scabies in Fiji

In 2019, the Murdoch Children’s Research Institute in partnership with the Fiji Ministry of Health and Medical Services carried out an integrated mass drug administration (MDA) for the treatment of scabies and lymphatic filariasis in the Northern Division of Fiji (population estimate 131,914). We conducted a retrospective micro-costing exercise focused on the cost of scabies control in order to inform budgeting and policy decision making in an endemic setting. We collected detailed information on financial and economic costs incurred by both parties during the course of the MDA campaign (April 2018 to July 2019). We also conducted interviews with personnel involved in the financial administration of the MDA campaign. The economic cost of delivering two doses of ivermectin was US$4.88 per person. The cost of donated drugs accounted for 36.3% of total MDA costs. In this first large-scale MDA for the public health control of scabies, the estimated cost of delivering MDA per person for scabies was considerably more expensive than the costs reported for other neglected tropical diseases. The important cost drivers included the remuneration of health care workers who were extensively involved in the campaign, coverage of hard-to-reach, mainly rural populations and the two-dose regimen of ivermectin. These results highlight the importance of these cost determinants and can be used to plan current and future MDA programs.     

Influence of cover crops and tillage systems on nematode populations in a maize-cover crop intercrop

Cropping systems affect the distribution/diversity of soil microorganisms, including soilborne pathogens. In order to examine the effect of the cropping systems on soil nematodes, maize (Zea mays) was intercropped with different cover crops [Glycine max (GM), Macrotyloma uniflorum (MU), Centrosema pascuorum (CP), Cucurbita maxima (CM) and a control experiment with no cover crop (NC)] under different tillage systems [no till, reduced tillage and conventional tillage] to evaluate the effect of the various treatments on nematode population. The treatments were arranged in a split-plot design with three replications each. Tillage was the main treatment while cover crops were applied to subtreatment. In all, nematodes belonging to twenty-two (22) plant parasitic nematode genera were identified. While most of the genera were identified on all the treatments, the interaction of tillage systems and cover crops had significant effect on the population of Xiphinema and Trichodorus only, showing the nullifying effect of some tillage practices on the other nematodes which were significant under crops as only treatments inter alia. This information could be used in nematode management when integrated management systems are being considered for such intercrop mixtures.     

Control of Golgi morphology and function by Sed5 t-SNARE phosphorylation

Previously, we demonstrated that the phosphorylation of t-SNAREs by protein kinase A (PKA) affects their ability to participate in SNARE complexes and to confer endocytosis and exocytosis in yeast. Here, we show that the presumed phosphorylation of a conserved membrane-proximal PKA consensus site (serine-317) in the Sed5 t-SNARE regulates endoplasmic reticulum (ER)-Golgi transport, as well as Golgi morphology. Sed5 is a phosphoprotein, and both alanine and aspartate substitutions in serine-317 directly affect intracellular protein trafficking. The aspartate substitution results in elaboration of the ER, defects in Golgi-ER retrograde transport, an accumulation of small transport vesicles, and the inhibition of growth of most cell types. In contrast, the alanine substitution has no deleterious effects upon transport and growth, but results in ordering of the Golgi into a structure reminiscent of mammalian apparatus. This structure seems to require the recycling of Sed5, because it was found not to occur in sec21-2 cells that are defective in retrograde transport. Thus, a cycle of Sed5 phosphorylation and dephosphorylation is required for normal t-SNARE function and may choreograph Golgi ordering and dispersal.     

一种从直流到超高频生物电磁学实验系统

阐述了环境对生物电磁学实验的影响和电磁计量在生物电磁学实验中的重要性。提出了一种用于从直流到超高频（ＤＣ—ＵＨＦ）段生物电磁学实验的封闭系统,计算了其中的电磁场分布,从而给出了电磁计量方法。     

Involvement of specific COPI subunits in protein sorting from the late endosome to the vacuole in yeast

Although COPI function on the early secretory pathway in eukaryotes is well established, earlier studies also proposed a nonconventional role for this coat complex in endocytosis in mammalian cells. Here we present results that suggest an involvement for specific COPI subunits in the late steps of endosomal protein sorting in Saccharomyces cerevisiae. First, we found that carboxypeptidase Y (CPY) was partially missorted to the cell surface in certain mutants of the COPIB subcomplex (COPIb; Sec27, Sec28, and possibly Sec33), which indicates an impairment in endosomal transport. Second, integral membrane proteins destined for the vacuolar lumen (i.e., carboxypeptidase S [CPS1]; Fur4, Ste2, and Ste3) accumulated at an aberrant late endosomal compartment in these mutants. The observed phenotypes for COPIb mutants resemble those of class E vacuolar protein sorting (vps) mutants that are impaired in multivesicular body (MVB) protein sorting and biogenesis. Third, we observed physical interactions and colocalization between COPIb subunits and an MVB-associated protein, Vps27. Together, our findings suggest that certain COPI subunits could have a direct role in vacuolar protein sorting to the MVB compartment.     

