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Emerging research suggests that regular physical activity can reduce the risk of cognitive decline. However, most prior studies rely on self-reported measures, which are subject to recall bias, subjectivity, and limited temporal resolution. This study aims to investigate whether objectively measured physical activity, captured through passive accelerometry, is associated with incident cognitive impairment and neuropsychological test performance and to evaluate its potential as an early indicator of cognitive decline. We analyzed data from the Framingham Heart Study (FHS), a community-based cohort with longitudinal surveillance of cognitive impairment. Participants wore an Actical accelerometer for at least 3 days (excluding bathing). A total of 30 accelerometer-derived physical activity measures were categorized into intensity-specific durations, step and cadence summaries, and peak cadence. At FHS, diagnoses of cognitive impairment were established by a review committee based on established criteria. Cox proportional hazard models were used to examine the association with incident cognitive impairment, adjusting for age, gender, education, and accelerometer wear time. Time-dependent area under the receiver operating characteristic curves, derived from random survival forest models, were used to assess predictive performance. Linear regression models were used to evaluate the associations between physical activity measures and 18 neuropsychological test scores. Among 1212 participants from the FHS Offspring cohort (age: mean 70, SD 8 y; women: 651/1212, 53.71%; follow-up period: mean 9, SD 2 y), 10 physical activity measures, including all peak cadence metrics, were nominally associated with incident cognitive impairment. Higher peak 1-minute cadence (steps/min) was significantly associated with lower risk (hazard ratio 0.82; 95% CI 0.69-0.97; P=.02). Incorporating peak 1-minute cadence into the base model (age, gender, education, and accelerometer wear time) improved the 8-year prediction area under the curve by 10.2%. Peak 1-minute cadence and total steps per day were also associated with better performance on trail making tests A and B. This study highlights significant associations between accelerometer-based physical activity metrics and both incident cognitive impairment and cognitive test performance. In particular, moderate-intensity movement, as reflected by cadence measures, may serve as a valuable marker for cognitive health and a potential target for early intervention.

Screening for cognitive impairment in primary care is important, yet primary care physicians (PCPs) report conducting routine cognitive assessments for less than half of patients older than 60 years of age. Linus Health's Core Cognitive Evaluation (CCE), a tablet-based digital cognitive assessment, has been used for the detection of cognitive impairment, but its application in primary care is not yet studied. This study aimed to explore the integration of CCE implementation in a primary care setting. A cohort of participants was recruited from the upcoming schedules of participating PCPs at UMass Memorial Medical Center. Eligibility criteria included individuals aged ≥65 years; ability to read, write, and speak in English or Spanish; no previous diagnosis of cognitive impairment; and no known untreated hearing or vision impairment. Research coordinators collected consent from participants and facilitated the screening process. PCPs reviewed reports in real time, immediately before the scheduled visits, and shared results at their discretion. A report was uploaded to each participant's REDCap (Research Electronic Data Capture; Vanderbilt University) record and linked to the encounter in the electronic health record. Feedback from patients and their caregivers (if applicable) was collected by a tablet-based survey in the clinic before and after screening. Participating PCPs were interviewed following the completion of the study. The screened cohort included 150 patients with a mean age of 74 (SD 7) years, of whom 65% (97/150) were female. The CCE identified 40 patients as borderline and 7 as positive for cognitive impairment. A total of 84 orders were placed for select laboratory tests or referrals to neurology and neuropsychology within 20 days of CCE administration. Before the assessment, 95% (143/150) of patients and all 15 caregivers expressed a desire to know if their or their loved one's brain health was declining. All except one patient also completed the postassessment survey. Among them, 96% (143/149) of patients reported finding the CCE easy to complete, and 70% (105/149) felt that the experience was beneficial. In addition, 87% (130/149) of patients agreed or strongly agreed that they wanted to know their CCE results. Among the 7 participating PCPs, 6 stated that the CCE results influenced their patient care management, and all 7 indicated they would continue using the CCE if it were made available after the study. We explored the integration of the CCE into primary care visits, which showed minimal disruption to the practice workflow. Future studies will be warranted to further validate the implementation of digital cognitive impairment screening tools within primary care settings in the real world.

