Endosomal transport is essential for cellular organization and compartmentalization and cell-cell communication. Sorting endosomes provide a crossroad for various trafficking pathways and determine recycling, secretion or degradation of proteins.The organisation of these processes requires membrane tethering factors to coordinate Rab GTPase function with membrane fusion. Here, we report a conserved tethering platform that acts in the Rab11 recycling pathways at sorting endosomes, which we name FERARI (Factor for Endosome Recycling And Rab Interactions). The Rab binding module of FERARI consists of Rab11FIP5/RFIP-2 and rabenosyn-5/RABS-5, while the SNARE interacting module comprises VPS45 and VIPAS39/SPE-39. Unexpectedly, the membrane fission protein EHD1/RME-1 is also a FERARI component. Thus, FERARI appears to combine fusion activity through the SM protein VPS45 with pinching activity through EHD1/RME-1 on SNX-1-positive endosomal membranes. We propose that coordination of fusion and pinching through a kiss-and-run mechanism drives cargo at endosomes into recycling pathways.45 in E. coli. His-VPS-45 co-purified with SPE-39-GST (Figure 1a, Extended Data 3d). VPS-33.2, which together with SPE-39 is part of the CHEVI complex 27,28 served as a positive control, while the HOPS specific VPS-33.1 did not bind SPE-39.These data indicate direct binding of SPE-39 to VPS-45. This interaction was confirmed by yeast-two-hybrid (Y2H) and pull-down experiments (Figure 1b, Extended Data 2d, d', Supplementary Table 3). Moreover, FERARI is conserved in mammalian cells (Figure 1c). VPS45 has been shown to directly interact with rabenosyn-5 29,30 . Similar to VPS45, rabenosyn-5 interacted with VIPAS39 (Figure 1b-e, Fig. Extended Data 1b, 1b', 2b, 2b', 2d, 2d').Based on HOPS and CORVET, we speculated that FERARI might contain more subunits (Extended Data 1a). To identify additional components, we incubated the bacterially expressed SPE-39/VPS-45 complex with worm lysate and performed mass spectrometry (Supplementary Table 1), followed by Y2H assays and pulldowns from selected, streamlined candidates. We discovered two additional components of FERARI: the Epsin-homology domain (EHD) containing protein RME-1 and UNC-44 (Figure 1f, Supplementary Table 3).UNC-44 contains ankyrin motifs and a death domain. SPE-39 interacted well with RME-1 and the ankyrin motifs of Supplementary Table 3, Extended Data 1c, 1c',1d, 1d', 2a, 2a'). RME-1 is homologous to mammalian EHD1-4, and UNC-44 to ANK1-3. Since EHD1 has been shown to act at endosomes and EHD2 at the plasma membrane 31, 32 , we focused on EHD1. EHD1 co-precipitated and co-localized with rabenosyn-5 (Figure 1h, Extended Data 4a, b). Much less is known about ANK1-3. However, ANK3 appears to be the ANK protein most highly expressed in HeLa cells (Extended Data 4d). ANK3 co-precipitated with endogenous VIPAS39 (Figure 1g). Finally, endogenous VIPAS39 was pulled-down with all other
Bangladesh faces huge challenges in achieving food security due to its high population, diet changes, and limited room for expanding cropland and cropping intensity. The objective of this study is to assess the degree to which Bangladesh can be self-sufficient in terms of domestic maize, rice and wheat production by the years 2030 and 2050 by closing the existing gap (Yg) between yield potential (Yp) and actual farm yield (Ya), accounting for possible changes in cropland area. Yield potential and yield gaps were calculated for the three crops using well-validated crop models and site-specific weather, management and soil data, and upscaled to the whole country. We assessed potential grain production in the years 2030 and 2050 for six land use change scenarios (general decrease in arable land; declining ground water tables in the north; cropping of fallow areas in the south; effect of sea level rise; increased cropping intensity; and larger share of cash crops) and three levels of Yg closure (1: no yield increase; 2: Yg closure at a level equivalent to 50% (50% Yg closure); 3: Yg closure to a level of 85% of Yp (irrigated crops) and 80% of water-limited yield potential or Yw (rainfed crops) (full Yg closure)). In addition, changes in demand with low and high population growth rates, and substitution of rice by maize in future diets were also examined. Total aggregated demand of the three cereals (in milled rice equivalents) in 2030 and 2050, based on the UN median population variant, is projected to be 21 and 24% higher than in 2010. Current Yg represent 50% (irrigated rice), 48–63% (rainfed rice), 49% (irrigated wheat), 40% (rainfed wheat), 46% (irrigated maize), and 44% (rainfed maize) of their Yp or Yw. With 50% Yg closure and for various land use changes, self-sufficiency ratio will be > 1 for rice in 2030 and about one in 2050 but well below one for maize and wheat in both 2030 and 2050. With full Yg closure, self-sufficiency ratios will be well above one for rice and all three cereals jointly but below one for maize and wheat for all scenarios, except for the scenario with drastic decrease in boro rice area to allow for area expansion for cash crops. Full Yg closure of all cereals is needed to compensate for area decreases and demand increases, and then even some maize and large amounts of wheat imports will be required to satisfy demand in future. The results of this analysis have important implications for Bangladesh and other countries with high population growth rate, shrinking arable land due to rapid urbanization, and highly vulnerable to climate change.
Manganese (Mn) is an important trace element present in human body, which acts as an enzyme co-factor or activator in various metabolic reactions. While essential in trace amounts, excess levels of Mn in human brain can produce neurotoxicity, including idiopathic Parkinson’s disease (PD)-like extrapyramidal manganism symptoms. This study aimed to investigate the protective role of polyphenolic extract of Euphorbia supina (PPEES) on Mn-induced neurotoxicity and the underlying mechanism in human neuroblastoma SKNMC cells and Sprague-Dawley (SD) male rat brain. PPEES possessed significant amount of total phenolic and flavonoid contents. PPEES also showed significant antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and reducing power capacity (RPC) assays. Our results showed that Mn treatment significantly reduced cell viability and increased lactate dehydrogenase (LDH) level, which was attenuated by PPEES pretreatment at 100 and 200 µg/mL. Additionally, PPEES pretreatment markedly attenuated Mn-induced antioxidant status alteration by resolving the ROS, MDA and GSH levels and SOD and CAT activities. PPEES pretreatment also significantly attenuated Mn-induced mitochondrial membrane potential (ΔΨm) and apoptosis. Meanwhile, PPEES pretreatment significantly reversed the Mn-induced alteration in the GRP78, GADD34, XBP-1, CHOP, Bcl-2, Bax and caspase-3 activities. Furthermore, administration of PPEES (100 and 200 mg/kg) to Mn exposed rats showed improvement of histopathological alteration in comparison to Mn-treated rats. Moreover, administration of PPEES to Mn exposed rats showed significant reduction of 8-OHdG and Bax immunoreactivity. The results suggest that PPEES treatment reduces Mn-induced oxidative stress and neuronal cell loss in SKNMC cells and in the rat brain. Therefore, PPEES may be considered as potential treat-ment in Mn-intoxicated patients.
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