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Abstract Interest in winter limnology is growing rapidly, but progress is hindered by a shortage of standardized multivariate datasets on winter conditions. Addressing the winter data gap will enhance our understanding of winter ecosystem function and of lake response to environmental change. Here, we describe a dataset generated by a multi‐institutional winter sampling campaign across all five Laurentian Great Lakes and some of their connecting waters (the Great Lakes Winter Grab). The objective of Winter Grab was to characterize mid‐winter limnological conditions in the Great Lakes using standard sample collection and analysis methods. Nineteen research groups sampled 49 locations varying widely in depth and trophic status, collecting a range of limnological data. This dataset includes physical, chemical, and biological measurements. These data can be used to examine diverse aspects of Great Lakes ecosystems or integrated with winter observations from other lakes to improve understanding of winter limnology across different aquatic systems.

Abstract Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP1,2) are the standard of care for Ebola virus disease (EVD). Anti-GP1,2 mAbs targeting the stalk and membrane proximal external region (MPER) potently neutralize EBOV in vitro and are protective in a mouse model of EVD. However, their neutralization mechanism is poorly understood because they target a GP1,2 epitope that has evaded structural characterization. Using X-ray crystallography and cryo-electron tomography of mAb 3A6 complexed with its stalk–MPER epitope, we reveal a previously undescribed mechanism in which 3A6 binds to a conformation of GP1,2 that is lifted from the virion membrane. We further show that in both domestic guinea pig and rhesus monkey EVD models, 3A6 provides therapeutic benefit at high-viremia advanced disease stages and at the lowest dose yet demonstrated for any anti-EBOV mAb-based monotherapy. The findings reported here can guide design of next-generation highly potent anti-EBOV therapeutics and vaccines.

Abstract With current treatments addressing only a fraction of pathogens and new viral threats constantly evolving, there is a critical need to expand our existing therapeutic arsenal. To speed the rate of discovery and better prepare against future threats, we establish a high-throughput platform capable of screening compounds against 40 diverse viral proteases simultaneously. This multiplex approach is enabled by using cellular biosensors of viral protease activity combined with DNA-barcoding technology, as well as several design innovations that increase assay sensitivity and correct for plate-to-plate variation. Among >100,000 compound-target interactions explored within our initial screen, a series of broad-acting inhibitors against coronavirus proteases were uncovered and validated through orthogonal assays. A medicinal chemistry campaign was performed to improve one of the inhibitor’s potency while maintaining its broad activity. This work highlights the power of multiplex screening to efficiently explore chemical space at a fraction of the time and costs of previous approaches.

Purpose: Functional recovery from peripheral nerve injuries remains unpredictable and continues to pose a major clinical challenge to surgeons. This study sought to investigate the utility of intraoperative nerve stimulation following neurolysis surgery as a prognostic indicator of functional recovery. Methods: A retrospective chart review of adult patients who underwent peripheral nerve neurolysis between September 2021 and December 2022 was performed. A handheld nerve stimulator was used intraoperatively before and after neurolysis. Patients with preoperative motor deficits corresponding to the nerve that underwent neurolysis, intraoperative nerve stimulation, and postoperative follow-up length of at least 3 months were included. Muscle strength as measured by the Medical Research Council scale was used to evaluate nerve function. A scale grade of 0 or 1 meant “no recovery,” between 2 and 4 was classified as “partial recovery,” and 5 was classified as “full recovery.” Fisher exact tests were employed to test for an association between stimulation thresholds and functional recovery. Results: A total of 27 patients and 45 nerves were included in the study, with a mean follow-up of 8.0 months. Intraoperative stimulation at 0.5 mA was observed in 73% (33/45) of nerves, with 76% achieving full recovery, 18% partial recovery, and 6% no recovery. Two nerves stimulated at 2 mA and one at 20 mA, with both showing partial recovery. In contrast, 22% (10/45) of nerves showed no stimulation, leading to full recovery in 20%, partial recovery in 30%, and no recovery in 50% of cases. A significant (P < .001) association was found between stimulation thresholds and functional recovery. Conclusions: Intraoperative nerve stimulation is strongly linked to functional recovery postneurolysis, demonstrating its potential as a prognostic tool for guiding surgical decisions. Type of study/level of evidence: Prognostic, IV.