The decapping complex is a dynamic enzyme that is involved in dynamic processes of development and environment stress responses. In vivo , and to some extent in vitro, decapping has been shown to be modulated by numerous cellular cofactors; including Dhh1 and Pat1:Lsm1-7, which help define the timing of decapping. Additional coactivating sequences contained in lineage specific proteins allow for plasticity in recruiting the complex to novel pathways. Recently, great progress has been made in describing the structured, core domains of the various 5’ decay factors and the decapping structure has been solved in multiple forms that represent various conformations along its enzymatic trajectory; including coactivator bound. Much less is known about the intrinsically disorder regions (IDRs) of these proteins. In vivo results have implicated that there could be a negative regulatory element in the decapping complex. Following this insight, I have discovered and subsequently characterized an autoinhibitory region of the fungal Dcp2 IDR. Additionally, this autoinhibitory complex reveals a potentially larger role for Edc3 in cytoplasmic decay that had previously been unappreciated. This autoinhibition provides new possibilities for our understanding of mRNA decay and this system provides the opportunity to resolve differences between in vivo and in vitro decapping results. Finally, our biochemical and structural insights into the core Dcp1:Dcp2 activation have resulted in an enzyme that may prove useful for RNA cloning methods.

5' mediated cytoplasmic RNA decay is a conserved cellular process in eukaryotes. While the functions of the structured core domains in this pathway are understood, the role of abundant intrinsically disordered regions (IDRs) is lacking. Here we reconstitute the Dcp1:Dcp2 complex containing a portion of the disordered C-terminus and show its activity is autoinhibited by linear interaction motifs. Enhancers of decapping (Edc) 1 and 3 cooperate to activate decapping by different mechanisms: Edc3 alleviates autoinhibition by binding IDRs and destabilizing an inactive form of the enzyme, whereas Edc1 stabilizes the transition state for catalysis. Both activators are required to fully stimulate an autoinhibited Dcp1:Dcp2 as Edc1 alone cannot overcome the decrease in activity attributed to the C-terminal extension. Our data provide a mechanistic framework for combinatorial control of decapping by protein cofactors, a principle that is likely conserved in multiple 5' mRNA decay pathways.

Data mining methods have been used to identify 356 Cyt P450 genes and 99 related pseudogenes in the rice (Oryza sativa) genome using sequence information available from both the indica and japonica strains. Because neither of these genomes is completely available, some genes have been identified in only one strain, and 28 genes remain incomplete. Comparison of these rice genes with the 246 P450 genes and 26 pseudogenes in the Arabidopsis genome has indicated that most of the known plant P450 families existed before the monocot-dicot divergence that occurred approximately 200 million years ago. Comparative analysis of P450s in the Pinus expressed sequence tag collections has identified P450 families that predated the separation of gymnosperms and flowering plants. Complete mapping of all available plant P450s onto the Deep Green consensus plant phylogeny highlights certain lineage-specific families maintained (CYP80 in Ranunculales) and lineage-specific families lost (CYP92 in Arabidopsis) in the course of evolution.

This work investigates the relationships between partial melting, melt extraction, pluton growth and silicic volcanism in garnet-bearing felsic volcanic rocks that were extruded in the Iberian Pyrite Belt, at ca . 345 Ma. The garnets are of peritectic origin, displaying textural and chemical features of disequilibrium crystallization during partial melting reactions involving biotite at high temperatures (up to 870 °C) in the middle-lower crust. Major element composition suggests compositional equilibrium with the entrained and pinitized peritectic cordierite, but reveals some subsequent homogenization by diffusion. Trace element maps and spot analyses of garnet show, nonetheless, significant trace element variations, reflecting biotite and Y-REE-P-rich accessory phase breakdown during partial melting reactions. Peritectic garnet and cordierite growth resulted in the preservation of Th- and Y-rich prograde suprasolidus monazite, which constrains the timing of partial melting of the metapelitic protolith at ca. 356.8 ± 2.4 Ma. The zircon cargo further shows that a significant amount of zircon crystals from previously crystallized felsic melts were also remobilized and erupted. These were likely stored in an upper crustal pluton that grew episodically since ca . 390 Ma during voluminous melt generation periods within the middle to lower crust, which also resulted in voluminous volcanism. The geochemical trends of the felsic volcanic rocks reflect the entrainment of xenoliths of peritectic garnet, cordierite and feldspar, and as such, the garnet-bearing felsic volcanic rocks represent an erupted mixture of a lower-temperature ( ca. 770 °C) silicic melt and autocrysts, and peritectic phases and zircon crystals from previously crystallized and stored felsic melts.

