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Neurodegenerative diseases (NDs) in mammals, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and transmissible spongiform encephalopathies (TSEs), are characterized by the accumulation of misfolded proteins in the central nervous system (CNS). Despite the presence of these pathogenic proteins, the immune response in affected individuals remains notably muted. Traditional immunological strategies, particularly those reliant on monoclonal antibodies (mAbs), face challenges related to tissue penetration, blood-brain barrier (BBB) crossing, and maintaining protein stability. This has led to a burgeoning interest in alternative immunotherapeutic avenues. Notably, single-domain antibodies (or nanobodies) and aptamers have emerged as promising candidates, as their reduced size facilitates high affinity antigen binding and they exhibit superior biophysical stability compared to mAbs. Aptamers, synthetic molecules generated from DNA or RNA ligands, present both rapid production times and cost-effective solutions. Both nanobodies and aptamers exhibit inherent qualities suitable for ND research and therapeutic development. Cross-seeding events must be considered in both traditional and small-molecule-based immunodiagnostic and therapeutic approaches, as well as subsequent neurotoxic impacts and complications beyond protein aggregates. This review delineates the challenges traditional immunological methods pose in ND research and underscores the potential of nanobodies and aptamers in advancing next-generation ND diagnostics and therapeutics.

Prion diseases, including chronic wasting disease (CWD), are caused by prions, which are misfolded aggregates of normal cellular prion protein. Prions possess many characteristics that distinguish them from conventional pathogens, in particular, an extraordinary recalcitrance to inactivation and a propensity to avidly bind to surfaces. In middle to late stages of CWD, prions begin accumulating in cervid muscle tissues. Those features collectively create scenarios in which occupational hazards arise for workers processing venison and pose risks to consumers through direct prion exposure through ingestion and cross-contamination of food products. In this study, we demonstrate that steel and plastic surfaces used in venison processing can be directly contaminated with CWD prions and that cross-contamination of CWD-negative venison can occur from equipment that had previously been used with CWD-positive venison. We also show that several decontaminant solutions (commercial bleach and potassium peroxymonosulfate) are efficacious for prion inactivation on those same surfaces.

Neurodegenerative protein misfolding diseases impact tens of millions of people worldwide, contributing to millions of deaths and economic hardships across multiple scales. The prevalence of neurodegenerative disease is predicted to greatly increase over the coming decades, yet effective diagnostics for such diseases are limited. Most diagnoses come from the observation of external symptoms in clinical settings, which typically manifest during relatively advanced stages of disease, thus limiting potential therapeutic applications. While progress is being made on biomarker testing, the underlying methods largely rely on fragile and expensive equipment that limits their point-of-care potential, especially in developing countries. Here we present Capillary-based Quaking Induced Conversion (Cap-QuIC) as a visual diagnostic assay based on simple capillary action for the detection of neurodegenerative disease without necessitating expensive and complex capital equipment. We demonstrate that Cap-QuIC has the potential to be a detection tool for a broad range of misfolded proteins by successfully distinguishing misfolded versus healthy proteins associated with Parkinson’s disease ( α -synuclein) and Chronic Wasting Disease (prions). Additionally, we show that Cap-QuIC can accurately classify biological tissue samples from wild white-tailed deer infected with Chronic Wasting Disease. Our findings elucidate the underlying mechanism that enables the Cap-QuIC assay to distinguish misfolded protein, highlighting its potential as a diagnostic technology for neurodegenerative diseases.

Prion Diseases, or Transmissible Spongiform Encephalopathies (TSEs), are rapidly progressive and fatal neurodegenerative diseases of mammals. TSEs of global importance include Creutzfeldt-Jakob Disease (CJD) in humans, Chronic Wasting Disease (CWD) in cervids, and Bovine Spongiform Encephalopathy (BSE) in cattle. These diseases occur when the normal cellular prion protein (PrPC) misfolds, producing the infectious isoform PrPSc ,which can readily self propagate with no nucleic acid intermediate. PrPSc aggregates are insoluble self-molecules, which results in a large number of limitations pertaining to the prevention, detection, and treatment of TSEs; including a lack of accessible isoform-specific antibodies. Here, we describe a quantitative PCR method to explore prion protein epitope variability and availability by leveraging proximity ligation technology (PLA). We use a repertoire of nine known monoclonal anti-PrP antibodies to assess differences in prion protein conformations and establish “functional” and “non-functional” antibody probe pairs. In light of our results, we posit that exploring PrPSc strain diversity with available anti-PrP antibodies will lead to the development of ultrasensitive qPCR-PLA Protein Assays for precise detection and quantification of particular PrPSc strains.

Prion diseases, including chronic wasting disease (CWD), are caused by prions, which are misfolded aggregates of normal cellular prion protein. Prions possess many characteristics that distinguish them from conventional pathogens, in particular, an extraordinary recalcitrance to inactivation and a propensity to avidly bind to surfaces. In mid to late stages of CWD, prions begin accumulating in cervid muscle tissues. These features collectively create scenarios where occupational hazards arise for workers processing venison and pose risks to consumers through direct prion exposure via ingestion and cross-contamination of food products. In this work, we show that steel and plastic surfaces used in venison processing can be directly contaminated with CWD prions and that cross-contamination of CWD-negative venison can occur from equipment that had previously been used with CWD-positive venison. We also show that several decontaminant solutions (commercial bleach and potassium peroxymonosulfate) are efficacious for prion inactivation on these same surfaces.

