Gait and Turning Characteristics from Daily Life increase ability to predict future falls in people with Parkinson’s disease

Objectives: To investigate if digital measures of gait (walking and turning) collected passively over a week of daily activities in people with Parkinson’s disease (PD) increases the discriminative ability to predict future falls compared to fall history alone. Methods: We recruited 34 individuals with PD (17 with history of falls and 17 non-fallers), age: 68 ± 6 years, MDS-UPDRS III ON: 31 ± 9. Participants were classified as fallers (at least one fall) or non-fallers based on self-reported falls in past 6 months. Eighty digital measures of gait were derived from 3 inertial sensors (Opal® V2 System) placed on the feet and lower back for a week of passive gait monitoring. Logistic regression employing a “best subsets selection strategy” was used to find combinations of measures that discriminated future fallers from non- fallers, and the Area Under Curve (AUC). Participants were followed via email every 2 weeks over the year after the study for self-reported falls. Results: Twenty-five subjects reported falls in the follow-up year. Quantity of gait and turning measures (e.g., number of gait bouts and turns per hour) were similar in future fallers and non-fallers. The AUC to discriminate future fallers from non-fallers using fall history alone was 0.77 (95% CI: [0.50–1.00]). In contrast, the highest AUC for gait and turning digital measures with 4 combinations was 0.94 [0.84–1.00]. From the top 10 models (all AUCs\u3e0.90) via the best subsets strategy, the most consistently selected measures were variability of toe-out angle of the foot (9 out of 10), pitch angle of the foot during mid-swing (8 out of 10), and peak turn velocity (7 out of 10). Conclusions: These findings highlight the importance of considering precise digital measures, captured via sensors strategically placed on the feet and low back, to quantify several dierent aspects of gait (walking and turning) during daily life to improve the classification of future fallers in PD

A Habitat Stronghold on the Precipice: A call‐to‐action for supporting lemur conservation in northeast Madagascar

The northeast of Madagascar is as diverse as it is threatened. The area bordering the Analanjirofo and SAVA regions contains six protected areas and at least 22 lemur species. Many applied research and conservation programs have been established in the region with the aim of ensuring both wildlife and people thrive in the long term. While most of the remaining humid evergreen forest of northeast Madagascar is formally protected, the local human population depends heavily on the land, and unsustainable natural resource use threatens this biodiversity hotspot. Drawing from our collective experiences managing conservation activities and research programs in northeast Madagascar, we discuss the major threats to the region and advocate for eight conservation activities that help reduce threats and protect the environment, providing specific examples from our own programs. These include (1) empowering local conservation actors, (2) ensuring effectively protected habitat, (3) expanding reforestation, (4) establishing and continuing long-term research and monitoring, (5) reducing food insecurity, (6) supporting environmental education, (7) promoting sustainable livelihoods, and (8) expanding community health initiatives. Lastly, we provide a list of actions that individuals can take to join us in supporting and promoting lemur conservation

chi sequences switch the RecBCD helicase–nuclease complex from degradative to replicative modes during the completion of DNA replication

Accurately completing DNA replication when two forks converge is essential to genomic stability. The RecBCD helicase–nuclease complex plays a central role in completion by promoting resection and joining of the excess DNA created when replisomes converge. chi sequences alter RecBCD activity and localize with crossover hotspots during sexual events in bacteria, yet their functional role during chromosome replication remains unknown. Here, we use two-dimensional agarose gel analysis to show that chi induces replication on substrates containing convergent forks. The induced replication is processive but uncoupled with respect to leading and lagging strand synthesis and can be suppressed by ter sites which limit replisome progression. Our observations demonstrate that convergent replisomes create a substrate that is processed by RecBCD and that chi, when encountered, switches RecBCD from a degradative to replicative function. We propose that chi serves to functionally differentiate DNA ends created during completion, which require degradation, from those created by chromosomal double-strand breaks, which require resynthesis

Dissecting succulence: Crassulacean acid metabolism and hydraulic capacitance are independent adaptations in Clusia leaves

