Search

The COVID-19 pandemic hindered the ability to conduct field geology courses in a hands-on and boots-on traditional manner. In response, we designed a multi-part virtual field module that encompasses many of the basic requirements of an advanced field exercise, including designing a mapping strategy, collecting and processing field observations, synthesizing data from field-based and laboratory analyses, and communicating the results to a broad audience. For the mapping exercise, which is set in deformed Proterozoic crystalline basement exposed in the Front Range of Colorado (USA), student groups make daily navigational decisions and choose stations based on topographic maps, Google Earth satellite imagery, and iterative geological reasoning. For each station, students receive outcrop descriptions, measurements, and photographs from which they input field data and create geologic maps using StraboSpot. Building on the mapping exercise, student groups then choose from six supplements, including advanced field structure, microstructure, metamorphic petrology, and several geochronological datasets. Because scientific projects rarely end when the mapping is complete, the students are challenged to see how samples and analytical data may commonly be collected and integrated with field observations to produce a more holistic understanding of the geological history of the field area. While a virtual course cannot replace the actual field experience, modules like the one shared here can successfully address, or even improve on, some of the key learning objectives that are common to field-based capstone experiences while also fostering a more accessible and inclusive learning environment for all students.

Creating inclusive and supportive environments in science, technology, engineering, and mathematics (STEM) educational settings are important tools for countering racially hostile academic spaces and attracting and retaining talented Black and African American students. STEM faculty and other university members may display Black Lives Matter and similar "signs of solidarity" to express their support for Black students. However, how Black students perceive such signs is unknown. On the one hand, the "identity safety cue" literature suggests such signs relate to increased comfort and a sense of belonging among individuals from minoritized groups. On the other hand, some contemporary perspectives toward Black Lives Matter and other signs of solidarity have been criticized for lacking substance and impact. Given the extant literature's omission of Black students' perspectives about signs of solidarity, the current study employed semi-structured interviews and qualitative analytic methods to solicit and analyze the perspectives of 12 Black STEM graduate students. The findings revealed a general preference for some signs over others, as well as nuanced perspectives toward each sign of solidarity. Implications for STEM researchers and faculty who aspire to support Black students are discussed. Further, recommendations for adopting an "informed ally approach" are provided.

Summary Objective Minimizing program dropout is essential for weight‐loss success, but factors that influence dropout among commercial programs are unclear. This study's objective was to determine factors associated with early dropout in a commercial weight‐loss program. Methods A retrospective analysis of a remotely delivered, employer‐based commercial program from 2013 to 2016 was conducted. The dependent variable was ‘early dropout’, defined as enrollees who disengaged from telephone coaching by month 2's end. Independent variables included demographics, program website engagement and early weight change. Multivariate logistic regression analyses were used to assess for differences in early dropout by several factors, adjusted for employer clustering. Results Of the 5,274 participants, 26.8% dropped out early. Having ≥1 chronic condition (odds ratio [OR] 1.41, p

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

Abstract Objective The objective of this study was to report the 12‐month oncological outcomes for patients with non‐muscle‐invasive bladder cancer (NMIBC) within the prospective, international COVIDSurg Cancer study. Patients and methods Eligible patients were aged ≥18 years and scheduled for elective surgical management of NMIBC with curative intent (transurethral resection of bladder tumour [TURBT] or bladder biopsy) from 21 January to 14 April 2020. The primary outcome was disease recurrence within 12 months of previous elective TURBT/bladder biopsy. Secondary outcomes included disease progression within 12 months of previous elective TURBT/bladder biopsy, site‐declared delay to surgery from diagnosis as a consequence of COVID‐19 and deviation in standard care due to COVID‐19. Comparisons were made to cohorts from the pre‐pandemic era. Results Bladder cancer accounted for 2.2% (n = 446) of patients in the COVIDSurg Cancer study, with data contributed by 27 centres across 12 countries internationally. Within this included cohort, 229 patients had NMIBC and 12‐month follow‐up data available. On application of National Institute for Health and Care Excellence (NICE) criteria, 47.2% were classified as having high‐risk disease. Overall disease recurrence and progression rates were 29.3% and 9.7% at 12 months, respectively. In purely high‐risk pre‐pandemic cohorts, the International Bladder Cancer Group (IBCG) estimates a recurrence rate of 25% at 12 months, and the European Association of Urology (EAU) NMIBC 2021 scoring model estimates a 12‐month progression rate of 3.5%. As a consequence of the COVID‐19 pandemic, 10.9% of patients had site‐declared delay to TURBT/bladder biopsy; 7.4% did not undergo intravesical therapy or had early discontinuation of this; 9.2% did not undergo early repeat resection for high‐risk disease; and 18.3% had a delay to cystoscopic follow‐up surveillance. Conclusions This prospective study indicates that there were widespread deviations in usual care for NMIBC during the pandemic and that 12‐month oncological outcomes appear to be impaired compared to published pre‐pandemic outcomes.