High rates of land conversion and land use change have vastly increased the proportion of secondary forest in the lowland tropics relative to mature forest. As secondary forests recover following abandonment, nitrogen (N) and phosphorus (P) must be present in sufficient quantities to sustain high rates of net primary production and to replenish the nutrients lost during land use prior to secondary forest establishment. Biogeochemical theory and results from individual studies suggest that N can recuperate during secondary forest recovery, especially relative to P. Here, we synthesized 23 metrics of N and P in soil and plants from 45 secondary forest chronosequences located in the wet tropics to empirically explore (1) whether there is a consistent change in nutrients and nutrient cycling processes during secondary succession in the biome; (2) which metrics of N and P in soil and plants recuperate most consistently; (3) if the recuperation of nutrients during succession approaches similar nutrient concentrations and fluxes as those in mature forest in ∼100 yr following the initiation of succession; and (4) whether site characteristics, including disturbance history, climate, and soil order are significantly related to nutrient recuperation. During secondary forest succession, nine metrics of N and/or P cycling changed consistently and substantially. In most sites, N concentrations and fluxes in both plants and soil increased during secondary succession, and total P concentrations increased in surface soil. Changes in nutrient concentrations and nutrient cycling processes during secondary succession were similar whether mature forest was included or excluded from the analysis, indicating that nutrient recuperation in secondary forest leads to biogeochemical conditions that are similar to those of mature forest. Further, of the N and P metrics that recuperated, only soil total P and foliar δ15N were strongly influenced by site characteristics like climate, soils, or disturbance history. Predictable nutrient recuperation across a diverse and productive ecosystem may support future forest growth and could provide a means to quantify successful restoration of ecosystem function in secondary tropical forest beyond biomass or species composition.

The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF 50 ) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines. Defined levels of SARS-CoV-2-specific binding and neutralizing antibodies elicited by the COVID-19 vaccine ChAdOx1 nCoV-19 are identified as correlates of protection against symptomatic infection.

Background Targeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms. Methods Two hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer’s Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up). Discussion Establishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as “medicine” to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health. Trial registration ClinicalTrials.gov NCT02737878 . Registered on April 14, 2016.

Human modification of water and nutrient flows has resulted in widespread degradation of aquatic ecosystems. The resulting global water crisis causes millions of deaths and trillions of USD in economic damages annually. Semiarid regions have been disproportionately affected because of high relative water demand and pollution. Many proven water management strategies are not fully implemented, partially because of a lack of public engagement with freshwater ecosystems. In this context, we organized a large citizen science initiative to quantify nutrient status and cultivate connection in the semiarid watershed of Utah Lake (USA). Working with community members, we collected samples from ~200 locations throughout the 7,640 km 2 watershed on a single day in the spring, summer, and fall of 2018. We calculated ecohydrological metrics for nutrients, major ions, and carbon. For most solutes, concentration and leverage (influence on flux) were highest in lowland reaches draining directly to the lake, coincident with urban and agricultural sources. Solute sources were relatively persistent through time for most parameters despite substantial hydrological variation. Carbon, nitrogen, and phosphorus species showed critical source area behavior, with 10–17% of the sites accounting for most of the flux. Unlike temperate watersheds, where spatial variability often decreases with watershed size, longitudinal variability showed an hourglass shape: high variability among headwaters, low variability in mid-order reaches, and high variability in tailwaters. This unexpected pattern was attributable to the distribution of human activity and hydrological complexity associated with return flows, losing river reaches, and diversions in the tailwaters. We conclude that participatory science has great potential to reveal ecohydrological patterns and rehabilitate individual and community relationships with local ecosystems. In this way, such projects represent an opportunity to both understand and improve water quality in diverse socioecological contexts.

Achieving elimination of lymphatic filariasis (LF) as a public health problem requires a minimum of five effective rounds of mass drug administration (MDA) and demonstrating low prevalence in subsequent assessments. The first assessments recommended by the World Health Organization (WHO) are sentinel and spot-check sites-referred to as pre-transmission assessment surveys (pre-TAS)-in each implementation unit after MDA. If pre-TAS shows that prevalence in each site has been lowered to less than 1% microfilaremia or less than 2% antigenemia, the implementation unit conducts a TAS to determine whether MDA can be stopped. Failure to pass pre-TAS means that further rounds of MDA are required. This study aims to understand factors influencing pre-TAS results using existing programmatic data from 554 implementation units, of which 74 (13%) failed, in 13 countries. Secondary data analysis was completed using existing data from Bangladesh, Benin, Burkina Faso, Cameroon, Ghana, Haiti, Indonesia, Mali, Nepal, Niger, Sierra Leone, Tanzania, and Uganda. Additional covariate data were obtained from spatial raster data sets. Bivariate analysis and multilinear regression were performed to establish potential relationships between variables and the pre-TAS result. Higher baseline prevalence and lower elevation were significant in the regression model. Variables statistically significantly associated with failure (p-value ≤0.05) in the bivariate analyses included baseline prevalence at or above 5% or 10%, use of Filariasis Test Strips (FTS), primary vector of Culex, treatment with diethylcarbamazine-albendazole, higher elevation, higher population density, higher enhanced vegetation index (EVI), higher annual rainfall, and 6 or more rounds of MDA. This paper reports for the first time factors associated with pre-TAS results from a multi-country analysis. This information can help countries more effectively forecast program activities, such as the potential need for more rounds of MDA, and prioritize resources to ensure adequate coverage of all persons in areas at highest risk of failing pre-TAS.