Abstract Spinal cord injury (SCI) is a significant cause of lifelong disability, with no available disease-modifying treatments to promote neuroprotection and axon regeneration after injury. Photobiomodulation (PBM) is a promising therapy which has proven effective at restoring lost function after SCI in pre-clinical models. However, the precise mechanism of action is yet to be determined. Here, we used an in-vivo model of SCI in adult rats that received daily PBM (660 nm, 24 mW/cm2, 1 min) and at three days post-injury, the injured spinal cord segment was harvested and subjected to whole transcriptome sequencing and subsequent pathway analysis (generally applicable gene-set enrichment (GAGE)). Pathway analysis demonstrated 1275 differentially expressed genes (DEGs) after PBM treatment, of which 397 were upregulated and 878 were downregulated. Key pathways were significantly enriched, including 8.6-fold enrichment of “neuron projection morphogenesis” (adjusted p = 8.10 × 10− 14), with upregulation of Notch3, Slit1/Robo2 and Sema3g pathways. Ribosomal and oxidative phosphorylation pathways and NADH dehydrogenase were downregulated, and there was upregulation of ATP-dependent activity, cAMP and calcium signalling pathways. Key genes in apoptotic pathways were downregulated, as were S100 and cyclo-oxygenase components. Together, our study supports the favourable effects of PBM in promoting neuroregeneration and suppressing apoptosis after neurological injury. Further findings from pathway analysis suggest that downregulation of metabolism-associated pathways is a mechanism by which acute post-injury mitochondrial dysfunction may be averted by PBM therapy.

Abstract The rapid advancements in additive manufacturing (AM) across different scales and material classes have enabled the creation of architected materials with highly tailored properties. Beyond geometric flexibility, multi-material AM further expands design possibilities by combining materials with distinct characteristics. While machine learning has recently shown great potential for the fast inverse design of lattice structures, its application has largely been limited to single-material systems. In this work, we propose a novel approach that incorporates material properties as edge features within the graph representation of multi-material truss lattices, utilizing graph neural networks (GNNs) to develop a fast and efficient inverse design framework. We validate this framework by designing lattices with tunable thermal expansion and stiffness properties, showcasing its ability to explore a broad and flexible design space. We showcase the framework’s inverse design capabilities for both single and multi-objective optimization tasks and assess its limitations. Additionally, we demonstrate the superior capacity of GNNs in capturing structure-property relationships for multi-material systems. We anticipate that the continued advancement of GNN-assisted inverse design will play a key role in unlocking the full potential of multi-material truss lattices.

Abstract Assembly of actin-based stereocilia is critical for cochlear hair cells to detect sound. To tune their mechanosensivity, stereocilia form bundles composed of graded rows of ascending height, necessitating the precise control of actin polymerization. Myosin 15 (MYO15A) drives hair bundle development by delivering critical proteins to growing stereocilia that regulate actin polymerization via an unknown mechanism. Here, we show that MYO15A is itself an actin nucleation-promoting factor. Moreover, a deafness-causing mutation in the MYO15A actin-binding interface inhibits nucleation activity but still preserves some movement on filaments in vitro and partial trafficking on stereocilia in vivo. Stereocilia fail to elongate correctly in this mutant mouse, providing evidence that MYO15A-driven actin nucleation contributes to hair bundle biogenesis. Our work shows that in addition to generating force and motility, the ATPase domain of MYO15A can directly regulate actin polymerization and that disrupting this activity can promote cytoskeletal disease, such as hearing loss.

Abstract The simultaneous administration of multiple drugs within identical nanocarriers to cancer cells or tissues can result in the effective action of drugs at reduced concentrations. In this investigation, PAMAM dendrimers (G4-PAMAM) were employed to link with methotrexate (MTX) using DCC/NHS chemistry and followed by the entrapment of curcumin (Cur) within it. The establishment of covalent bonds between MTX and the PAMAM dendrimer led to PAMAM-MTX interaction, verified and described through FT-IR. Various techniques were employed to evaluate the structural properties of the prepared Cur-PAMAM-MTX NC. The Cur-PAMAM-MTX NC, after preparation, exhibited a particle size of 249 nm, with an encapsulation efficiency (EE) of ~ 81% for Cur. The cumulative in vitro release of Cur-loaded NC indicated a controlled release influenced by time and pH. The cell study results revealed that Cur-PAMAM-MTX NC exhibited significantly higher cytotoxicity than free MTX, Cur, and other formulations tested in vitro. The synergistic effect of co-delivery of MTX and Cur by PAMAM significantly increased cytotoxicity. Besides, the significant ROS level rising has been shown in the treated cells with MTX-PAMAM-Cur. Considering these findings, the co-delivery NC shows promise for additional in vitro investigations and possesses the capacity to function as an effective framework for the combined delivery of MTX and Cur in cervical cancer chemotherapy.