El asfalto es un material constituido por una mezcla de diversos hidrocarburos de origen natural cuyas buenas propiedades aglutinantes e hidrofóbicas lo han llevado a ser ampliamente utilizado en aplicaciones que van desde la impermeabilización hasta la fabricación de vías. Mundialmente, la técnica de adicionar polímeros al asfalto ha permitido obtener materiales que cumplen con prestaciones que un asfalto por si solo no resistiría. En este trabajo se presenta el efecto de la modificación polimérica de un asfalto de origen colombiano en sus características: morfológicas, reológicas y térmicas con el objeto de identificar diferentes niveles de modificación. Se utilizaron como polímeros modificadores: cera de polietileno (CPE), copolímero de estireno butadieno estireno (SBS) y caucho molido de llanta (CR), que fueron adicionados al asfalto en proporciones de 3 al 15 %p/p. Los asfaltos, tanto en estado crudo como modificados, fueron caracterizados mediante ensayos de penetración y punto de ablandamiento. Las características térmicas y reológicas se analizaron mediante calorimetría diferencial de barrido (DSC) y reometría rotacional. Los cambios en la morfología se analizaron mediante microscopía de fuerza atómica (AFM). Los resultados experimentales demostraron que las mezclas con la CPE tuvieron el efecto más acentuado sobre las propiedades convencionales logrando una disminución del 75% en la penetración y un aumento 250% en el punto de ablandamiento, con respecto al asfalto sin modificar. Los resultados obtenidos mediante DSC permitieron identificar tres temperaturas de transición vítreas (Tg) en el asfalto crudo que están relacionadas con sus componentes fundamentales. Las mezclas con SBS alteraron dichas Tg evidenciando la modificación de las características térmicas del asfalto crudo. Las mezclas con CPE y SBS presentaron los mayores valores de G*. Los resultados obtenidos mediante AFM, permitieron identificar tres fases diferentes en el asfalto crudo y su variación con la adición de los polímeros modificadores, evidenciando cambios estructurales considerables que conllevaron a cambios en las características y propiedades del material a nivel macro.

Background: Change in the oxygen consumption (VO2) at the ventilatory anaerobic threshold (VAT) is an important outcome in research studies of children with congenital heart disease (CHD). The range of values reported by different raters for any given VAT is needed to contextualize a change in VAT in intervention studies. Methods: Sixty maximal cardiopulmonary exercise tests (CPET) for CHD patients 8–21 years old were independently reviewed by six exercise physiologists and four pediatric cardiologists. For each of the unique rater pairs for the 60 CPETs, the absolute difference in VAT was calculated and displayed on a histogram to demonstrate the distribution of inter-rater variability. This method was repeated for subgroups of test modality (cycle/treadmill), patient factors (diagnoses, exercise capacity), and rater factors (cardiologist/physiologist, years of experience). Results: Rater agreement was good with an intraclass correlation coefficient of 0.79–0.91 but the distribution of differences was broad. The median difference was 2.7 % predicted peak VO2 (60 mL/min, 1.0 mL/kg/min), the 75th percentile was 6.4 % (140 mL/min, 2.5 mL/kg/min), and the 95th percentile was 16.3 % (421 mL/min, 6.5 mL/kg/min). Distributions were similar for CPET modality and years of rater experience, but differed for other factors. Conclusions: The baseline distribution of reported VAT is relatively broad, varied by units, and was not explained by differences in rater experience or test modality, but varies by patient factors. When evaluating clinical relevance, a change in the VO2 at VAT in response to an intervention of

