ShK toxin from the sea anemone Stichodactyla helianthus is a 35-residue protein that binds to the Kv1.3 ion channel with high affinity. Recently we determined the X-ray structure of ShK toxin by ...racemic crystallography, in the course of which we discovered that d-ShK has a near-background IC50 value ∼50,000 times lower than that of the l-ShK toxin. This lack of activity was at odds with previously reported results for an ShK diastereomer designated d-allo-ShK, for which significant biological activity had been observed in a similar receptor-blocking assay. As reported, d-allo-ShK was made up of d-amino acids, but with retention of the natural stereochemistry of the chiral side chains of the Ile and Thr residues, i.e. containing d-allo-Ile and d-allo-Thr along with d-amino acids and glycine. To understand its apparent biological activity, we set out to chemically synthesize d-allo-ShK and determine its X-ray structure by racemic crystallography. Using validated allo-Thr and allo-Ile, both l-allo-ShK and d-allo-ShK polypeptide chains were prepared by total chemical synthesis. Neither the l-allo-ShK nor the d-allo-ShK polypeptides folded, whereas both l-ShK and d-ShK folded smoothly under the same conditions. Re-examination of NMR spectra of the previously reported d-allo-ShK protein revealed that diagnostic Thr and Ile signals were the same as for authentic d-ShK. On the basis of these results, we conclude that the previously reported d-allo-ShK was in fact d-ShK, the true enantiomer of natural l-ShK toxin, and that the apparent biological activity may have arisen from inadvertent contamination with trace amounts of l-ShK toxin.
Niemann-Pick type C (NPC) disease is a rare lysosomal storage disorder caused by mutations in either the NPC1 or the NPC2 gene. A new class of lipids, N-acyl-O-phosphocholineserines were recently ...identified as NPC biomarkers. The most abundant species in this class of lipid, N-palmitoyl-O-phosphocholineserine (PPCS), was evaluated for diagnosis of NPC disease and treatment efficacy assessment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) in NPC. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed and validated to measure PPCS in human plasma and cerebrospinal fluid (CSF). A cutoff of 248 ng/mL in plasma provided a sensitivity of 100.0% and specificity of 96.6% in identifying NPC1 patients from control and NPC1 carrier subjects. PPCS was significantly elevated in CSF from NPC1 patients, and CSF PPCS levels were significantly correlated with NPC neurological disease severity scores. Plasma and CSF PPCS did not change significantly in response to intrathetical (IT) HPβCD treatment. In an intravenous (IV) HPβCD trial, plasma PPCS in all patients was significantly reduced. These results demonstrate that plasma PPCS was able to diagnose NPC1 patients with high sensitivity and specificity, and to evaluate the peripheral treatment efficacy of IV HPβCD treatment.
Acute meningitis has a high case-fatality rate and survivors can have severe lifelong disability. We aimed to provide a comprehensive assessment of the levels and trends of global meningitis burden ...that could help to guide introduction, continuation, and ongoing development of vaccines and treatment programmes.
The Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2016 study estimated meningitis burden due to one of four types of cause: pneumococcal, meningococcal, Haemophilus influenzae type b, and a residual category of other causes. Cause-specific mortality estimates were generated via cause of death ensemble modelling of vital registration and verbal autopsy data that were subject to standardised data processing algorithms. Deaths were multiplied by the GBD standard life expectancy at age of death to estimate years of life lost, the mortality component of disability-adjusted life-years (DALYs). A systematic analysis of relevant publications and hospital and claims data was used to estimate meningitis incidence via a Bayesian meta-regression tool. Meningitis deaths and cases were split between causes with meta-regressions of aetiological proportions of mortality and incidence, respectively. Probabilities of long-term impairment by cause of meningitis were applied to survivors and used to estimate years of life lived with disability (YLDs). We assessed the relationship between burden metrics and Socio-demographic Index (SDI), a composite measure of development based on fertility, income, and education.
