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RNA-binding properties orchestrate TDP-43 homeostasis through condensate formation in vivo
No full textInsoluble cytoplasmic aggregate formation of the RNA-binding protein TDP-43 is a major hallmark of neurodegenerative diseases including Amyotrophic Lateral Sclerosis. TDP-43 localizes predominantly in the nucleus, arranging itself into dynamic condensates through liquid–liquid phase separation (LLPS). Mutations and post-translational modifications can alter the condensation properties of TDP-43, contributing to the transition of liquid-like biomolecular condensates into solid-like aggregates. However, to date it has been a challenge to study the dynamics of this process in vivo. We demonstrate through live imaging that human TDP-43 undergoes nuclear condensation in spinal motor neurons in a living animal. RNA-binding deficiencies as well as post-translational modifications can lead to aberrant condensation and altered TDP-43 compartmentalization. Single-molecule tracking revealed an altered mobility profile for RNA-binding deficient TDP-43. Overall, these results provide a critically needed in vivo characterization of TDP-43 condensation, demonstrate phase separation as an important regulatory mechanism of TDP-43 accessibility, and identify a molecular mechanism of how functional TDP-43 can be regulated
Associations between fruit and vegetable intakes and incident depression in middle-aged and older adults from 10 diverse international longitudinal cohorts
No full textBackground: Emerging observational evidence supports a role for higher fruit and vegetable intake in protecting against the development of depression. However, there is a scarcity of research in older adults or in low- to middle-income countries (LMICs). Methods: Participants were 7801 community-based adults (mean age 68.6 ± 8.0 years, 55.8 % female) without depression, from 10 diverse cohorts, including four cohorts from LMICs. Fruit and vegetable intake was self-reported via comprehensive food frequency questionnaire, short food questionnaire or diet history. Depressive symptoms were assessed using validated measures, and depression defined applying validated cut-offs. The associations between baseline fruit and vegetable intakes and incident depression over a follow-up period of three to nine years were examined using Cox regression. Analyses were performed by cohort with results meta-analysed. Results: There were 1630 cases of incident depression (21 % of participants) over 40,258 person-years of follow-up. Higher intake of fruit was associated with a lower risk of incident depression (HR 0.87, 95%CI [0.77, 0.99], I2 = 4 %). No association was found between vegetable intake and incident depression (HR 0.93, 95%CI [0.84, 1.04], I2 = 0 %). Limitations: Diverse measures used across the different cohorts and the modest sample size of our study compared with prior studies may have prevented an association being detected for vegetable intake. Conclusions: Our study supports a role for fruit, but not vegetable intake in protecting against depression. Research investigating different types of fruits and vegetables using standardised measures in larger cohorts of older adults from low- and middle-income countries is warranted
Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021
No full textBackground: Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. Methods: We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. Findings: Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. Interpretation: As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed. Funding: Bill & Melinda Gates Foundation
Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021
No full textBackground: Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. Methods: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model—a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates—with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality—which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. Findings: The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2–100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1–290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1–211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4–48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3–37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7–9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. Interpretation: Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. Funding: Bill & Melinda Gates Foundation
Dietary Emulsifier Exposure in People with Inflammatory Bowel Disease Compared with Healthy Controls: Is There a Cause for Concern?
No full textBackground: Emulsifiers are implicated in the pathogenesis of inflammatory bowel disease (IBD). Few studies have examined emulsifier intake in people with existing IBD. We aimed to describe the frequency of exposure to 6 selected emulsifiers in a contemporary cohort of people with IBD and compare intake with healthy controls (HCs). Methods: Baseline food records from participants in an Australian prospective cohort study examining the microbiome of IBD patients and HCs were analyzed. Exposure to inflammatory emulsifiers polysorbate-80 (P80); carboxymethylcellulose (CMC); carrageenan; xanthan gum (XG); lecithin (soy and sunflower) and mono-And diglycerides of fatty acids (MDGs) were determined by examining ingredient lists. Frequency of emulsifier exposure between groups (IBD vs HC, Crohn's disease [CD] vs ulcerative colitis [UC], IBD children vs adults, active disease vs remission) was examined after controlling for confounders. Results: Records from 367 participants were analyzed (n=176 IBD, of which there were 101 CD, 75 UC, and 191 HC patients). In total, 5022 unique food items were examined, with 18% containing 1 or more emulsifier of interest. Inflammatory bowel disease participants had significantly higher total daily emulsifier exposure compared with HCs (2.7±1.8 vs 2.3±1.6, P=.02). In IBD participants, emulsifiers with the highest daily exposure were MDGs (1.2±0.93), lecithin (0.85±0.93), and XG (0.38±0.42). There were no recorded exposures to P80. Conclusions: Inflammatory bowel disease participants were exposed to more emulsifiers than HCs. Intake of inflammatory emulsifiers were low or nonexistent, suggesting their presence in the food supply are not as common as frequently stated