Gene therapies using recombinant adeno-associated virus (AAV) vectors have demonstrated considerable clinical success in the treatment of genetic disorders. Improved vectors with favorable tropism profiles, decreased immunogenicity, and enhanced manufacturability are poised to further improve the state of gene therapies. Such vectors can be identified through directed evolution, a process of subjecting a diverse capsid library to a selection pressure to identify individual variants with a desired trait. Currently, libraries that involve changes distributed throughout the AAV capsid coding region, such as DNA family shuffled libraries, are largely characterized using low-throughput Sanger sequencing of individual clones. However, improvements in long-read sequencing technologies have increased their applicability to capsid libraries and evaluation of the selection process. Here, we explore the application of Oxford Nanopore Technologies refined by a concatemeric consensus method for initial library characterization and monitoring selection of a shuffled AAV capsid library. Furthermore, we present AAVolve, a bioinformatic pipeline for processing long-read data from AAV-directed evolution experiments. Our approach allows high-throughput characterization of AAV capsids in a streamlined manner, facilitating deeper insights into library composition through multiple rounds of selection, and generalization through training of machine learning models.

Cardiovascular disease (CVD) is one of the top contributors to global disease burden. Meeting the physical activity guidelines can effectively control and prevent several CVD risk factors, including obesity, hypertension and diabetes mellitus. The effects of climate change are multifactorial and have direct impacts on cardiovascular health. Increasing ambient temperatures, worsening air and water quality and urbanisation and loss of greenspace will also have indirect effects of cardiovascular health by impacting the ability and opportunity to participate in physical activity. A changing climate also has implications for large scale sporting events and policies regarding risk mitigation during exercise in hot climates. This review will discuss the impact of a changing climate on cardiovascular health and physical activity and the implications for the future of organised sport.

Bitumen is a black material composed of a mixture of various natural hydrocarbons. Bitumen has been commonly used in road paving and roofing applications thanks to its hydrophobic and adhesives properties. The production of Polymer Modified Bitumens (PMB) has allowed the development of materials with better performance in comparison to pure bitumen. This work presents the effect of addition of polymer to a Colombian bitumen from its morphological, rheological and thermal properties, in order to identify different modification levels. The polymers used as modifiers were polyethylene wax (CPE), styrene butadiene styrene (SBS) and crumb rubber (CR). They were added to bitumen in proportions between 3 to 15% w / w. Both neat bitumen and PMB were characterized by penetration and softening point. Thermal and rheological characteristics were analyzed by differential scanning calorimetry (DSC) and rotational rheometry, respectively. Changes in the morphology were measured by atomic force microscopy (AFM). The experimental results showed that the CPE mixtures had the most pronounced effect on the conventional properties, achieving a 75% reduction in penetration and a 250% increase in the softening point compared to neat bitumen. The results obtained by DSC allowed identifying three glass transition temperatures (Tg) in neat bitumen. Mixtures with SBS altered Tg, showing changes on the thermal characteristics of neat bitumen. Mixtures with CPE and SBS showed the highest values of G*. The results obtained by AFM help identifying three different phases in neat bitumen and its variation with the addition of different polymer modifiers, showing considerable structural changes that led to changes in the material properties at the macroscopic level.

Homocysteine (Hcy) is a cardiovascular risk factor implicated in cognitive impairment and cerebrovascular disease but has also been associated with Alzheimer’s disease. In 160 healthy older adults (mean age = 69.66 ± 9.95 years), we sought to investigate the association of cortical brain volume with white matter hyperintensity (WMH) burden and a previously identified Hcy-related multivariate network pattern showing reductions in subcortical gray matter (SGM) volumes of hippocampus and nucleus accumbens with relative preservation of basal ganglia. We additionally evaluated the potential role of these brain imaging markers as a series of mediators in a vascular brain pathway leading to age-related cognitive dysfunction in healthy aging. We found reductions in parietal lobar gray matter associated with the Hcy-SGM pattern, which was further associated with WMH burden. Mediation analyses revealed that slowed processing speed related to aging, but not executive functioning or memory, was mediated sequentially through increased WMH lesion volume, greater Hcy-SGM pattern expression, and then smaller parietal lobe volume. Together, these findings suggest that volume reductions in parietal gray matter associated with a pattern of Hcy-related SGM volume differences may be indicative of slowed processing speed in cognitive aging, potentially linking cardiovascular risk to an important aspect of cognitive dysfunction in healthy aging.

