Successful use of axonal transport for drug delivery by synthetic molecular vehicles

We report the use of axonal transport to achieve intraneural drug delivery. We constructed a novel tripartite complex of an axonal transport facilitator conjugated to a linker molecule bearing up to a hundred reversibly attached drug molecules. The complex efficiently enters nerve terminals after intramuscular or intradermal administration and travels within axonal processes to neuron cell bodies. The tripartite agent provided 100-fold amplification of saturable neural uptake events, delivering multiple drug molecules per complex. _In vivo_, analgesic drug delivery to systemic and to non-targeted neural tissues was greatly reduced compared to existing routes of administration, thus exemplifying the possibility of specific nerve root targeting and effectively increasing the potency of the candidate drug gabapentin 300-fold relative to oral administration

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.

BACKGROUND: Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. RESULTS: We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. CONCLUSION: Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Sleep is required to consolidate odor memory and remodel olfactory synapses

Animals with complex nervous systems demand sleep for memory consolidation and synaptic remodeling. Here, we show that, although the Caenorhabditis elegans nervous system has a limited number of neurons, sleep is necessary for both processes. In addition, it is unclear if, in any system, sleep collaborates with experience to alter synapses between specific neurons and whether this ultimately affects behavior. C. elegans neurons have defined connections and well-described contributions to behavior. We show that spaced odor-training and post-training sleep induce long-term memory. Memory consolidation, but not acquisition, requires a pair of interneurons, the AIYs, which play a role in odor-seeking behavior. In worms that consolidate memory, both sleep and odor conditioning are required to diminish inhibitory synaptic connections between the AWC chemosensory neurons and the AIYs. Thus, we demonstrate in a living organism that sleep is required for events immediately after training that drive memory consolidation and alter synaptic structures

Noninvasive optical inhibition with a red-shifted microbial rhodopsin

Optogenetic inhibition of the electrical activity of neurons enables the causal assessment of their contributions to brain functions. Red light penetrates deeper into tissue than other visible wavelengths. We present a red-shifted cruxhalorhodopsin, Jaws, derived from Haloarcula (Halobacterium) salinarum (strain Shark) and engineered to result in red light–induced photocurrents three times those of earlier silencers. Jaws exhibits robust inhibition of sensory-evoked neural activity in the cortex and results in strong light responses when used in retinas of retinitis pigmentosa model mice. We also demonstrate that Jaws can noninvasively mediate transcranial optical inhibition of neurons deep in the brains of awake mice. The noninvasive optogenetic inhibition opened up by Jaws enables a variety of important neuroscience experiments and offers a powerful general-use chloride pump for basic and applied neuroscience.McGovern Institute for Brain Research at MIT (Razin Fellowship)United States. Defense Advanced Research Projects Agency. Living Foundries Program (HR0011-12-C-0068)Harvard-MIT Joint Research Grants Program in Basic NeuroscienceHuman Frontier Science Program (Strasbourg, France)Institution of Engineering and Technology (A. F. Harvey Prize)McGovern Institute for Brain Research at MIT. Neurotechnology (MINT) ProgramNew York Stem Cell Foundation (Robertson Investigator Award)National Institutes of Health (U.S.) (New Innovator Award 1DP2OD002002)National Institute of General Medical Sciences (U.S.) (EUREKA Award 1R01NS075421)National Institutes of Health (U.S.) (Grant 1R01DA029639)National Institutes of Health (U.S.) (Grant 1RC1MH088182)National Institutes of Health (U.S.) (Grant 1R01NS067199)National Science Foundation (U.S.) (Career Award CBET 1053233)National Science Foundation (U.S.) (Grant EFRI0835878)National Science Foundation (U.S.) (Grant DMS0848804)Society for Neuroscience (Research Award for Innovation in Neuroscience)Wallace H. Coulter FoundationNational Institutes of Health (U.S.) (RO1 MH091220-01)Whitehall FoundationEsther A. & Joseph Klingenstein Fund, Inc.JPB FoundationPIIF FundingNational Institute of Mental Health (U.S.) (R01-MH102441-01)National Institutes of Health (U.S.) (DP2-OD-017366-01)Massachusetts Institute of Technology. Simons Center for the Social Brai

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic

Predicting the environmental suitability for onchocerciasis in Africa as an aid to elimination planning