Abstract Background Rotator cuff repairs may fail because of compromised blood supply, suture anchor pullout, or poor fixation to bone. To augment the repairs and promote healing of the tears, orthobiologics, such a platelet-rich plasma (PRP), and biologic scaffolds have been applied with mixed results. Adipose allograft matrix (AAM), which recruits native cells to damaged tissues, may also be a potential treatment for rotator cuff tears. Methods To assess the potential use of AAM on rotator cuff tears, humeral head cartilage and subscapularis tendon were collected from patients undergoing reverse shoulder arthroplasty (RSA). Punch biopsies of the tissues were used to create explants for tissue culture, and the remaining tissue was digested to isolate the chondrocytes and tenocytes for cell culture. Explants and cells were then cultured in media containing AAM. After 48 h, the tissues and cells were measured for cell viability, cell proliferation, extracellular matrix (ECM) and metalloproteinase (MMP) gene expression and for MMP, inflammatory cytokine, and growth factor concentrations. Results Cell viability was increased in humeral head chondrocytes and rotator cuff tenocytes cultured with AAM. Gene expression of the matrix proteoglycan, aggrecan, and of the proteolytic enzyme MMP-13 were downregulated in humeral head chondrocytes. MMP-13 concentrations were increased in subscapularis tenocytes and in humeral head chondrocyte/subscapularis tenocyte co-cultures. The anti-inflammatory cytokine, IL-1ra was increased in cartilage/tendon explant co-cultures. TGF-β1 concentrations were increased in chondrocytes, but decreased in tenocytes. Conclusions Overall, AAM had no significant negative effects on the cells or explants. The results of these experiments provide the basis for the future use of AAM as a scaffolding for tissue engineering, preclinical animal models of rotator cuff tear and glenohumeral osteoarthritis, and clinical models. Clinical trial number Not applicable.

Abstract Dysregulation in aversive contextual processing is believed to affect several forms of psychopathology, including post-traumatic stress disorder (PTSD). The dentate gyrus (DG) is an important brain region in contextual discrimination and disambiguation of new experiences from prior memories. The DG also receives dense projections from the locus coeruleus (LC), the primary source of norepinephrine (NE) in the mammalian brain, which is active during stressful events. However, how noradrenergic dynamics impact DG-dependent function during contextual discrimination and pattern separation remains unclear. Here, we report that aversive contextual processing in mice is linked to linear elevations in tonic norepinephrine release dynamics within the DG and report that this engagement of prolonged norepinephrine release is sufficient to produce contextual disambiguation, even in the absence of a salient aversive stimulus. These findings suggest that spatiotemporal ramping characteristics of LC-NE release in the DG during stress likely serve an important role in driving contextual processing.

Clinical trials previously demonstrated the notable capacity to elicit visual percepts in individuals with visual impairments caused by retinal diseases by electrically stimulating the remaining neurons on the retina. However, these implants restored very limited visual acuity and required transcutaneous cables traversing the eyeball, leading to reduced reliability and complex surgery with high postoperative infection risks. To overcome the limitations imposed by cables, a retinal implant architecture in which near-infrared illumination carries both power and data through the pupil to a digital stimulation controller is presented. A high efficiency multi-junction photovoltaic cell transduces the optical power to a CMOS stimulator capable of delivering flexible interleaved sequential stimulation through a diamond microelectrode array. To demonstrate the capacity to elicit a neural response with this approach while complying with the optical irradiance limit at the pupil, fluorescence imaging with a calcium indicator is used on a degenerate rat retina. The power delivered by the laser at the permissible irradiance of 4 mW/mm2 at 850 nm is shown to be sufficient to both power the stimulator ASIC and elicit a response in retinal ganglion cells (RGCs), with the ability to generate of up to 35 000 pulses per second at the average stimulation threshold. This confirms the feasibility of generating a response in RGCs with an infrared-powered digital architecture capable of delivering complex sequential stimulation patterns at high repetition rates, albeit with some limitations.

