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The Cretaceous-Paleogene boundary approximately 65.5 million years ago marks one of the three largest mass extinctions in the past 500 million years. The extinction event coincided with a large asteroid impact at Chicxulub, Mexico, and occurred within the time of Deccan flood basalt volcanism in India. Here, we synthesize records of the global stratigraphy across this boundary to assess the proposed causes of the mass extinction. Notably, a single ejecta-rich deposit compositionally linked to the Chicxulub impact is globally distributed at the Cretaceous-Paleogene boundary. The temporal match between the ejecta layer and the onset of the extinctions and the agreement of ecological patterns in the fossil record with modeled environmental perturbations (for example, darkness and cooling) lead us to conclude that the Chicxulub impact triggered the mass extinction.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) accounts for up to 2 percent of all brain protein and is essential to memory function. CaMKII activity is known to regulate dynamic shifts in the size and signaling strength of neuronal connections, a process known as synaptic plasticity. Increasingly, computational models are used to explore synaptic plasticity and the mechanisms regulating CaMKII activity. Conventional modeling approaches may exclude biophysical detail due to the impractical number of state combinations that arise when explicitly monitoring the conformational changes, ligand binding, and phosphorylation events that occur on each of the CaMKII holoenzyme's subunits. To manage the combinatorial explosion without necessitating bias or loss in biological accuracy, we use a specialized syntax in the software MCell to create a rule-based model of a twelve-subunit CaMKII holoenzyme. Here we validate the rule-based model against previous experimental measures of CaMKII activity and investigate molecular mechanisms of CaMKII regulation. Specifically, we explore how Ca2+/CaM-binding may both stabilize CaMKII subunit activation and regulate maintenance of CaMKII autophosphorylation. Noting that Ca2+/CaM and protein phosphatases bind CaMKII at nearby or overlapping sites, we compare model scenarios in which Ca2+/CaM and protein phosphatase do or do not structurally exclude each other's binding to CaMKII. Our results suggest a functional mechanism for the so-called \"CaM trapping\" phenomenon, wherein Ca2+/CaM may structurally exclude phosphatase binding and thereby prolong CaMKII autophosphorylation. We conclude that structural protection of autophosphorylated CaMKII by Ca2+/CaM may be an important mechanism for regulation of synaptic plasticity.

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer’s disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini–Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer’s disease, which supports its potential utility as a clinically useful biomarker.In a longitudinal cohort of familial Alzheimer’s disease patients, the rate of change of blood biomarker levels identifies disease carriers much earlier than absolute levels and predicts both neurodegeneration and cognitive decline.

Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; ncontrol = 13; nAD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA–AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis.

•Open Science principles are vital for ensuring reproducibility, trust, and legacy.•Evidence synthesis is a vital means of summarizing research for decision-making.•Open Synthesis is the application of Open Science principles to evidence synthesis.•Open approaches to planning, conducting, and reporting synthesis have many benefits.•We call on the evidence synthesis community to embrace Open Synthesis.

Mobile health (mHealth) technology has the ability to integrate personalized health management into patients' daily routines. In prior investigations of mHealth apps for asthma, patient satisfaction and acceptability have been high. However, rigorous randomized controlled trials (RCTs) examining their effectiveness are sparse; the majority of mHealth asthma apps lack personalization and real-time feedback and fail to include at-risk pediatric populations, and many previous studies are not randomized. This full-scale RCT will examine the effectiveness of the Pulmonary Education and Asthma Knowledge Mobile Asthma Action Plan (PEAKmAAP), an interactive mHealth asthma action plan (mAAP) smartphone app, among adolescents compared to enhanced usual care (eUC). The study has 3 aims: (1) examine the effectiveness of PEAKmAAP in reducing asthma morbidity, as measured by the Asthma Control Test (ACT) score, health care use, medication use, and lung function; (2) examine the effectiveness of PEAKmAAP in asthma self-efficacy and medication adherence; and (3) examine the impact of sharing PEAKmAAP-generated data with the primary care provider (PCP) for a subset of enrolled subjects. We hypothesize that the PEAKmAAP groups will experience reduced asthma morbidity compared to the eUC group. Furthermore, we hypothesize that PCP data sharing is expected to enhance PCP prescribing patterns and that more adolescents in the Pulmonary Education and Asthma Knowledge Mobile Asthma Action Plan with data sharing (PEAKmAAP-DS) group will have sustained controlled at follow-up visits compared to PEAKmAAP alone or eUC. Using a 3-arm RCT lasting 12 months, we will assess the effectiveness of PEAKmAAP in reducing morbidity among 432 adolescents (age 12-20 years). The study population includes adolescents with uncontrolled symptoms who receive primary care at the Arkansas Children's Hospital (ACH) or asthma care at ACH specialty clinics. At baseline, participants are randomly assigned to 1 of 3 groups: (1) PEAKmAAP group, (2) PEAKmAAP-DS group, and (3) eUC group using a smartphone app with daily non-asthma-related notifications. Study procedures will include baseline, 3-month, and 12-month in-person visits and telephone visits at 6 and 9 months. In-person visits will measure the ACT score, lung function, and self-efficacy; telephone visits will measure the ACT score. Participants will complete monthly online surveys to assess health care use and medication use. Recruitment and data collection began in March 2019, and data collection concluded in May 2024. Full data analysis began in December 2024. This RCT aims to examine the effectiveness of a mAAP with real-time feedback and PCP data sharing. The study addresses existing gaps in knowledge regarding implementation of a mAAP for high-risk adolescents and has the potential to serve as a model for other populations at high risk for asthma. ClinicalTrials.gov NCT03842033; https://clinicaltrials.gov/study/NCT03842033. DERR1-10.2196/69903.