Succulence is found across the world as an adaptation to water-limited niches. The fleshy organs of succulent plants develop via enlarged photosynthetic chlorenchyma and/or achlorophyllous water storage hydrenchyma cells. The precise mechanism by which anatomical traits contribute to drought tolerance is unclear, as the effect of succulence is multifaceted. Large cells are believed to provide space for nocturnal storage of malic acid fixed by crassulacean acid metabolism (CAM), whilst also buffering water potentials by elevating hydraulic capacitance (CFT). The effect of CAM and elevated CFT on growth and water conservation have not been compared, despite the assumption that these adaptations often occur together. We assessed the relationship between succulent anatomical adaptations, CAM, and CFT, across the genus Clusia. We also simulated the effects of CAM and CFT on growth and water conservation during drought using the Photo3 model. Within Clusia leaves, CAM and CFT are independent traits: CAM requires large palisade chlorenchyma cells, whereas hydrenchyma tissue governs interspecific differences in CFT. In addition, our model suggests that CAM supersedes CFT as a means to maximise CO2 assimilation and minimise transpiration during drought. Our study challenges the assumption that CAM and CFT are mutually dependent traits within succulent leaves

Self-assembly of Exfoliated Graphene Flakes as anticorrosive coatings for additive manufactured steels

This study demonstrates the feasibility of using liquid exfoliation of expandable graphite into multilayer exfoliated graphene flakes (EGFs) to form a self-assembled thin film on an air–water interface. The film can coat the surface of additive manufactured (AM) steel substrates to enhance surface properties, specifically AM 316 stainless-steel (AM316), AM 8620 steel (AM8620), and samples of the same alloys made by conventional manufacturing (CM) processes. Liquid exfoliation offers a high yield route for an EGF coating that can cover up to 95% of the sample surface with a single application. The thin, flexible EGFs can coat a rough AM metal surface, while the highly intact crystal lattice protects covered areas against diffusing ions and prevents localized corrosion compared to similar coatings made with graphene oxide (GO) or reduced GO (rGO). The EGF coating exploits a unique self-assembly process without surfactants or stabilizers, wherein the hydrophobicity and hydrophilicity of EGFs arrange the flakes, then van der Waals (vdW) forces bond them together and to the substrate for a coherent anti-corrosive coating. Electrochemical measurements indicate lower corrosion potential for coated samples, nanoindentation measurements show surface hardness protection against corrosive attack, and weight loss measurements demonstrate long-term protective capabilities. Density functional theory calculations, using the optB88-vdW exchange functional of the graphene and iron (111) interface demonstrated stronger binding and shorter interface distance compared to the well-studied graphene/nickel (111) interface. These calculations and experimental results can further elucidate the superior performance of EGF thin film coatings on high iron content steels, especially AM steels

Reduced Fire Severity offers Near-term Buffer to climate-driven declines in conifer resilience across the western United States

Increasing fire severity and warmer, drier postfire conditions are making forests in the western United States (West) vulnerable to ecological transformation. Yet, the relative importance of and interactions between these drivers of forest change remain unresolved, particularly over upcoming decades. Here, we assess how the interactive impacts of changing climate and wildfire activity influenced conifer regeneration after 334 wildfires, using a dataset of postfire conifer regeneration from 10,230 field plots. Our findings highlight declining regeneration capacity across the West over the past four decades for the eight dominant conifer species studied. Postfire regeneration is sensitive to high-severity fire, which limits seed availability, and postfire climate, which influences seedling establishment. In the near-term, projected differences in recruitment probability between low- and high-severity fire scenarios were larger than projected climate change impacts for most species, suggesting that reductions in fire severity, and resultant impacts on seed availability, could partially offset expected climate-driven declines in postfire regeneration. Across 40 to 42% of the study area, we project postfire conifer regeneration to be likely following low-severity but not high-severity fire under future climate scenarios (2031 to 2050). However, increasingly warm, dry climate conditions are projected to eventually outweigh the influence of fire severity and seed availability. The percent of the study area considered unlikely to experience conifer regeneration, regardless of fire severity, increased from 5% in 1981 to 2000 to 26 to 31% by mid-century, highlighting a limited time window over which management actions that reduce fire severity may effectively support postfire conifer regeneration

7-Deazaguanines in DNA: Functional and Structural elucidation of a DNA modification system

The modified nucleosides 2′-deoxy-7-cyano- and 2′-deoxy-7-amido-7-deazaguanosine (dPreQ0 and dADG, respectively) recently discovered in DNA are the products of the bacterial queuosine tRNA modification pathway and the dpd gene cluster, the latter of which encodes proteins that comprise the elaborate Dpd restriction–modification system present in diverse bacteria. Recent genetic studies implicated the dpdA, dpdB and dpdC genes as encoding proteins necessary for DNA modification, with dpdD–dpdK contributing to the restriction phenotype. Here we report the in vitro reconstitution of the Dpd modification machinery from Salmonella enterica serovar Montevideo, the elucidation of the roles of each protein and the X-ray crystal structure of DpdA supported by small-angle X-ray scattering analysis of DpdA and DpdB, the former bound to DNA. While the homology of DpdA with the tRNA-dependent tRNA-guanine transglycosylase enzymes (TGT) in the queuosine pathway suggested a similar transglycosylase activity responsible for the exchange of a guanine base in the DNA for 7-cyano-7-deazaguanine (preQ0), we demonstrate an unexpected ATPase activity in DpdB necessary for insertion of preQ0 into DNA, and identify several catalytically essential active site residues in DpdA involved in the transglycosylation reaction. Further, we identify a modification site for DpdA activity and demonstrate that DpdC functions independently of DpdA/B in converting preQ0-modified DNA to ADG-modified DNA