Recent evidence suggests that, in some foci, elimination of onchocerciasis from Africa may be feasible with mass drug administration (MDA) of ivermectin. To achieve continental elimination of transmission, mapping surveys will need to be conducted across all implementation units (IUs) for which endemicity status is currently unknown. Using boosted regression tree models with optimised hyperparameter selection, we estimated environmental suitability for onchocerciasis at the 5 × 5-km resolution across Africa. In order to classify IUs that include locations that are environmentally suitable, we used receiver operating characteristic (ROC) analysis to identify an optimal threshold for suitability concordant with locations where onchocerciasis has been previously detected. This threshold value was then used to classify IUs (more suitable or less suitable) based on the location within the IU with the largest mean prediction. Mean estimates of environmental suitability suggest large areas across West and Central Africa, as well as focal areas of East Africa, are suitable for onchocerciasis transmission, consistent with the presence of current control and elimination of transmission efforts. The ROC analysis identified a mean environmental suitability index of 071 as a threshold to classify based on the location with the largest mean prediction within the IU. Of the IUs considered for mapping surveys, 502% exceed this threshold for suitability in at least one 5 × 5-km location. The formidable scale of data collection required to map onchocerciasis endemicity across the African continent presents an opportunity to use spatial data to identify areas likely to be suitable for onchocerciasis transmission. National onchocerciasis elimination programmes may wish to consider prioritising these IUs for mapping surveys as human resources, laboratory capacity, and programmatic schedules may constrain survey implementation, and possibly delaying MDA initiation in areas that would ultimately qualify.SUPPORTING INFORMATION : FIGURE S1. Data coverage by year. Here we visualise the volume of data used in the analysis by country and year. Larger circles indicate more data inputs. ‘NA’ indicates records for which no year was reported (eg, ‘pre-2000’). https://doi.org/10.1371/journal.pntd.0008824.s001FIGURE S2. Illustration of covariate values for year 2000. Maps were produced using ArcGIS Desktop 10.6. https://doi.org/10.1371/journal.pntd.0008824.s002FIGURE S3. Environmental suitability of onchocerciasis including locations that have received MDA for which no pre-intervention data are available. This plot shows suitability predictions from green (low = 0%) to pink (high = 100%), representing those areas where environmental conditions are most similar to prior pathogen detections. Countries in grey with hatch marks were excluded from the analysis based on a review of national endemicity status. Areas in grey only represent locations masked due to sparse population. Maps were produced using ArcGIS Desktop 10.6 and shapefiles to visualize administrative units are available at https://espen.afro.who.int/tools-resources/cartography-database. https://doi.org/10.1371/journal.pntd.0008824.s003FIGURE S4. Environmental suitability prediction uncertainty including locations that have received MDA for which no pre-intervention data are available. This plot shows uncertainty associated with environmental suitability predictions colored from blue to red (least to most uncertain). Countries in grey with hatch marks were excluded from the analysis based on a review of national endemicity status. Areas in grey only represent locations masked due to sparse population. Maps were produced using ArcGIS Desktop 10.6 and shapefiles to visualize administrative units are available at https://espen.afro.who.int/tools-resources/cartography-database. https://doi.org/10.1371/journal.pntd.0008824.s004FIGURE S5. Environmental suitability of onchocerciasis excluding morbidity data. This plot shows suitability predictions from green (low = 0%) to pink (high = 100%), representing those areas where environmental conditions are most similar to prior pathogen detections. Countries in grey with hatch marks were excluded from the analysis based on a review of national endemicity status. Areas in grey only represent locations masked due to sparse population. Maps were produced using ArcGIS Desktop 10.6 and shapefiles to visualize administrative units are available at https://espen.afro.who.int/tools-resources/cartography-database. https://doi.org/10.1371/journal.pntd.0008824.s005FIGURE S6. Environmental suitability prediction uncertainty excluding morbidity data. This plot shows uncertainty associated with environmental suitability predictions colored from blue to red (least to most uncertain). Countries in grey with hatch marks were excluded from the analysis based on a review of national endemicity status. Areas in grey only represent locations masked due to sparse population. https://doi.org/10.1371/journal.pntd.0008824.s006FIGURE