Abstract Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important in the era of personalized medicine. Liver-directed gene therapies present a unique challenge due to the complexity of the human liver. In this work, we describe the application of whole human liver explants in an ex situ normothermic perfusion system to evaluate a set of fourteen natural and bioengineered adeno-associated viral (AAV) vectors directly in human liver, in the presence and absence of neutralizing human sera. Under non-neutralizing conditions, the recently developed AAV variants, AAV-SYD12 and AAV-LK03, emerged as the most functional variants in terms of cellular uptake and transgene expression. However, when assessed in the presence of human plasma containing anti-AAV neutralizing antibodies (NAbs), vectors of human origin, specifically those derived from AAV2/AAV3b, were extensively neutralized, whereas AAV8- derived variants performed efficiently. This study demonstrates the potential of using normothermic liver perfusion as a model for early-stage testing of liver-focused gene therapies. The results offer preliminary insights that could help inform the development of more effective translational strategies.

Abstract Adiponectin (APN) is an adipokine which predominantly expresses in adipocytes with neuroprotective and anti-inflammatory effects. We have recently indicated that circulatory trimeric APN can enter the brain by crossing the blood–brain barrier (BBB) and modulate microglia-mediated neuroinflammation. Here, we found that the microglial NLR family pyrin domain containing 3 (NLRP3)-inflammasome activation was exacerbated in APN −/− 5xFAD mice in age-dependent manner. The focus of this study was to develop a new and tractable therapeutic approach for treating Alzheimer’s disease (AD)-related pathology in 5xFAD mice using peripheral APN gene therapy. We have generated and transduced adeno-associated virus (AAV2/8) expressing the mouse mutated APN gene (APNC39S) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APNTri). Single dose of AAV2/8-APNC39S in the liver increased circulatory and cerebral APN levels indicating the overexpressed APNTri was able to cross the BBB. Overexpression of APNTri decreased both the soluble and fibrillar Aβ in the brains of 5xFAD mice. AAV2/8-APNTri treatment reduced Aβ-induced IL-1β and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APNTri-treated 5xFAD mice with reduction of dystrophic neurites. These findings demonstrate that peripheral gene delivery to overexpress trimeric APN can be a potential therapy for AD. Graphical Abstract

Background: Pharmacological interventions for depression and anxiety in older adults often have significant side effects, presenting the need for more tolerable alternatives. Transcranial direct current stimulation (tDCS) is a promising non-pharmacological intervention for depression in clinical populations. However, its effects on depression and anxiety symptoms, particularly in older adults from the general public, are understudied. Objective: We conducted a secondary analysis of the Augmenting Cognitive Training in Older Adults (ACT) trial to assess tDCS efficacy in reducing psychological symptoms in older adults. We hypothesized that active stimulation would yield greater reductions in depression and state anxiety compared to sham post-intervention and at the one-year follow-up. We also explored tDCS effects in subgroups characterized by baseline symptom severity. Methods: A sample of 378 older adults recruited from the community completed a 12-week tDCS intervention with cognitive or education training. Electrodes were placed at F3/F4, and participants received active or sham tDCS during training sessions. We assessed the association between tDCS group and changes in depression, state anxiety, and trait anxiety from baseline to post-intervention and one-year controlling for covariates. Results: The active tDCS group demonstrated greater reductions in depression and state anxiety compared to sham post-intervention, particularly in individuals with mild depression and moderate/severe state anxiety at baseline. Furthermore, the active tDCS group with moderate/severe state anxiety maintained greater symptom reductions at one-year. Conclusions: tDCS effectively reduced depression and state anxiety symptoms in a large sample of older adults. These findings highlight the importance of considering symptom severity when identifying those who may benefit most from this intervention.