Longitudinal changes in Alzheimer’s-related plasma biomarkers and brain amyloid

Introduction Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer’s progression assessment strategies. Methods We examined the temporal order of changes in plasma amyloid-β ratio (Aβ42/Aβ40), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios (p-tau181/Aβ42, p-tau231/Aβ42) relative to 11C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB−/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up. Results PiB groups exhibited different rates of longitudinal change in Aβ42/Aβ40 (β = 5.41 × 10-4, SE = 1.95 × 10-4, p = 0.0073). Change in brain amyloid correlated with change in GFAP (r = 0.5, 95% CI = [0.26, 0.68]). Greatest relative decline in Aβ42/Aβ40 (-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]). Discussion Plasma Aβ42/Aβ40 may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time

Nanoscale Hafnium Metal-organic Frameworks Enhance Radiotherapeutic Effects by Upregulation of Type I Interferon and TLR7 Expression

Recent preclinical and clinical studies have highlighted the improved outcomes of combination radiotherapy and immunotherapy. Concurrently, the development of high-Z metallic nanoparticles as radiation dose enhancers has been explored to widen the therapeutic window of radiotherapy and potentially enhance immune activation. In this study, we evaluate folate-modified hafnium-based metal-organic frameworks (HfMOF-PEG-FA) in combination with imiquimod, a TLR7 agonist, as a well-defined interferon regulatory factor (IRF) stimulator for local antitumor immunotherapy. The enhancement of radiation dose deposition by HfMOF-PEG-FA and subsequent generation of reactive oxygen species (ROS) deregulates cell proliferation and increases apoptosis. HfMOF-PEG-FA loaded with imiquimod (HfMOF-PEG-FA@IMQ) increases DNA double-strand breaks and cell death, including apoptosis, necrosis, and calreticulin exposure, in response to X-ray irradiation. Treatment with this multipronged therapy promotes IRF stimulation for subsequent interferon production within tumor cells themselves. We report the novel observation that, HfMOF itself increased TLR7 expression, unexpectedly pairing immune agonist and receptor up-regulation in a tumor intrinsic manner, and supporting the synergistic affect observed with the γH2AX assay. T cell analysis of CT26 tumors following intratumoral administration of HfMOF-PEG-FA@IMQ with radiotherapy reveals a promising antitumor response, characterized by an increase in CD8+ and proliferative T cells

Novel Viruses of the Family Partitiviridae Discovered in Saccharomyces cerevisiae

It has been 49 years since the last discovery of a new virus family in the model yeast Saccharomyces cerevisiae. A large-scale screen to determine the diversity of double-stranded RNA (dsRNA) viruses in S. cerevisiae has identified multiple novel viruses from the family Partitiviridae that have been previously shown to infect plants, fungi, protozoans, and insects. Most S. cerevisiae partitiviruses (ScPVs) are associated with strains of yeasts isolated from coffee and cacao beans. The presence of partitiviruses was confirmed by sequencing the viral dsRNAs and purifying and visualizing isometric, non-enveloped viral particles. ScPVs have a typical bipartite genome encoding an RNA-dependent RNA polymerase (RdRP) and a coat protein (CP). Phylogenetic analysis of ScPVs identified three species of ScPV, which are most closely related to viruses of the genus Cryspovirus from the mammalian pathogenic protozoan Cryptosporidium parvum. Molecular modeling of the ScPV RdRP revealed a conserved tertiary structure and catalytic site organization when compared to the RdRPs of the Picornaviridae. The ScPV CP is the smallest so far identified in the Partitiviridae and has structural homology with the CP of other partitiviruses but likely lacks a protrusion domain that is a conspicuous feature of other partitivirus particles. ScPVs were stably maintained during laboratory growth and were successfully transferred to haploid progeny after sporulation, which provides future opportunities to study partitivirus-host interactions using the powerful genetic tools available for the model organism S. cerevisiae