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Amur honeysuckle (Lonicera maackii) is an important invasive plant species in the Ohio River Valley. Previous work has shown extensive dieback of honeysuckle in the region, coupled with the appearance of the native fungal pathogen, honeysuckle leaf blight (Insolibasidium deformans). Our goal was to find if the blight causes growth decline or mortality in Amur honeysuckle. Seedlings were grown under greenhouse conditions in 2017. Treated seedlings were sprayed with a spore solution prepared from blighted leaves that were collected from the field. They were placed into a growth chamber with conditions set for optimum spore growth and then returned to the greenhouse after leaf blight began to develop. Growth (height, total stem length, leaf area, and leaf number) and dark-adapted chlorophyll fluorescence (F v/F m) were measured periodically over the growing season. A repeated-measures analysis of aboveground growth indicated that larger, faster-growing plants were more likely to be infected, but their growth rates were subsequently reduced much more than uninfected treated plants and controls. There were positive correlations between F v/F m and RGR (relative growth rate). Blighted leaves had lower values of F v/F m than uninfected leaves. No infected plants died, but this experiment supports our hypothesis that leaf blight causes a significant growth decline in Amur honeysuckle. Future work will determine if the patterns seen under greenhouse conditions hold in the field.

Amur honeysuckle (Lonicera maackii) is an important invasive plant species in the Ohio River Valley. Previous work has shown extensive dieback of honeysuckle in the region, coupled with the appearance of the native fungal pathogen, honeysuckle leaf blight (Insolibasidium deformans). Our goal was to find if the blight causes growth decline or mortality in Amur honeysuckle. Seedlings were grown under greenhouse conditions in 2017. Treated seedlings were sprayed with a spore solution prepared from blighted leaves that were collected from the field. They were placed into a growth chamber with conditions set for optimum spore growth and then returned to the greenhouse after leaf blight began to develop. Growth (height, total stem length, leaf area, and leaf number) and dark-adapted chlorophyll fluorescence (Fv/Fm) were measured periodically over the growing season. A repeated-measures analysis of aboveground growth indicated that larger, faster-growing plants were more likely to be infected, but their growth rates were subsequently reduced much more than uninfected treated plants and controls. There were positive correlations between Fv/Fm and RGR (relative growth rate). Blighted leaves had lower values of Fv/Fm than uninfected leaves. No infected plants died, but this experiment supports our hypothesis that leaf blight causes a significant growth decline in Amur honeysuckle. Future work will determine if the patterns seen under greenhouse conditions hold in the field.

Small passerines, sometimes referred to as perching birds or songbirds, are the most abundant bird group in the United States (US) and Canada, and the most common among bird fatalities caused by collision with turbines at wind energy facilities. We used data compiled from 116 studies conducted in the US and Canada to estimate the annual rate of small-bird fatalities. It was necessary for us to calculate estimates of small-bird fatality rates from reported all-bird rates for 30% of studies. The remaining 70% of studies provided data on small-bird fatalities. We then adjusted estimates to account for detection bias and loss of carcasses from scavenging. These studies represented about 15% of current operating capacity (megawatts [MW]) for all wind energy facilities in the US and Canada and provided information on 4,975 bird fatalities, of which we estimated 62.5% were small passerines comprising 156 species. For all wind energy facilities currently in operation, we estimated that about 134,000 to 230,000 small-passerine fatalities from collision with wind turbines occur annually, or 2.10 to 3.35 small birds/MW of installed capacity. When adjusted for species composition, this indicates that about 368,000 fatalities for all bird species are caused annually by collisions with wind turbines. Other human-related sources of bird deaths, (e.g., communication towers, buildings [including windows]), and domestic cats) have been estimated to kill millions to billions of birds each year. Compared to continent-wide population estimates, the cumulative mortality rate per year by species was highest for black-throated blue warbler and tree swallow; 0.043% of the entire population of each species was estimated to annually suffer mortality from collisions with turbines. For the eighteen species with the next highest values, this estimate ranged from 0.008% to 0.038%, much lower than rates attributed to collisions with communication towers (1.2% to 9.0% for top twenty species).

Presenilin heterodimers apparently contain the active site of γ-secretase, a polytopic aspartyl protease involved in the transmembrane processing of both the Notch receptor and the amyloid-β precursor protein. Although critical to embryonic development and the pathogenesis of Alzheimer's disease, this protease is difficult to characterize, primarily because it is a multicomponent complex of integral membrane proteins. Here the functional γ-secretase complex was isolated by using an immobilized active site-directed inhibitor of the protease. Presenilin heterodimers and nicastrin bound specifically to this inhibitor under conditions tightly correlating with protease activity, whereas several other presenilin-interacting proteins (β-catenin, calsenilin, and presenilin-associated protein) did not bind. Moreover, anti-nicastrin antibodies immunoprecipitated γ-secretase activity from detergent-solubilized microsomes. Unexpectedly, C83, the major endogenous amyloid-β precursor protein substrate of γ-secretase, was also quantitatively associated with the complex. These results provide direct biochemical evidence that nicastrin is a member of the active γ-secretase complex, indicate that β-catenin, calsenilin, and presenilin-associated protein are not required for γ activity, and suggest an unprecedented mechanism of substrate-protease interaction.

Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

To validate retinal capillary density and caliber associations with diabetic retinopathy (DR) severity in different clinical settings. This cross-sectional study assessed retinal capillary density and caliber in the superficial retinal layer of 3-mm OCTA scans centered on the fovea. Images were collected from non-diabetic controls and subjects with mild or referable DR (defined DR worse than mild DR) between February 2016 and December 2019 at secondary and tertiary eye care centers. Vessel Skeleton Density (VSD), a measure of capillary density, and Vessel Diameter Index (VDI), a measure of vascular caliber, were calculated from these images. Discriminatory performance of VSD and VDI was evaluated using multivariable logistic regression models predicting DR severity with adjustments for sex, hypertension, and hyperlipidemia. Area under the curve (AUC) was estimated. Model performance was evaluated in two different cohorts. This study included 594 eyes from 385 subjects. Cohort 1 was a training cohort of 509 eyes including 159 control, 155 mild non-proliferative DR (NPDR) and 195 referable DR eyes. Cohort 2 was a validation cohort consisting of 85 eyes including 16 mild NPDR and 69 referable DR eyes. In Cohort 1, addition of VSD and VDI to a model using only demographic data significantly improved the model's AUC for discrimination of eyes with any DR severity from controls (0.91 [95% CI, 0.88-0.93] versus 0.80 [95% CI, 0.76-0.83], p < 0.001) and eyes with referable DR from mild NPDR (0.90 [95% CI, 0.86-0.93] versus 0.69 [95% CI, 0.64-0.75], p < 0.001). The transportability of this regression model was excellent when implemented in Cohort 2 for the referable DR versus mild NPDR comparison. The odds ratio of having any DR compared to control subjects, and referable DR compared to mild DR decreased by 15% (95% CI: 12-18%), and 13% (95% CI: 10-15%), respectively, for every 0.001 unit increase in VSD after adjusting for comorbidities. OCTA-derived capillary density has real world clinical value for rapidly assessing DR severity.

Alcohol promotes lasting neuroadaptive changes that may provide relief from depressive symptoms, often referred to as the self-medication hypothesis. However, the molecular/synaptic pathways that are shared by alcohol and antidepressants are unknown. In the current study, acute exposure to ethanol produced lasting antidepressant and anxiolytic behaviours. To understand the functional basis of these behaviours, we examined a molecular pathway that is activated by rapid antidepressants. Ethanol, like rapid antidepressants, alters γ-aminobutyric acid type B receptor (GABA B R) expression and signalling, to increase dendritic calcium. Furthermore, new GABA B Rs are synthesized in response to ethanol treatment, requiring fragile-X mental retardation protein (FMRP). Ethanol-dependent changes in GABA B R expression, dendritic signalling, and antidepressant efficacy are absent in Fmr1- knockout (KO) mice. These findings indicate that FMRP is an important regulator of protein synthesis following alcohol exposure, providing a molecular basis for the antidepressant efficacy of acute ethanol exposure. Alcohol is thought to lead to neuroadaptive changes, although the underlying molecular mechanisms are unclear. Here, the authors find ethanol treatment alters GABA B -receptor expression via fragile-X mental retardation protein in mice, leading to antidepressant-like behaviours.

IntroductionPreoperative anxiety and depression symptoms among older surgical patients are associated with poor postoperative outcomes, yet evidence-based interventions for anxiety and depression have not been applied within this setting. We present a protocol for randomised controlled trials (RCTs) in three surgical cohorts: cardiac, oncological and orthopaedic, investigating whether a perioperative mental health intervention, with psychological and pharmacological components, reduces perioperative symptoms of depression and anxiety in older surgical patients.Methods and analysisAdults ≥60 years undergoing cardiac, orthopaedic or oncological surgery will be enrolled in one of three-linked type 1 hybrid effectiveness/implementation RCTs that will be conducted in tandem with similar methods. In each trial, 100 participants will be randomised to a remotely delivered perioperative behavioural treatment incorporating principles of behavioural activation, compassion and care coordination, and medication optimisation, or enhanced usual care with mental health-related resources for this population. The primary outcome is change in depression and anxiety symptoms assessed with the Patient Health Questionnaire-Anxiety Depression Scale from baseline to 3 months post surgery. Other outcomes include quality of life, delirium, length of stay, falls, rehospitalisation, pain and implementation outcomes, including study and intervention reach, acceptability, feasibility and appropriateness, and patient experience with the intervention.Ethics and disseminationThe trials have received ethics approval from the Washington University School of Medicine Institutional Review Board. Informed consent is required for participation in the trials. The results will be submitted for publication in peer-reviewed journals, presented at clinical research conferences and disseminated via the Center for Perioperative Mental Health website.Trial registration numbersNCT05575128, NCT05685511, NCT05697835, pre-results.

The β-amyloid precursor protein (β-APP), which is involved in the pathogenesis of Alzheimer’s disease, and the Notch receptor, which is responsible for critical signalling events during development, both undergo unusual proteolysis within their transmembrane domains by unknown γ-secretases. Here we show that an affinity reagent designed to interact with the active site of γ-secretase binds directly and specifically to heterodimeric forms of presenilins, polytopic proteins that are mutated in hereditary Alzheimer’s and are known mediators of γ-secretase cleavage of both β-APP and Notch. These results provide evidence that heterodimeric presenilins contain the active site of γ-secretase, and validate presenilins as principal targets for the design of drugs to treat and prevent Alzheimer’s disease.

It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene 1 . The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches 2 – 5 . For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases 6 – 8 . This includes muscle biopsies from patients with undiagnosed rare muscle disorders 6 , 9 , and cultured fibroblasts from patients with mitochondrial disorders 7 . However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls ( n  = 1,594 unrelated controls and n  = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution. A diagnostic tool based on blood RNA-seq is shown to identify causal genes and variants linked to clinical phenotypes in individuals with rare diseases for which whole-exome genetic sequencing was uninformative.