Forests are a substantial terrestrial carbon sink, but anthropogenic changes in land use and climate have considerably reduced the scale of this system 1 . Remote-sensing estimates to quantify carbon losses from global forests 2–5 are characterized by considerable uncertainty and we lack a comprehensive ground-sourced evaluation to benchmark these estimates. Here we combine several ground-sourced 6 and satellite-derived approaches 2,7,8 to evaluate the scale of the global forest carbon potential outside agricultural and urban lands. Despite regional variation, the predictions demonstrated remarkable consistency at a global scale, with only a 12% difference between the ground-sourced and satellite-derived estimates. At present, global forest carbon storage is markedly under the natural potential, with a total deficit of 226 Gt (model range = 151–363 Gt) in areas with low human footprint. Most (61%, 139 Gt C) of this potential is in areas with existing forests, in which ecosystem protection can allow forests to recover to maturity. The remaining 39% (87 Gt C) of potential lies in regions in which forests have been removed or fragmented. Although forests cannot be a substitute for emissions reductions, our results support the idea 2,3,9 that the conservation, restoration and sustainable management of diverse forests offer valuable contributions to meeting global climate and biodiversity targets.

The Additively‐Manufactured, System‐Integrated Tip (AMSIT) project is leveraging the flexibility of 3D printing to integrate several technologies in a wind turbine blade tip, while reducing the levelized cost of electricity (LCOE) produced. The design integration is demonstrated for a 200‐kW–scale turbine with 13‐m blades, with the outer 15% of the blade replaced with a 3D‐printed design. Aerodynamic performance is enhanced without increasing swept area through inclusion of a winglet and surface texturing, both challenging for traditional manufacturing. Longevity and durability are improved through integrated lightning and leading edge erosion protection. Increased power, reduced repair frequency, and ease of repair through blade modularity all contribute to reduced LCOE. The analysis is also extended to modern MW‐scale designs to estimate the impact of the technology at scale, demonstrating the potential to reduce LCOE significantly for modern onshore turbines, with even higher potential savings offshore.

Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations. Though tractography is widely used, it has not been systematically validated. Here, authors report results from 20 groups showing that many tractography algorithms produce both valid and invalid bundles.

IntroductionSARS-CoV-2 is now endemic and expected to remain a health threat, with new variants continuing to emerge and the potential for vaccines to become less effective. While effective vaccines and natural immunity have significantly reduced hospitalisations and the need for critical care, outpatient treatment options remain limited, and real-world evidence on their clinical and cost-effectiveness is lacking. In this paper, we present the design of the Canadian Adaptive Platform Trial of Treatments for COVID in Community Settings (CanTreatCOVID). By evaluating multiple treatment options in a pragmatic adaptive platform trial, this study will generate high-quality, generalisable evidence to inform clinical guidelines and healthcare decision-making.Methods and analysisCanTreatCOVID is an open-label, individually randomised, multicentre, national adaptive platform trial designed to evaluate the clinical and cost-effectiveness of therapeutics for non-hospitalised SARS-CoV-2 patients across Canada. Eligible participants must present with symptomatic SARS-CoV-2 infection, confirmed by PCR or rapid antigen testing (RAT), within 5 days of symptom onset. The trial targets two groups that are expected to be at higher risk of more severe disease: (1) individuals aged 50 years and older and (2) those aged 18–49 years with one or more comorbidities. CanTreatCOVID uses numerous approaches to recruit participants to the study, including a multifaceted public communication strategy and outreach through primary care, outpatient clinics and emergency departments. Participants are randomised to receive either usual care, including supportive and symptom-based management, or an investigational therapeutic selected by the Canadian COVID-19 Outpatient Therapeutics Committee. The first therapeutic arm evaluates nirmatrelvir/ritonavir (Paxlovid), administered two times per day for 5 days. The second therapeutic arm investigates a combination antioxidant therapy (selenium 300 µg, zinc 40 mg, lycopene 45 mg and vitamin C 1.5 g), administered for 10 days. The primary outcome is all-cause hospitalisation or death within 28 days of randomisation.Ethics and disseminationThe CanTreatCOVID master protocol and subprotocols have been approved by Health Canada and local research ethics boards in the participating provinces across Canada. The results of the study will be disseminated to policy-makers, presented at conferences and published in peer-reviewed journals to ensure that findings are accessible to the broader scientific and medical communities. This study was approved by the Unity Health Toronto Research Ethics Board (#22-179) and Clinical Trials Ontario (Project ID 4133).Trial registration numberNCT05614349