Btn3 is a negative regulator of Btn2-mediated endosomal protein trafficking and prion curing in yeast

Yeast Btn2 facilitates the retrieval of specific proteins from late endosomes (LEs) to the Golgi, a process that may be adversely affected in Batten disease patients. We isolated the putative yeast orthologue of a human complex I deficiency gene, designated here as BTN3, as encoding a Btn2-interacting protein and negative regulator. First, yeast overexpressing BTN3 phenocopy the deletion of BTN2 and mislocalize certain trans-Golgi proteins, like Kex2 and Yif1, to the LE and vacuole, respectively. In contrast, the deletion of BTN3 results in a tighter pattern of protein localization to the Golgi. Second, BTN3 overexpression alters Btn2 localization from the IPOD compartment, which correlates with a sharp reduction in Btn2-mediated [URE3] prion curing. Third, Btn3 and the Snc1 v-SNARE compete for the same binding domain on Btn2, and this competition controls Btn2 localization and function. The inhibitory effects upon protein retrieval and prion curing suggest that Btn3 sequesters Btn2 away from its substrates, thus down-regulating protein trafficking and aggregation. Therefore Btn3 is a novel negative regulator of intracellular protein sorting, which may be of importance in the onset of complex I deficiency and Batten disease in humans.     

Mechanisms of copper ion mediated Huntington's disease progression

Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron found in human HD brain are reiterated in the brains of affected HD transgenic mice. Increased brain copper correlated with decreased levels of the copper export protein, amyloid precursor protein. We hypothesized that increased amounts of copper bound to low affinity sites could contribute to pro-oxidant activities and neurodegeneration. We focused on two proteins: huntingtin, because of its centrality to HD, and lactate dehydrogenase (LDH), because of its documented sensitivity to copper, necessity for normoxic brain energy metabolism and evidence for altered lactate metabolism in HD brain. The first 171 amino acids of wild-type huntingtin, and its glutamine expanded mutant form, interacted with copper, but not iron. N171 reduced Cu(2+)in vitro in a 1:1 copper:protein stoichiometry indicating that this fragment is very redox active. Further, copper promoted and metal chelation inhibited aggregation of cell-free huntingtin. We found decreased LDH activity, but not protein, and increased lactate levels in HD transgenic mouse brain. The LDH inhibitor oxamate resulted in neurodegeneration when delivered intra-striatially to healthy mice, indicating that LDH inhibition is relevant to neurodegeneration in HD. Our findings support a role of pro-oxidant copper-protein interactions in HD progression and offer a novel target for pharmacotherapeutics.     

Fluctuated water depth with high nutrient concentrations promote the invasiveness of Wedelia trilobata in Wetland

The distribution of invasive and native species in wetlands is determined by hydrological conditions; whereas conditions such as water depth fluctuations, variations in the nutrient concentrations are expected to affect the growth and physiological traits of plants. For the assessment of such effects, we conduct greenhouse experiment with three factors; 1) water depth of 5 cm and 15 cm (static and fluctuated); 2) three levels of nutrient concentrations (i) full‐strength Hoagland solution (N1), (ii) ¼‐strength Hoagland solution (N2), and (iii) ¹/₈‐strength Hoagland solution (N3); and 3) species, invasive Wedelia trilobata (L.) and its congener, native Wedelia chinensis (Osbeck.) under mono and mixed culture. Water depth of 5 cm combined with any of the nutrient treatments significantly restrained the photosynthesis, intracellular CO₂ concentration and leaf chlorophyll of both W. trilobata and W. chinensis. Increase in the water depth to 15 cm with low‐nutrient treatment N3 did not sustain the physiological traits of W. chinensis under mono and mixed planting. A great loss was noted in the growth of W. chinensis at 15 cm static and fluctuated water depth with low‐nutrient treatment (N3) and under mixed culture. In addition, water depth fluctuations with both low‐ and high‐nutrient treatments significantly affected the root‐shoot ratio, relative growth rate, and interspecific interaction among these two species. W. trilobata benefited more from competitive interaction index (CII) under fluctuated water depth at 15 cm with high nutrients, and the value of CII was clearly positive. Therefore, higher competitive ability may contribute to the invasiveness of W. trilobata in wetlands.     

Chromatin Assembly Factor I Mutants Defective for PCNA Binding Require Asf1/Hir Proteins for Silencing

Chromatin assembly factor I (CAF-I) is a conserved histone H3/H4 deposition complex. Saccharomyces cerevisiae mutants lacking CAF-I subunit genes (CAC1 to CAC3) display reduced heterochromatic gene silencing. In a screen for silencing-impaired cac1 alleles, we isolated a mutation that reduced binding to the Cac3p subunit and another that impaired binding to the DNA replication protein PCNA. Surprisingly, mutations in Cac1p that abolished PCNA binding resulted in very minor telomeric silencing defects but caused silencing to be largely dependent on Hir proteins and Asf1p, which together comprise an alternative silencing pathway. Consistent with these phenotypes, mutant CAF-I complexes defective for PCNA binding displayed reduced nucleosome assembly activity in vitro but were stimulated by Asf1p-histone complexes. Furthermore, these mutant CAF-I complexes displayed a reduced preference for depositing histones onto newly replicated DNA. We also observed a weak interaction between Asf1p and Cac2p in vitro, and we hypothesize that this interaction underlies the functional synergy between these histone deposition proteins.