Global meningitis deaths decreased by 21·0% from 1990 to 2016, from 403 012 (95% uncertainty interval UI 319 426–458 514) to 318 400 (265 218–408 705). Incident cases globally increased from 2·50 million (95% UI 2·19–2·91) in 1990 to 2·82 million (2·46–3·31) in 2016. Meningitis mortality and incidence were closely related to SDI. The highest mortality rates and incidence rates were found in the peri-Sahelian countries that comprise the African meningitis belt, with six of the ten countries with the largest number of cases and deaths being located within this region. Haemophilus influenzae type b was the most common cause of incident meningitis in 1990, at 780 070 cases (95% UI 613 585–978 219) globally, but decreased the most (–49·1%) to become the least common cause in 2016, with 397 297 cases (291 076–533 662). Meningococcus was the leading cause of meningitis mortality in 1990 (192 833 deaths 95% UI 153 358–221 503 globally), whereas other meningitis was the leading cause for both deaths (136 423 112 682–178 022) and incident cases (1·25 million 1·06–1·49) in 2016. Pneumococcus caused the largest number of YLDs (634 458 444 787–839 749) in 2016, owing to its more severe long-term effects on survivors. Globally in 2016, 1·48 million (1·04—1·96) YLDs were due to meningitis compared with 21·87 million (18·20—28·28) DALYs, indicating that the contribution of mortality to meningitis burden is far greater than the contribution of disabling outcomes.
Meningitis burden remains high and progress lags substantially behind that of other vaccine-preventable diseases. Particular attention should be given to developing vaccines with broader coverage against the causes of meningitis, making these vaccines affordable in the most affected countries, improving vaccine uptake, improving access to low-cost diagnostics and therapeutics, and improving support for disabled survivors. Substantial uncertainty remains around pathogenic causes and risk factors for meningitis. Ongoing, active cause-specific surveillance of meningitis is crucial to continue and to improve monitoring of meningitis burdens and trends throughout the world.
Bill & Melinda Gates Foundation.
Niemann-Pick disease type C (NPC) is a neurodegenerative disease in which mutation of NPC1 or NPC2 gene leads to lysosomal accumulation of unesterified cholesterol and sphingolipids. Diagnosis of NPC ...disease is challenging due to non-specific early symptoms. Biomarker and genetic tests are used as first-line diagnostic tests for NPC. In this study, we developed a plasma test based on N-(3β,5α,6β-trihydroxy-cholan-24-oyl)glycine (TCG) that was markedly increased in the plasma of human NPC1 subjects. The test showed sensitivity of 0.9945 and specificity of 0.9982 to differentiate individuals with NPC1 from NPC1 carriers and controls. Compared to other commonly used biomarkers, cholestane-3β,5α,6β-triol (C-triol) and N-palmitoyl-O-phosphocholine (PPCS, also referred to as lysoSM-509), TCG was equally sensitive for identifying NPC1 but more specific. Unlike C-triol and PPCS, TCG showed excellent stability and no spurious generation of marker in the sample preparation or aging of samples. TCG was also elevated in lysosomal acid lipase deficiency (LALD) and acid sphingomyelinase deficiency (ASMD). Plasma TCG was significantly reduced after intravenous (IV) 2-hydroxypropyl-β-cyclodextrin (HPβCD) treatment. These results demonstrate that plasma TCG was superior to C-triol and PPCS as NPC1 diagnostic biomarker and was able to evaluate the peripheral treatment efficacy of IV HPβCD treatment.
Summary
The MJA–Lancet Countdown on health and climate change in Australia was established in 2017 and produced its first national assessment in 2018 and annual updates in 2019, 2020, 2021 and 2022. ...It examines five broad domains: health hazards, exposures and impacts; adaptation, planning and resilience for health; mitigation actions and health co‐benefits; economics and finance; and public and political engagement. In this, the sixth report of the MJA–Lancet Countdown, we track progress on an extensive suite of indicators across these five domains, accessing and presenting the latest data and further refining and developing our analyses.
Our results highlight the health and economic costs of inaction on health and climate change. A series of major flood events across the four eastern states of Australia in 2022 was the main contributor to insured losses from climate‐related catastrophes of $7.168 billion — the highest amount on record. The floods also directly caused 23 deaths and resulted in the displacement of tens of thousands of people.