Abstract Background The search for alternatives to antibiotic growth promoters in poultry production has increased interest in probiotics. However, the complexity of the interactions between probiotics, gut microbiome, and the host hinders the development of effective probiotic interventions. This study explores metabolic modelling to examine the possibility of designing informed probiotic interventions within poultry production. Results Genomic metabolic models of fungi were generated and simulated in the context of poultry gut microbial communities. The modelling approach correlated with short-chain fatty acid production, particularly in the caecum. Introducing fungi to poultry microbiomes resulted in strain-specific and diet-dependent effects on the gut microbiome. The impact of fungal probiotics on microbiome diversity and pathogen inhibition varied depending on the specific strain, resident microbiome composition, and host diet. This context-dependency highlights the need for tailored probiotic interventions that consider the unique characteristics of each poultry production environment. Conclusions This study demonstrates the potential of metabolic modelling to elucidate the complex interactions between probiotics, the gut microbiome, and diet in poultry. While the effects of specific fungal strains were found to be context-dependent, the approach itself provides a valuable tool for designing targeted probiotic interventions. By considering the specific characteristics of the host microbiome and dietary factors, this methodology could guide the deployment of effective probiotics in poultry production. However, the current work relies on computational predictions, and further in vivo validation studies are needed to confirm the efficacy of the identified probiotic candidates. Nonetheless, this study represents a significant step in using metabolic models to inform probiotic interventions in the poultry industry. Video Abstract

Objective: The study objective was to investigate the effect of free-edge length on valve performance in bicuspidization repair of congenitally diseased aortic valves. Methods: In addition to a constructed unicuspid aortic valve disease model, 3 representative groups—free-edge length to aortic diameter ratio 1.2, 1.57, and 1.8—were replicated in explanted porcine aortic roots (n = 3) by adjusting native free-edge length with bovine pericardium. Each group was run on a validated ex vivo univentricular system under physiological parameters for 20 cycles. All groups were tested within the same aortic root to minimize inter-root differences. Outcomes included transvalvular gradient, regurgitation fraction, and orifice area. Linear mixed effects model and pairwise comparisons were used to compare outcomes across groups. Results: The diseased control group had a mean transvalvular gradient of 28.3 ± 5.5 mm Hg, regurgitation fraction of 29.6% ± 8.0%, and orifice area of 1.03 ± 0.15 cm2. In ex vivo analysis, all repair groups had improved regurgitation and transvalvular gradient compared with the diseased control group (P

Abstract Despite significant technological progress in prosthetic hands, a device with functionality akin to a biological extremity is far from realization. To better support the development of next-generation technologies, we investigated the grasping capabilities of clinically prescribable and commercially available (CPCA) prosthetic hands against those that are 3D-printed, which offer cost-effective and customizable solutions. Our investigation utilized the Anthropomorphic Hand Assessment Protocol (AHAP) as a benchtop evaluation of the multi-grasp performance of 3D-printed devices against CPCA prosthetic hands. Our comparison sample included three open-source 3D-printed prosthetic hands (HACKberry Hand, HANDi Hand, and BEAR PAW) and three CPCA prosthetic hands (Össur i-Limb Quantum, RSL Steeper BeBionic Hand V3, and Psyonic Ability Hand), along with including previously published AHAP data for four additional 3D-printed hands (Dextrus v2.0, IMMA, InMoov, and Limbitless). Our findings revealed a notable grasping performance disparity, with 3D-printed prostheses generally underperforming compared to their CPCA counterparts, specifically in cylindrical, diagonal volar, extension, and spherical grips. We propose that the observed performance shortfalls are likely attributed to the design or build quality of the 3D-printed prostheses, owing to the fact that 3D-printed hands often have a lower technology readiness level for widespread use. Addressing the limitations highlighted in this work and subsequent research will play a crucial role in refining the design and functionality of both 3D-printed and CPCA prosthetic devices.