This article discusses how the key players' multilayered collaboration may be enacted by the Change Laboratory methodology in the footsteps of Virkkunen and Newnham (2013) to address a complex issue for the benefit of adolescents. It can be defined as a group processing approach used by a group to solve a problem of its own defining. Over six months, members of a school community played an important role in participating in the modelling of classroom lessons with adolescents facing the new guidelines of the Canadian Cannabis Act in 2018. Drawing on the theory of expansive learning and the cultural-historical activity theory (CHAT), we used the Change Laboratory approach to dialogue on the problems and solutions to be implemented. The results examine specifically how some of the school community members contributed to the co-modelling of these lessons, taking into account the adolescents' needs in two schools. The collaboration between the members evolved over time. The vertical power hierarchy usually present in schools was modified as parents, grandparents, a medical doctor, a special education teacher, two teachers, and five students agreed to sit together to address the health issue. The qualitative analysis brings to light how the participants shared their needs and engaged in taking transformative actions to intervene directly in two high school classrooms.

Introduction: The mainstreaming of genomics across healthcare specialties necessitates that all nurses and midwives have a high literacy in genomics.Methods: We aimed to design, develop, implement and evaluate a genomics education workshop for nurses and midwives using action research principles.Results: Registered nurses and midwives completed an online survey regarding genomics confidence and learning needs (n = 274). The results of this survey were used to develop the genomics education workshop. The workshop was run three times (n = 105) with evaluation data being collected both before and after each workshop. Significant improvements in confidence across all learning domains was found following the workshops (p < 0.001). A desire for more education across all learning domains except for genetics knowledge was also identified (p < 0.001).Discussion: Genomics education workshops were found to increase the confidence of nurses and midwives across a range of specialties. Nurses and midwives also expressed a desire for further education in genomics.

Abstract INTRODUCTION We examined the relationship between sedentary behavior (SB), moderate‐to‐vigorous physical activity (MVPA), and white matter hyperintensity (WMH) volumes, a common magnetic resonance imaging (MRI) marker associated with risk of neurodegenerative disease in middle‐aged to older adults. METHODS We used data from the UK Biobank (n = 14,415; 45 to 81 years) that included accelerometer‐derived measures of SB and MVPA, and WMH volumes from MRI. RESULTS Both MVPA and SB were associated with WMH volumes (βMVPA = −0.03 [−0.04, −0.01], p

Gene therapies and associated technologies are transforming biomedical research and enabling novel therapeutic options for patients living with debilitating and incurable genetic disorders. The vector system based on recombinant adeno-associated viral vectors (AAVs) has shown great promise in recent clinical trials for genetic diseases of multiple organs, such as the liver and the nervous system. Despite recent successes toward the development of novel bioengineered AAV variants for improved transduction of primary human tissues and cells, vectors that can efficiently transduce human Schwann cells (hSCs) have yet to be identified. Here, we report the application of the functional transduction-RNA selection method in primary hSCs for the development of AAV variants for specific and efficient transgene delivery to hSCs. The two identified capsid variants, Pep2hSC1 and Pep2hSC2, show conserved potency for delivery across various in vitro, in vivo, and ex vivo models of hSCs. These novel AAV capsids will serve as valuable research tools, forming the basis for therapeutic solutions for both SC-related disorders or peripheral nervous system injury.

Despite the availability of life-saving corticosteroids for 70 years, treatment for adrenal insufficiency is not able to recapitulate physiological diurnal cortisol secretion and results in numerous complications. Gene therapy is an attractive possibility for monogenic adrenocortical disorders such as congenital adrenal hyperplasia; however, requires further development of gene transfer/editing technologies and knowledge of the target progenitor cell populations. Vectors based on adeno-associated virus are the leading system for direct in vivo gene delivery but have limitations in targeting replicating cell populations such as in the adrenal cortex. One strategy to overcome this technological limitation is to deliver the relevant adrenocortical gene to a currently targetable organ outside of the adrenal cortex. To explore this possibility, we developed a vector encoding human 21-hydroxylase and directed expression to the liver in a mouse model of congenital adrenal hyperplasia. This extra-adrenal expression resulted in reconstitution of the steroidogenic pathway. Aldosterone and renin levels normalized, and corticosterone levels improved sufficiently to reduce adrenal hyperplasia. This strategy could provide an alternative treatment option for monogenic adrenal disorders, particularly for mineralocorticoid defects. These findings also demonstrate, when targeting the adrenal gland, that inadvertent liver transduction should be precluded as it may confound data interpretation.