High red meat and processed meat consumption and insufficient consumption of fruit and vegetables accounted for about half of the 87 166 diet‐related deaths in Australia in 2021. Correction of this imbalance would both save lives and reduce the heavy carbon footprint associated with meat production.
We find signs of progress on health and climate change. Importantly, the Australian Government released Australia's first National Health and Climate Strategy, and the Government of Western Australia is preparing a Health Sector Adaptation Plan. We also find increasing action on, and engagement with, health and climate change at a community level, with the number of electric vehicle sales almost doubling in 2022 compared with 2021, and with a 65% increase in coverage of health and climate change in the media in 2022 compared with 2021.
Overall, the urgency of substantial enhancements in Australia's mitigation and adaptation responses to the enormous health and climate change challenge cannot be overstated. Australia's energy system, and its health care sector, currently emit an unreasonable and unjust proportion of greenhouse gases into the atmosphere. As the Lancet Countdown enters its second and most critical phase in the leadup to 2030, the depth and breadth of our assessment of health and climate change will be augmented to increasingly examine Australia in its regional context, and to better measure and track key issues in Australia such as mental health and Aboriginal and Torres Strait Islander health and wellbeing.
The goal of NASA’s Europa Clipper Mission is to investigate the habitability of the subsurface ocean within the Jovian moon Europa using a suite of ten investigations. The Europa Clipper Magnetometer ...(ECM) and Plasma Instrument for Magnetic Sounding (PIMS) investigations will be used in unison to characterize the thickness and electrical conductivity of Europa’s subsurface ocean and the thickness of the ice shell by sensing the induced magnetic field, driven by the strong time-varying magnetic field of the Jovian environment. However, these measurements will be obscured by the magnetic field originating from the Europa Clipper spacecraft. In this work, a magnetic field model of the Europa Clipper spacecraft is presented, characterized with over 260 individual magnetic sources comprising various ferromagnetic and soft-magnetic materials, compensation magnets, solenoids, and dynamic electrical currents flowing within the spacecraft. This model is used to evaluate the magnetic field at arbitrary points around the spacecraft, notably at the locations of the three fluxgate magnetometer sensors and four Faraday cups which make up ECM and PIMS, respectively. The model is also used to evaluate the magnetic field uncertainty at these locations via a Monte Carlo approach. Furthermore, both linear and non-linear gradiometry fitting methods are presented to demonstrate the ability to reliably disentangle the spacecraft field from the ambient using an array of three fluxgate magnetometer sensors mounted along an 8.5-meter (m) long boom. The method is also shown to be useful for optimizing the locations of the magnetometer sensors along the boom. Finally, we illustrate how the model can be used to visualize the magnetic field lines of the spacecraft, thus providing very insightful information for each investigation.
In rapidly developing countries, intensive agriculture faces the conflict between food security and environmental deterioration. To improve the sustainability of agricultural land use, this paper ...proposes an integrated framework for risk assessment and conflict coordination to cope with these salient challenges at the administrative unit level. This framework is demonstrated using a case study conducted in the Dongting Lake area in China. Drawing upon diverse sources of statistical data concerning agricultural inputs and outputs, water resources and natural hazards as well as questionnaire surveys conducted at the household level, this paper uses the Cobb-Douglas production function and the water environmental pressure index to assess food insecurity risk and environmental risk from food production, respectively. A double matrix method is used to characterize the degree of sustainability based on the risk assessment. The results indicate that the overall food security of the region can be maintained in the negligible-risk range. However, rising agro-environmental risks from grain production in the coming years are likely to threaten the sustainability of agricultural land use in most administrative units. It is suggested that optimization of land use patterns and mitigation of natural hazards could be effective approaches to improve the sustainability of local agricultural land use.
•Food security and environmental deterioration are considered as a conflict.•We use the C-D production function to assess food insecurity risk.•We use the water environmental pressure index to assess environmental risk.•Most cities and counties are expected to suffer from a poor sustainability status.•Optimization of land use patterns could improve agricultural sustainability.
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