FGF-23, a novel member of the FGF family, is the product of the gene mutated in autosomal dominant hypophosphatemic rickets (ADHR). FGF-23 has been proposed as a circulating factor causing renal phosphate wasting not only in ADHR (as a result of inadequate degradation), but also in tumor-induced osteomalacia (as a result of excess synthesis by tumor cells). Renal phosphate wasting occurs in approximately 50% of patients with McCune-Albright syndrome (MAS) and fibrous dysplasia of bone (FD), which result from postzygotic mutations of the GNAS1 gene. We found that FGF-23 is produced by normal and FD osteoprogenitors and bone-forming cells in vivo and in vitro. In situ hybridization analysis of FGF-23 mRNA expression identified \"fibrous\" cells, osteogenic cells, and cells associated with microvascular walls as specific cellular sources of FGF-23 in FD. Serum levels of FGF-23 were increased in FD/MAS patients compared with normal age-matched controls and significantly higher in FD/MAS patients with renal phosphate wasting compared with those without, and correlated with disease burden bone turnover markers commonly used to assess disease activity. Production of FGF-23 by FD tissue may play an important role in the renal phosphate-wasting syndrome associated with FD/MAS.

Aims/hypothesisType 2 diabetes mellitus can manifest over a broad clinical range, although there is no clear consensus on the categorisation of disease complexity. We assessed the effects of canagliflozin, compared with placebo, on cardiovascular and kidney outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program over a range of type 2 diabetes mellitus complexity, defined separately by baseline intensity of treatment, duration of diabetes and glycaemic control.MethodsWe performed a post hoc analysis of the effects of canagliflozin on major adverse cardiovascular events (MACE) according to baseline glucose-lowering treatments (0 or 1, 2 or 3+ non-insulin glucose-lowering treatments, or insulin-based treatment), duration of diabetes (<10, 10 to 16, >16 years) and HbA1c (≤53.0 mmol/mol [<7.0%], >53.0 to 58.5 mmol/mol [>7.0% to 7.5%], >58.5 to 63.9 mmol/mol [>7.5 to 8.0%], >63.9 to 69.4 mmol/mol [8.0% to 8.5%], >69.4 to 74.9 mmol/mol [>8.5 to 9.0%] or >74.9 mmol/mol [>9.0%]). We analysed additional secondary endpoints for cardiovascular and kidney outcomes, including a combined kidney outcome of sustained 40% decline in eGFR, end-stage kidney disease or death due to kidney disease. We used Cox regression analyses and compared the constancy of HRs across subgroups by fitting an interaction term (p value for significance <0.05).ResultsAt study initiation, 5095 (50%) CANVAS Program participants were treated with insulin, 2100 (21%) had an HbA1c > 74.9 mmol/mol (9.0%) and the median duration of diabetes was 12.6 years (interquartile interval 8.0–18 years). Canagliflozin reduced MACE (HR 0.86 [95% CI 0.75, 0.97]) with no evidence that the benefit differed between subgroups defined by the number of glucose-lowering treatments, the duration of diabetes or baseline HbA1c (all p-heterogeneity >0.17). Canagliflozin reduced MACE in participants receiving insulin with no evidence that the benefit differed from other participants in the trial (HR 0.85 [95% CI 0.72, 1.00]). Similar results were observed for other cardiovascular outcomes and for the combined kidney outcome (HR for combined kidney outcome 0.60 [95% CI 0.47, 0.77]), with all p-heterogeneity >0.37.Conclusions/interpretationIn people with type 2 diabetes mellitus at high cardiovascular risk, there was no evidence that cardiovascular and renal protection with canagliflozin differed across subgroups defined by baseline treatment intensity, duration of diabetes or HbA1c.

Anneke den Hollander, Patsy Nishina and colleagues report heterozygous missense mutations in CTNNA1 in three families with butterfly-shaped pigment dystrophy. Ctnna1 -mutant mice display a similar phenotype and show increased cell shedding and large multinucleated cells in the retinal pigment epithelium, suggesting defects in intercellular adhesion and cytokinesis. Butterfly-shaped pigment dystrophy is an eye disease characterized by lesions in the macula that can resemble the wings of a butterfly. Here we report the identification of heterozygous missense mutations in the CTNNA1 gene (encoding α-catenin 1) in three families with butterfly-shaped pigment dystrophy. In addition, we identified a Ctnna1 missense mutation in a chemically induced mouse mutant, tvrm5 . Parallel clinical phenotypes were observed in the retinal pigment epithelium (RPE) of individuals with butterfly-shaped pigment dystrophy and in tvrm5 mice, including pigmentary abnormalities, focal thickening and elevated lesions, and decreased light-activated responses. Morphological studies in tvrm5 mice demonstrated increased cell shedding and the presence of large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis. This study identifies CTNNA1 gene variants as a cause of macular dystrophy, indicates that CTNNA1 is involved in maintaining RPE integrity and suggests that other components that participate in intercellular adhesion may be implicated in macular disease.