IntroductionWe aimed to establish if stereotactic body radiotherapy to the prostate can be delivered safely using reduced clinical target volume (CTV) to planning target volume (PTV) margins on the 1.5T MR-Linac (MRL) (Elekta, Stockholm, Sweden), in the absence of gating.MethodsCine images taken in 3 orthogonal planes during the delivery of prostate SBRT with 36.25 Gray (Gy) in 5 fractions on the MRL were analysed. Using the data from 20 patients, the percentage of radiotherapy (RT) delivery time where the prostate position moved beyond 1, 2, 3, 4 and 5 mm in the left-right (LR), superior-inferior (SI), anterior-posterior (AP) and any direction was calculated.ResultsThe prostate moved less than 3 mm in any direction for 90% of the monitoring period in 95% of patients. On a per-fraction basis, 93% of fractions displayed motion in all directions within 3 mm for 90% of the fraction delivery time. Recurring motion patterns were observed showing that the prostate moved with shallow drift (most common), transient excursions and persistent excursions during treatment.ConclusionA 3 mm CTV-PTV margin is safe to use for the treatment of 5 fraction prostate SBRT on the MRL, without gating. In the context of gating this work suggests that treatment time will not be extensively lengthened when an appropriate gating window is applied.

Materials that generate structural color may be promising alternatives to dyes and pigments due to their relative long-term stability and environmentally benign properties. Liquid crystal (LC) mixtures of cholesteryl esters demonstrate structural color due to light reflected from the helical structure of the self-assembled molecules. The apparent color depends on the pitch length of the liquid crystal. While a wide range of colors have been achieved with such LC formulations, the nature of the pitch–concentration relationship has been difficult to define. In this work, various machine learning approaches to predict the reflected wavelength, i.e., the position of the selective reflection band, based on LC composition are compared to a Scheffe cubic model. The neural network regression model had a higher root mean squared error (RMSE) than the Scheffe cubic model with improved predictions for formulations not included in the dataset. Decision tree regression provided the best overall performance with the lowest RMSE and predicted position of the selective reflection band within 0.8% of the measured values for LC formulations not included in the dataset. The predicted values using the decision tree were over two-fold more accurate than the Scheffe cubic model. These results demonstrate the utility of machine learning models for predicting physical properties of LC formulations.

Prescriptions for fuel management are universally applied across the forest types in British Columbia, Canada, to reduce the fire behaviour potential in the wildland–urban interface. Fuel thinning treatments have been advocated as a means of minimizing the likelihood of crown fire development in conifer forests. We hypothesized that these types of prescriptions are inappropriate for the coastal rainforests of the Whistler region of the province. Our study examined the impact of fuel thinning treatments in four stands located in the Whistler community forest. We measured several in-stand microclimatic variables beginning with snow melt in the spring up to the height of fire danger in late summer, at paired thinned and unthinned stand locations. We found that the thinning led to warmer, drier, and windier fire environments. The difference in mean soil moisture, ambient air temperature, and relative humidity between thinned and unthinned stands was significant in the spring with approximate p-values of 0.000217, 9.40 × 10−5, and 4.33 × 10−8, respectively, though there were no discernible differences in the late summer. The difference in mean solar radiation, average wind speed, and average cross wind between thinned and unthinned locations are significant in the spring and late summer (with approximate p-values for spring of 9.54 × 10−7, 0.02101, 1.92 × 10−9, and for late summer of 2.45 × 10−7, 4.08 × 10−6, and 2.45 × 10−5, respectively).

