Assessing Future Water Availability in Arid Regions Using Composition and Salience of Decision Criteria

Water resources development options are usually selected on a least-cost basis. While economic considerations are dominant in choosing projects, there are also a mix of other factors including social demands, political expediency, social equity, and environmental considerations that impact final decisions and development of water supply systems. Understanding local priorities in water resource management decisions can allow for forming expectations of future regional water availability. In this research, we propose that future water availability in arid regions may be assessed by considering key projects that have been identified or planned by regional experts. Using Multi-Criteria Decision Analysis methods as a framework to organize set of decision criteria and their relative salience, the likelihood of selection (and development) of a project can be determined and used to form expectations of future regional water availability. We use this approach in a case study for Jordan, and find that large-scale desalination projects—that have been in the planning books for decades—are now most likely to be pursued and implemented in the country. Finally, we discuss strengths, limitations, and the general applicability of this method for assessing future water availability in other arid regions

Formulating Expectations for Future Water Availability through Infrastructure Development Decisions in Arid Regions

Water resources development options are usually selected on a least-cost basis. While economic considerations are dominant in choosing projects, there are also a mix of other factors including social demands, political viability, social equity, and environmental considerations that impact final decisions and development of water supply systems. Understanding local priorities in water resource management decisions can allow for forming expectations of future regional water availability through new infrastructure projects. In this research, we propose that future human mediated water availability in arid regions may be assessed by considering key projects that have been identified or proposed by regional experts and organizations. Using Multicriteria Decision Methods as a framework to organize a set of decision criteria and their relative salience, the likelihood of selection (and development) of a project can be determined and used to form expectations of future regional water availability. We apply this approach in a case study of Jordan, and find that large-scale desalination projects—that have been in the planning books for decades—are now most likely to be pursued and implemented in the country. Finally, we discuss strengths, limitations, and the general applicability of this method for assessing future water availability in other arid regions

Transient siRNA-mediated protein knockdown in mouse followed by feeding/starving cycle and liver tissue analysis.

We present a protocol for in vivo siRNA-mediated knockdown of a gene of interest in mouse liver using systemic delivery via intravenous injection. We describe a step-by-step protocol for delivery of siRNA particles, with tips on how to optimize dosage. We detail steps for feeding/starving cycles as well as for liver tissue isolation, followed by gene expression analysis, measured at the mRNA and protein levels. For complete information on the generation and use of this protocol, please refer to Wrobel et al. (2020).We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society) (to DCR), the Roger de Spoelberch Foundation (DCR), the European Molecular Biology Organisation (EMBO long-term fellowship to LW ALTF 135-2016). We thank the University of Cambridge core mice facility staff

LC3-positive structures are prominent in autophagy-deficient cells

Abstract: Autophagy is an evolutionarily conserved process across eukaryotes that degrades cargoes like aggregate-prone proteins, pathogens, damaged organelles and macromolecules via delivery to lysosomes. The process involves the formation of double-membraned autophagosomes that engulf the cargoes destined for degradation, sometimes with the help of autophagy receptors like p62, which are themselves autophagy substrates. LC3-II, a standard marker for autophagosomes, is generated by the conjugation of cytosolic LC3-I to phosphatidylethanolamine (PE) on the surface of nascent autophagosomes. As LC3-II is relatively specifically associated with autophagosomes and autolysosomes (in the absence of conditions stimulating LC3-associated phagocytosis), quantification of LC3-positive puncta is considered as a gold-standard assay for assessing the numbers of autophagosomes in cells. Here we find that the endogenous LC3-positive puncta become larger in cells where autophagosome formation is abrogated, and are prominent even when LC3-II is not formed. This occurs even with transient and incomplete inhibition of autophagosome biogenesis. This phenomenon is due to LC3-I sequestration to p62 aggregates, which accumulate when autophagy is impaired. This observation questions the reliability of LC3-immunofluorescence assays in cells with compromised autophagy

Sleep deprivation and its associated factors among general ward patients at a tertiary care hospital in Pakistan

Objective: To estimate the occurrence rate of sleep deprivation and to identify the environmental, staff-related and patient-related factors associated with SD among general ward patients of a tertiary care hospital in Pakistan.Methods: In a cross-sectional study, a pre-tested questionnaire was administered to 108 patients admitted into the general medical and general surgical wards of Aga Khan University Hospital, Karachi.Results: In all, 50 (46.3%) respondents felt deprived of adequate sleep in the hospital. Worry about illness disturbed the night-time sleep of 47 (43.5%) patients; most of these had SD (70%) (p \u3c 0.001). Other patients\u27 noise disturbed 31.5% of study subjects and a significant majority (68%) of these had SD (p = 0.003). Over 17% of study subjects reported cell phone\u27s ringing as a disturbing factor; more by those with SD (68%) compared to those with no SD (32%); again the difference was significant (p = 0.003). Physical discomfort and presence of cannula were reported as disturbing factors by 41.7% and 28.7% of the study subjects respectively but these were not significantly associated with SD.CONCLUSION: Our study revealed that sleep deprivation occurs commonly among general ward patients in tertiary care setting. Factors found to be associated with SD were amenable to modification to a greater extent

Transcriptional regulation of Annexin A2 promotes starvation-induced autophagy.