Motivation: The analysis of circulating cell-free DNA (cfDNA) holds immense promise as a non-invasive diagnostic tool across various human conditions. However, extracting biological insights from cfDNA fragments entails navigating complex and diverse bioinformatics methods, encompassing not only DNA sequence variation, but also epigenetic characteristics like nucleosome footprints, fragment length, and methylation patterns. Results: We introduce Liquid Biopsy Feature extract (LBFextract), a comprehensive package designed to streamline feature extraction from cfDNA sequencing data, with the aim of enhancing the reproducibility and comparability of liquid biopsy studies. LBFextract facilitates the integration of preprocessing and postprocessing steps through alignment fragment tags and a hook mechanism. It incorporates various methods, including coverage-based and fragment length-based approaches, alongside two novel feature extraction methods: an entropy-based method to infer TF activity from fragmentomics data and a technique to amplify signals from nucleosome dyads. Additionally, it implements a method to extract condition-specific differentially active TFs based on these features for biomarker discovery. We demonstrate the use of LBFextract for the subtype classification of advanced prostate cancer patients using coverage signals at transcription factor binding sites from cfDNA. We show that LBFextract can generate robust and interpretable features that can discriminate between different clinical groups. LBFextract is a versatile and user-friendly package that can facilitate the analysis and interpretation of liquid biopsy data. Data and Code Availability and Implementation: LBFextract is freely accessible at https://github.com/Isy89/LBF. It is implemented in Python and compatible with Linux and Mac operating systems. Code and data to reproduce these analyses have been uploaded to 10.5281/zenodo.10964406.

Objectives: This study aimed to identify novel fosfomycin resistance genes across diverse environmental samples, ranging in levels of anthropogenic pollution. We focused on fosfomycin resistance, and given its increasing clinical importance, explored the prevalence of these genes within different environmental contexts. Methods: Metagenomic DNA was extracted from wastewater and sediment samples collected from sites in India, Sweden, and Antarctica. Class 1 integron gene cassette libraries were prepared, and resistant clones were selected on fosfomycin-supplemented media. Long-read sequencing was performed followed by bioinformatics analysis to identify novel fosfomycin resistance genes. The genes were cloned and functionally characterized in E. coli, and the impact of phosphonoformate on the enzymes was assessed. Results: Four novel fosfomycin resistance genes were identified. Phylogenetic analysis placed these genes within the FosX family, a group of metalloenzymes that hydrolyse fosfomycin without thiol conjugation. The genes were subsequently renamed fosE2, fosI2, fosI3, and fosP. Functional assays confirmed that these genes conferred resistance to fosfomycin in E. coli, with MIC ranging from 32 μg/ml to 256 μg/ml. Unlike FosA/B enzymes, these FosX-like proteins were resistant to phosphonoformate inhibitory action. A fosI3 homolog was identified in Pseudomonas aeruginosa, highlighting potential clinical relevance. Conclusions: This study expands the understanding of fosfomycin resistance by identifying new FosX family members across diverse environments. The lack of phosphonoformate inhibition underscores the clinical importance of these poorly studied enzymes, which warrant further investigation, particularly in pathogenic contexts.

Background: Heart attacks caused by spontaneous coronary artery dissection (SCAD) are traumatic events. While stressful, traumatic events can also be catalysts for positive growth. Aims: This study investigated the nature, prevalence, and correlates of posttraumatic growth (PTG) after SCAD. Methods: A mixed-methods approach was used. Part 1 involved seven focus groups with SCAD survivors (n = 30), the findings of which were analyzed thematically. Part 2 involved an online survey of SCAD survivors (n = 263), which included the PTG inventory (PTGI). Bivariate and multivariable analyses determined the significant correlates of PTG after SCAD. Results: Part 1 revealed four key themes, namely appreciating life and living in the moment, personal agency, new work-life balance, and spiritual clarity. Part 2 demonstrated that 79% of participants reported some degree of PTG. The mean total PTGI score was 46.4; standard deviation = 25.5. In terms of PTGI factors, the most common aspects of growth were appreciation of life and personal strength. PTG was significantly associated (P < 0.05) with education, partner status, living arrangements, presence of a close confidante, social support, time since SCAD, number of SCADs, and cardiac rehabilitation (CR) attendance. Variables retained in the multivariable model were younger age, mid-level education, high social support, being nondepressed, longer time since SCAD, greater number of SCADs, and CR attendance. Conclusion: This is the first study to demonstrate that, despite the associated stresses and challenges, there is a great potential for positive growth after SCAD. These findings have implications for the development and targeting of interventions to support post-SCAD recovery.