Abstract Background The veterinary care of cats and dogs is increasingly embracing innovations first applied to human health, including an increased emphasis on preventative care and precision medicine. Large scale human population biobanks have advanced research in these areas; however, few have been established in veterinary medicine. The MARS PETCARE BIOBANK™ (MPB) is a prospective study that aims to build a longitudinal bank of biological samples, with paired medical and lifestyle data, from 20,000 initially healthy cats and dogs (10,000 / species), recruited through veterinary hospitals over a ten-year period. Here, we describe the MPB protocol and discuss its potential as a platform to increase understanding of why and how diseases develop and how to advance personalised veterinary healthcare. Methods At regular intervals, extensive diet, health and lifestyle information, electronic medical records, clinicopathology and activity data are collected, genotypes, whole genome sequences and faecal metagenomes analysed, and blood, plasma, serum, and faecal samples stored for future research. Discussion Proposed areas for research include the early detection and progression of age-related disease, risk factors for common conditions, the influence of the microbiome on health and disease and, through genome wide association studies, the identification of candidate loci for disease associated genetic variants. Genomic data will be open access and research proposals for access to data and samples will be considered. Over the coming years, the MPB will provide the longitudinal data and systematically collected biological samples required to generate important insights into companion animal health, identifying biomarkers of disease, supporting earlier identification of risk, and enabling individually tailored interventions to manage disease.

Hippocampal volume is particularly sensitive to the accumulation of total brain white matter hyperintensity volume (WMH) in aging, but how the regional distribution of WMH volume differentially impacts the hippocampus has been less studied. In a cohort of 194 healthy older adults ages 50–89, we used a multivariate statistical method, the Scaled Subprofile Model (SSM), to (1) identify patterns of regional WMH differences related to left and right hippocampal volumes, (2) examine associations between the multimodal neuroimaging covariance patterns and demographic characteristics, and (3) investigate the relation of the patterns to subjective and objective memory in healthy aging. We established network covariance patterns of regional WMH volume differences associated with greater left and right hippocampal volumes, which were characterized by reductions in left temporal and right parietal WMH volumes and relative increases in bilateral occipital WMH volumes. Additionally, we observed lower expression of these hippocampal-related regional WMH patterns were significantly associated with increasing age and greater subjective memory complaints, but not objective memory performance in this healthy older adult cohort. Our findings indicate that, in cognitively healthy older adults, left and right hippocampal volume reductions were associated with differences in the regional distribution of WMH volumes, which were exacerbated by advancing age and related to greater subjective memory complaints. Multivariate network analyses, like SSM, may help elucidate important early effects of regional WMH volume on brain and cognitive aging in healthy older adults.

(1) Background: The electroencephalogram (EEG) is frequently corrupted by ocular artifacts such as saccades and blinks. Methods for correcting these artifacts include independent component analysis (ICA) and recursive-least-squares (RLS) adaptive filtering (-AF). Here, we introduce a new method, AFFiNE, that applies Bayesian adaptive regression spline (BARS) fitting to the adaptive filter’s reference noise input to address the known limitations of both ICA and RLS-AF, and then compare the performance of all three methods. (2) Methods: Artifact-corrected P300 morphologies, topographies, and measurements were compared between the three methods, and to known truth conditions, where possible, using real and simulated blink-corrupted event-related potential (ERP) datasets. (3) Results: In both simulated and real datasets, AFFiNE was successful at removing the blink artifact while preserving the underlying P300 signal in all situations where RLS-AF failed. Compared to ICA, AFFiNE resulted in either a practically or an observably comparable error. (4) Conclusions: AFFiNE is an ocular artifact correction technique that is implementable in online analyses; it can adapt to being non-stationarity and is independent of channel density and recording duration. AFFiNE can be utilized for the removal of blink artifacts in situations where ICA may not be practically or theoretically useful.