Autophagy is an important degradation pathway, which is induced after starvation, where it buffers nutrient deprivation by recycling macromolecules in organisms from yeast to man. While the classical pathway mediating this response is via mTOR inhibition, there are likely to be additional pathways that support the process. Here, we identify Annexin A2 as an autophagy modulator that regulates autophagosome formation by enabling appropriate ATG9A trafficking from endosomes to autophagosomes via actin. This process is dependent on the Annexin A2 effectors ARP2 and Spire1. Annexin A2 expression increases after starvation in cells in an mTOR-independent fashion. This is mediated via Jun N-terminal kinase activation of c-Jun, which, in turn, enhances the trans-activation of the Annexin A2 promoter. Annexin A2 knockdown abrogates starvation-induced autophagy, while its overexpression induces autophagy. Hence, c-Jun-mediated transcriptional responses support starvation-induced autophagy by regulating Annexin A2 expression levels.Openheimer Memorial TrustThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms904

IGF-1 receptor antagonism inhibits autophagy

Inhibition of the insulin/insulin-like growth factor signalling pathway increases lifespan and protects against neurodegeneration in model organisms, and has been considered as a potential therapeutic target. This pathway is upstream of mTORC1, a negative regulator of autophagy. Thus, we expected autophagy to be activated by insulin-like growth factor-1 (IGF-1) inhibition, which could account for many of its beneficial effects. Paradoxically, we found that IGF-1 inhibition attenuates autophagosome formation. The reduced amount of autophagosomes present in IGF-1R depleted cells can be, at least in part, explained by a reduced formation of autophagosomal precursors at the plasma membrane. In particular, IGF-1R depletion inhibits mTORC2, which, in turn, reduces the activity of protein kinase C (PKCa/b). This perturbs the actin cytoskeleton dynamics and decreases the rate of clathrin-dependent endocytosis, which impacts autophagosome precursor formation. Finally, with important implications for human diseases, we demonstrate that pharmacological inhibition of the IGF-1R signalling cascade reduces autophagy also in zebrafish and mice models. The novel link we describe here has important consequences for the interpretation of genetic experiments in mammalian systems and for evaluating the potential of targeting the IGF-1R receptor or modulating its signalling through the downstream pathway for therapeutic purposes under clinically relevant conditions, such as neurodegenerative diseases, where autophagy stimulation is considered beneficial.This is the version of the manuscript that was first published on line. The final version can be found published in Human Molecular Genetics by OUP here: http://hmg.oxfordjournals.org/content/22/22/4528.full.pdf+html

PICALM modulates autophagy activity and tau accumulation.

Genome-wide association studies have identified several loci associated with Alzheimer's disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these loci may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagy substrate and which is causatively linked to AD, both in vitro and in vivo. Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models. CALM influences autophagy by regulating the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, which have diverse effects on different stages of the autophagy pathway, from autophagosome formation to autophagosome degradation. This study suggests that the AD genetic risk factor CALM modulates autophagy, and this may affect disease in a number of ways including modulation of tau turnover.We are grateful for funding from a Wellcome Trust Principal Research Fellowship (D.C.R.), a Wellcome Trust/MRC Strategic Grant on Neurodegeneration (D.C.R., C.J.O’.K.), a Wellcome Trust Strategic Award to Cambridge Institute for Medical Research, Wellcome Trust Studentship (E.Z.), the Alzheimer’s disease Biomedical Research Unit and Addenbrooke’s Hospital, the Tau Consortium, a fellowship from University of Granada (A.L.R.), a V Foundation/Applebee’s Research Grant (D.S.W.) and NCI R01 CA 109281 (D.S.W.).This is the final published version. It is also available from Nature Publishing at http://www.nature.com/ncomms/2014/140922/ncomms5998/full/ncomms5998.html

Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing.

Neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Huntington's disease manifest with the neuronal accumulation of toxic proteins. Since autophagy upregulation enhances the clearance of such proteins and ameliorates their toxicities in animal models, we and others have sought to re-position/re-profile existing compounds used in humans to identify those that may induce autophagy in the brain. A key challenge with this approach is to assess if any hits identified can induce neuronal autophagy at concentrations that would be seen in humans taking the drug for its conventional indication. Here we report that felodipine, an L-type calcium channel blocker and anti-hypertensive drug, induces autophagy and clears diverse aggregate-prone, neurodegenerative disease-associated proteins. Felodipine can clear mutant α-synuclein in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug. This is associated with neuroprotection in mice, suggesting the promise of this compound for use in neurodegeneration