Austenitization is significant for understanding the microstructure and residual stress evolution in additive manufacturing of non-austenitic steels. However, the accurate modeling of austenite transformation of additively manufactured parts is rarely reported. In this work, a new kinetic model is proposed to describe the diffusional austenitization of additively manufactured 17-4 PH martensitic stainless steel. The proposed kinetic model is based on the classic Johnson-Mehl-Avrami-Kolmogorov (JMAK) theory, and incorporates a new austenite grain growth model that accounts for the maximum austenite grain size and the effective driving force for growth. Experimental results obtained through dilatometry show that the proposed kinetic model is able to fit and predict the austenite transformation curves across a wide range of heating rates. This model accurately predicts the saturated austenite fraction by maximum austenite grain size and facilitates the understanding of the effect of heating rate on diffusional austenite transformation behavior. The findings imply that the drag force restricting the maximum austenite grain size originates from the initial martensitic microstructure. The transition from the diffusional austenitization to massive or displacive phase transformation at the heating rate of 100 °C/s is identified for additively manufactured 17-4 PH martensitic stainless steel.

The chemosensor properties of a bimetallic terbium(III)/copper(II) complex functionalized with a 4-(2-pyridyl)-1,2,3-triazole ligand for the detection of Cu2+ ions and, aqueous and gaseous hydrogen sulfide was investigated. The 4-(2-pyridyl)-1,2,3-triazole ligand functions both as an antenna chromophore and a receptor for Cu2+ ions; the Cu2+ complex was shown to be a chemosensor for the detection of aqueous hydrogen sulfide. The chemosensor exhibited significant reversibility over multiple cycles, observed with the sequential addition of Na2S followed by Cu2+ ions. The limit of detection for aqueous hydrogen sulfide was 0.63 μM (20 ppb). No luminescent changes of the bimetallic terbium(III)/copper(II) complex were observed in the presence of gaseous hydrogen sulfide, and thus this sensor can only be used for the detection of aqueous hydrogen sulfide.

Abstract C-terminal α-amidated peptides are attractive therapeutic targets, but preparative methods to access amidated pharmaceuticals are limited both on lab and manufacturing-scale. Here we report a straightforward and scalable approach to the C-terminal α-amidation of peptides and proteins from cysteine-extended polypeptide precursors. This amidation protocol consists of three highly efficient steps: 1) selective cysteine thiol substitution with a photolabel, 2) photoinduced decarboxylative elimination and 3) enamide cleavage by simple acidolysis or inverse electron demand Diels-Alder reaction. We provide a blueprint for applying this protocol to the semi-recombinant production of therapeutically relevant targets where gram scale C-terminal α-amidation is achieved in a photoflow reactor on a recombinantly prepared peptide YY analogue and a GLP-1/amylin co-agonist precursor peptide. Robust performance of this reaction cascade in flow highlights the potential of this chemistry to enable amidated drug leads to enter development that would not be viable on commercial scale using existing technology.

Abstract Ceramides are lipids that play vital roles in complex lipid synthesis, membrane function, and cell signaling. Disrupted ceramide homeostasis is implicated in cell-death and several neurologic diseases. Ceramides are often analyzed in tissue, but this approach fails to resolve cell-type differences in ceramide homeostasis that are likely essential to understanding cell and non-cell autonomous contributions to neurodegeneration. We show that human iPSC-derived neurons and glia differ in their rate of ceramide synthesis, ceramide isoform composition, and responses to altered ceramide levels. RNA-sequencing of cells treated to increase or decrease ceramides revealed connections to inflammation, ER stress, and apoptosis. Moreover, introducing labeled sphinganine showed that glia readily synthesize ceramide de novo and that neurons are relatively more sensitive to ceramide toxicity. Our findings provide a framework for understanding neurologic diseases with sphingolipid alternations and insights into designing therapeutics that target ceramide for treating them.

Abstract Adeno-associated virus (AAV) vectors can mediate long-term expression of immunogenic transgenes in vivo through transduction of tolerogenic cells in the liver. Tissue-targeted AAV vectors allow transduction of non-hepatic cells, but this necessitates development of strategies to minimize transgene immunogenicity. Here, we first validated that AAV capsids with tissue-specific tropism and transgene promoters enabled expression of the immunogenic protein, firefly luciferase, in liver, muscle, or adipose tissue. Cellular immunity was detectable in animals where luciferase was expressed in muscle or adipose, but not liver tissue. With the objective of enhancing tolerance of transduced non-hepatic cells, AAV vectors were engineered to co-express luciferase plus the immune checkpoint protein, PD-L1. In animals where transduced cells expressed luciferase but not PD-L1, there was incremental depletion of transduced cells over time. By contrast, the bioluminescent signal increased incrementally over the study, and was significantly greater, in the muscle and adipose tissue of animals where PD-L1 was co-expressed with luciferase. Our data demonstrate that PD-L1 co-expression facilitates persistent, tissue-targeted expression of immunogenic transgenes without transducing tolerogenic hepatic cells. Our strategy of PD-L1 co-expression may provide a versatile platform for sustained expression of immunogenic transgenes in gene and cell therapies.