Under pathological conditions such as multiple sclerosis (MS), leukocytes infiltrate the central nervous system where they, in concert with activated microglia, promote inflammatory demyelination resulting in a broad spectrum of symptoms, including paralysis. Therefore, all current therapeutic approaches to MS target the immune system, blocking inflammation and paralysis progression, but may compromise the immune system. In this focused review, we present an underestimated compartment, the blood–brain barrier, which is compromised during MS and becomes permeable to leukocytes infiltrating the central nervous system. This barrier has the potential to offer new therapeutic strategies and is easily accessible for drugs. We highlight this paradigm using the example of the therapeutic anti-Reelin strategy we have developed. Reelin is a plasma protein that regulates the expression of adhesion markers on the endothelial surface, thus promoting the infiltration of inflammatory cells and propagating inflammation. Building Back a Better Blood–Brain Barrier (the “6B” strategy) may have advantages compared to actual immunosuppressive drugs because it restores a physiological function rather than suppressing the immune system.

Recent clinical successes have intensified interest in using adeno-associated virus (AAV) vectors for therapeutic gene delivery. The liver is a key clinical target, given its critical physiological functions and involvement in a wide range of genetic diseases. Here, we report the bioengineering of a set of next-generation AAV vectors, named AAV-SYDs (where “SYD” stands for Sydney, Australia), with increased human hepato-tropism in a liver xenograft mouse model repopulated with primary human hepatocytes. We followed a two-step process that staggered directed evolution and domain-swapping approaches. Using DNA-family shuffling, we first mapped key AAV capsid regions responsible for efficient human hepatocyte transduction in vivo. Focusing on these regions, we next applied domain-swapping strategies to identify and study key capsid residues that enhance primary human hepatocyte uptake and transgene expression. Our findings underscore the potential of AAV-SYDs as liver gene therapy vectors and provide insights into the mechanism responsible for their enhanced transduction profile.

Characterising interspecific interaction strengths, combined with population abundances of prey and their novel predators, is critical to develop predictive invasion ecology. This is especially true of aquatic invasive species, which can pose a significant threat to the structure and stability of the ecosystems to which they are introduced. Here, we investigated consumer-resource dynamics of two globally-established aquatic invasive species, European green crab (Carcinus maenas) and brown trout (Salmo trutta). We explored the mediating effect of prey density on predatory impact in these invaders relative to functionally analogous native rock crab (Cancer irroratus) and Atlantic salmon (Salmo salar), respectively, feeding on shared prey (Mytilus sp. and Tenebrio molitor, respectively). We subsequently combined feeding rates with each predator’s regional abundance to forecast relative ecological impacts. All predators demonstrated potentially destabilising Type II functional responses towards prey, with native rock crab and invasive brown trout exhibiting greater per capita impacts relative to their trophic analogues. Functional Response Ratios (attack rates divided by handling times) were higher for both invasive species, reflecting greater overall per capita effects compared to natives. Impact projections that incorporated predator abundances with per capita effects predicted severe impacts by European green crabs. However, brown trout, despite possessing higher per capita effects than Atlantic salmon, are projected to have low impact owing to currently low abundances in the sampled watershed. Should brown trout density increase sixfold, we predict it would exert higher impact than Atlantic salmon. Such impact-forecasting metrics and methods are thus vital tools to assist in the determination of current and future adverse impacts associated with aquatic invasive species.

Recent successes in clinical gene therapy applications have intensified the interest in using adeno-associated viruses (AAVs) as vectors for gene delivery into human liver. An inherent intriguing characteristic of AAVs is that vector variants vary substantially in their ability to transduce hepatocytes from different species. This has historically limited the value of preclinical studies using rodent models for predicting the efficiency of AAV vectors in liver-targeted gene therapy clinical studies. In this work, we aimed to investigate the key determinants of the observed differential interspecies transduction abilities among AAV variants. We took advantage of domain swapping strategies between AAV-KP1, a newly identified variant with enhanced murine liver tropism, and AAV3b, which functions poorly in mice. The systematic in vivo comparison of AAV3b/AAV-KP1 chimeric variants allowed us to identify a threonine insertion at position 265 within variable region I (VR-I) as the key residue that confers murine hepatic transduction to human-derived clade B (AAV2-like) and clade C (AAV3b-like) variants. We propose to use this insertion to generate phylogenetically related AAV surrogates in support of toxicology and dosing studies in the murine liver model.