S7. Covariate Effect Curves for all onchocerciasis occurrences (measures of infection prevalence and disability). On the right set of axes we show the frequency density of the occurrences taking covariate values over 20 bins of the horizontal axis. The left set of axes shows the effect of each on the model, where the mean effect is plotted on the black line and its uncertainty is represented by the upper and lower confidence interval bounds plotted in dark grey. The figures show the fit per covariate relative to the data that correspond to specific values of the covariate. https://doi.org/10.1371/journal.pntd.0008824.s007FIGURE S8. Covariate Effect Curves for all onchocerciasis occurrences (measures of infection prevalence and disability). On the right set of axes we show the frequency density of the occurrences taking covariate values over 20 bins of the horizontal axis. The left set of axes shows the effect of each on the model, where the mean effect is plotted on the black line and its uncertainty is represented by the upper and lower confidence interval bounds plotted in dark grey. https://doi.org/10.1371/journal.pntd.0008824.s008FIGURE S9. ROC analysis for threshold. Results of the area under the receiver operating characteristic (ROC) curve analysis are presented below, with false positive rate (FPR) on the x-axis and true positive rate (TPR) on the y-axis. The red dot on the curve represents the location on the curve that corresponds to a threshold that most closely agreed with the input data. For each of the 100 BRT models, we estimated the optimal threshold that maximised agreement between occurrence inputs (considered true positives) and the mean model predictions as 0·71. https://doi.org/10.1371/journal.pntd.0008824.s009TABLE S1. Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) checklist. https://doi.org/10.1371/journal.pntd.0008824.s010TABLE S2. Total number of occurrence data classified as point and polygon inputs by diagnostic. We present the total number of occurrence points extracted from the input data sources by diagnostic type. ‘Other diagnostics’ include: DEC Patch test; Knott’s Method (Mazotti Test); 2 types of LAMP; blood smears; and urine tests. https://doi.org/10.1371/journal.pntd.0008824.s011TABLE S3. Total number of occurrence data classified as point and polygon inputs by location. https://doi.org/10.1371/journal.pntd.0008824.s012TABLE S4. Covariate information. https://doi.org/10.1371/journal.pntd.0008824.s013TEXT S1. Details outlining construction of occurrence dataset. https://doi.org/10.1371/journal.pntd.0008824.s014TEXT S2. Covariate rationale. https://doi.org/10.1371/journal.pntd.0008824.s015TEXT S3. Boosted regression tree methodology additional details. https://doi.org/10.1371/journal.pntd.0008824.s016APPENDIX S1. Country-level maps and data results. Maps were produced using ArcGIS Desktop 10.6 and shapefiles to visualize administrative units are available at https://espen.afro.who.int/tools-resources/cartography-database. https://doi.org/10.1371/journal.pntd.0008824.s017This work was primarily supported by a grant from the Bill & Melinda Gates Foundation OPP1132415 (SIH). Financial support from the Neglected Tropical Disease Modelling Consortium (https://www.ntdmodelling.org/), which is funded by the Bill & Melinda Gates Foundation (grants No. OPP1184344 and OPP1186851), and joint centre funding (grant No. MR/R015600/1) by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement which is also part of the EDCTP2 programme supported by the European Union (MGB).The Neglected Tropical Disease Modelling Consortium which is funded by the Bill & Melinda Gates Foundation, the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement which is also part of the EDCTP2 programme supported by the European Union (MGB).http://www.plosNTDS.orgam2022Medical Microbiolog

Sustainable futures : the new design landscape

Design talks LOUDLY!!! Is a series of interactive presentations exploring issues and opportunities involving professional design. These seminars are organised by the Industrial Design Network Queensland (IDnetQLD) in coordination with the Design Institute of Australia (DIA). This event was held at the State Library of Queensland (SLQ) with invited public presentations by a panel of industry experts from Brisbane City Council, Sims Recycling Solutions and BEST Futures. The second seminar "Sustainable Futures: The New Design Landscape" highlighted to design professionals the positive effect the design industry can achieve in moving towards a sustainable future. A series of presentations from specialist speakers outlined the new generation of design and how design can surf the sustainable shift. A product’s journey from concept to creation and a life beyond was presented and discussed as a basis of designing for sustainability. The intent of the seminar was to inject a brand new sense of purpose into the design world through inspiring designers to find solutions which move forward into this new sustainable landscape