Abstract Objective To review United States chiropractic state boards acceptance of chiropractic residencies and fellowships as continuing education (CE). Methods Between February 2024 and April 2024, board websites and accompanying policy documents for all 50 states and the District of Columbia were manually searched for content related to residencies and fellowships and whether they were considered CE. Information regarding CE credit requirements for new licensees was also collected. Results were tabulated in a spreadsheet and descriptive analysis was performed. Consensus among a minimum of 5 of 6 investigators was sought. Results Four states (Arizona, Indiana, Kansas, and Minnesota) accept residencies or fellowships for CE credit, 6 states possess unclear regulatory language regarding these programs, and 41 states make no mention of these training programs among approved CE. Twenty-one states required CE credits during a licensee’s initial renewal period, 1 state was unclear based on website content alone, and 29 states did not mandate CE for initial license renewal. More than 90% (19/21) of states that require CE for a licensee’s first renewal do not or are unclear if they accept residencies or fellowships for credit. Conclusion Few chiropractic state boards currently accept residencies and fellowships as approved CE. As the number of these postdoctoral training programs for chiropractors grow, more state boards may be asked to determine their CE policies on them.

Abstract ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition characterized by hyperpigmented and hypopigmented skin macules. Dyschromatosis universalis hereditaria can also present with hearing loss. Dyschromatosis universalis hereditaria-associated mutations in ABCB6 have been reported, but the role of this protein in the inner ear has not been studied. Here we determine a high-resolution (2.93 Å) cryo-EM structure of ABCB6 and functionally characterized several dyschromatosis universalis hereditaria mutants. We find that the L356P mutant abolishes ABCB6 function, and affirm the underlying loss of ATP binding mechanism using molecular dynamics simulations based on our cryo-EM structure. To test the role of ABCB6 in the inner ear, we characterize Abcb6 (the ABCB6 homolog) in zebrafish. We show that Abcb6 suppression by morpholinos reduces inner ear and lateral line hair cell numbers. Morphants also lack the utricular otolith, which is associated with vestibular function. Co-injecting morpholinos with human ABCB6 mRNA partially rescues the morphant phenotype, suggesting that Abcb6 plays a developmental role in inner ear structures. Further, we show that Abcb6 knockout mice exhibit an increased auditory brainstem response threshold, resulting in reduced hearing sensitivity. Taken together, these data suggest ABCB6 plays a role in inner ear development and function.

Abstract Neuroinflammation in the central nervous system (CNS), driven largely by resident phagocytes, has been proposed as a significant contributor to disability accumulation in multiple sclerosis (MS) but has not been addressed therapeutically. Bruton’s tyrosine kinase (BTK) is expressed in both B-lymphocytes and innate immune cells, including microglia, where its role is poorly understood. BTK inhibition may provide therapeutic benefit within the CNS by targeting adaptive and innate immunity-mediated disease progression in MS. Using a CNS-penetrant BTK inhibitor (BTKi), we demonstrate robust in vivo effects in mouse models of MS. We further identify a BTK-dependent transcriptional signature in vitro, using the BTKi tolebrutinib, in mouse microglia, human induced pluripotent stem cell (hiPSC)-derived microglia, and a complex hiPSC-derived tri-culture system composed of neurons, astrocytes, and microglia, revealing modulation of neuroinflammatory pathways relevant to MS. Finally, we demonstrate that in MS tissue BTK is expressed in B-cells and microglia, with increased levels in lesions. Our data provide rationale for targeting BTK in the CNS to diminish neuroinflammation and disability accumulation.