Integrating human expertise to optimize the fabrication of parts with complex geometries in WAAM
No full textWire arc additive manufacturing (WAAM) has emerged as a versatile solution for fabricating parts with complex geometries in recent years. However, the existing deposition parameter planning methods struggle to offer continuous and precise parameters when the part geometry varies dynamically due to the long-term dependence, strong coupling, and hysteresis properties of the WAAM process. To address this challenge, this research introduces an advanced algorithm for generating accurate and continuous deposition parameters by learning and utilizing the welding skills of proficient human welders. The first step involves capturing kinematic and welding parameter data from proficient human welders during practical welding processes. Following this, a human skill learning algorithm is developed based on a combination of the adaptive neuro-fuzzy inference system (ANFIS) architecture and particle swarm optimization (PSO) to analyse and model human motions and bead deposition results. Lastly, a practical backward model is established to generate continuous deposition parameters for weld beads with varying geometry. The effectiveness of the proposed algorithm is validated through the fabrication of two practical WAAM parts. The root mean square error (RMSE) values between the target geometry and the ground truth geometry of the parts are 0.1648 and 0.1805 respectively. The result demonstrates the algorithm's superior ability in optimal deposition parameters planning for fabricating parts with complex geometries
On the residual stress measurements for Wire-Arc Additive Manufactured (WAAM-ed) engineering components
No full textAdditive manufacturing methods like Wire-Arc Additive Manufacturing (WAAM) open a new field to reduce manufacturing costs and minimising waste for various components in the civil engineering and construction sector. High deposition rates and lack of limitations in large, complex build sizes promote WAAM over other metal additive manufacturing technologies for this sector. Furthermore, the ability to produce novel and individual geometries of structural parts enable unseen design possibilities for architects, and potential structural and corrosive improvements in critical areas are unique properties of additive manufacturing. Currently, the lack of studies and standardisation is holding this technology back from finding a broad industrial application. Especially the insufficient knowledge of the residual stress state within build components in both experimental and simulations. Expecting a strong texture with large grain sizes, this research evaluates the residual stress state utilising the contour method. Special focus is given on the influence of data processing during the analysis to provide recommendations and in consequence improve understanding of residual stress measurement challenges arising with large-scale WAAM components
Fully Dynamic Attribute-Based Signatures for Circuits from Codes
No full textAttribute-Based Signature (ABS), introduced by Maji et al. (CT-RSA’11), is an advanced privacy-preserving signature primitive that has gained a lot of attention. Research on ABS can be categorized into three main themes: expanding the expressiveness of signing policies, enabling new functionalities, and providing more diversity in terms of computational assumptions. We contribute to the development of ABS in all three dimensions, by providing a fully dynamic ABS scheme for arbitrary circuits from codes. The scheme is the first ABS from code-based assumptions and also the first ABS system offering the full dynamicity functionality (i.e., attributes can be enrolled and revoked simultaneously). Moreover, the scheme features much shorter signature size than a lattice-based counterpart proposed by El Kaafarani and Katsumata (PKC’18). In the construction process, we put forward a new theoretical abstraction of Stern-like zero-knowledge (ZK) protocols, which are the major tools for privacy-preserving cryptography from codes. Our main insight here actually lies in the questions we ask about the fundamental principles of Stern-like protocols that have remained unchallenged since their conception by Stern at CRYPTO’93. We demonstrate that these long-established principles are not essential, and then provide a refined framework generalizing existing Stern-like techniques and enabling enhanced constructions
Intermediated Communication via Social Media Platforms During the COVID-19 Pandemic
No full textDespite the ensemble scholarly exchange on health communication, social media, and translation, research has not fully explored all the domains of social media communication, whether individual or participatory, conceived during the pandemic. Considering the nature of digital communication and the production of wide-ranging digital content, as well as its circulation and translation, the essays selected here illuminate how various acts of intermediation spread novel forms of digital interaction and integration among different audiences and online infrastructures. The authors’ findings contribute to a growing discourse about how intermediated communications via social media have approached both misinformation and scientific knowledge about the coronavirus, thereby paving new pathways for future research into how individual and collective actions may continue to transform digital environments and everyday lived realities more broadly after COVID-19
Display lag effects on postural stability and cybersickness during active exposures to HMD virtual reality
No full textThis study examined whether a person's spontaneous postural sway before, and their head-movements during, exposure to virtual reality (VR) predicts their experiences of cybersickness. We compared the stability of head and body movements made by 50 HMD users to the sickness they experienced during VR simulations with different amounts of display lag. Consistent with Postural Instability Theory, we found that: 1) naturally unstable participants were significantly more likely to become sick during these laggy simulations; and 2) the severity of this sickness depended on the spatial magnitude and the temporal dynamics of their head movements during active HMD VR.</p