Abstract Classical electromagnetic radiation from moving point charges is foundational, but the thermal dynamics responsible for classical acceleration temperature are poorly understood. We investigate the thermal properties of classical electromagnetic radiation in the context of the correspondence between accelerated electrons and moving mirrors, focusing on three trajectories with asymptotically infinite (Davies–Fulling), asymptotically zero (Walker–Davies), and eternally uniform acceleration. The latter two are argued not to be thermal, while the former is found to emit thermal photons with a temperature that depends on the electron’s speed. Thermal radiation occurs in the absence of jerk.

Abstract Background Animal habitat use can be influenced by a suite of factors including intraspecific interactions and resource availability. The broad-snouted caiman (Caiman latirostris) is the largest crocodylian species distributed in freshwater environments of the Brazilian Atlantic Forest, where it inhabits many types of human-impacted and preserved habitats. Despite their ability to occupy ecologically different water bodies, little is known about their movement patterns and their habitat use. We investigated the variation in movements and space use of adult caimans relative to sex, body condition, and environmental conditions in northeastern Brazil. Methods We conducted long-term capture surveys from 2013 to 2022 and used GPS telemetry from 2021–2022 (n = 12 individuals) to assess movement patterns and home ranges of caimans and their habitat use based on Brownian Bridge Movement Modeling (BBMM) and Generalized Linear Mixed Modeling (GLMM). Results Females ranged farther from reservoir’s forested margins, exploring a greater diversity of habitats during the wet/non-reproductive season. During the dry/reproductive season, females remained close to nesting sites within forest fragments. The body condition of caimans did not change significantly over the wet and dry season, indicating that resources are available year-round. Caimans moved more at night than during daytime, likely due to nocturnal foraging and possibly avoiding periods of increased human activity. Female movement rates were positively associated with rainfall, in a pattern likely linked to nest attendance in the dry season. Male movement was positively correlated with reservoir volume in the wet season, possibly due to increased availability of habitats in comparison to dry periods and to decreased overlap with territories controlled by other males. Home ranges estimated as 95% utilization distributions were relatively small in both sexes, averaging 0.64 km2 (range: 0.001–1.4 km2), as were their core areas estimated as 50% utilization distributions, which averaged 0.12 km2 (range: 0.0003–0.12 km2). Small core areas may indicate that caimans remain most of their time in a specific habitat, suggesting abundant resource availability or territoriality. Conclusions Our work reveals the complexity of social interactions and how caimans select their habitats in a highly altered environment.

Abstract Viral infections in humans often cause excessive inflammation. In some viral infections, inflammation can be serious and even fatal, while in other infections it can promote viral clearance. Viruses can escape from the host immune system via regulating inflammatory pathways, thus worsening the illness. MicroRNAs (miRNAs) are tiny non-coding RNA molecules expressed within diverse tissues as well as cells and are engaged in different normal pathological and physiological pathways. Emerging proof suggests that miRNAs can impact innate and adaptive immunity, inflammatory responses, cell invasion, and the progression of viral infections. We discuss some intriguing new findings in the current work, focusing on the impacts of different miRNAs on host inflammatory responses and virus-mediated inflammation. A better understanding of dysregulated miRNAs in viral infections could improve the identification, prevention, and treatment of several serious diseases.

Abstract Single-photon detectors based on the superconducting transition-edge sensor are used in a number of visible to near-infrared applications, particularly for photon-number-resolving measurements in quantum information science. To be practical for large-scale spectroscopic imaging or photonic quantum computing applications, the size of visible to near-infrared transition-edge sensor arrays and their associated readouts must be increased from a few pixels to many thousands. In this manuscript, we introduce the kinetic inductance current sensor, a scalable readout technology that exploits the nonlinear kinetic inductance in a superconducting resonator to make sensitive current measurements. Kinetic inductance current sensors can replace superconducting quantum interference devices for many applications because of their ability to measure fast, high slew-rate signals, their compatibility with standard microwave frequency-division multiplexing techniques, and their relatively simple fabrication. Here, we demonstrate the readout of a visible to near-infrared transition-edge sensor using a kinetic inductance current sensor with 3.7 MHz of bandwidth. We measure a readout noise of $$1.4\,{{{\rm{pA}}}}/\sqrt{{{{\rm{Hz}}}}}$$ 1.4 pA / Hz , considerably below the detector noise at frequencies of interest, and an energy resolution of (0.137 ± 0.001) eV at 0.8 eV, comparable to resolutions observed with non-multiplexed superconducting quantum interference device readouts.

Abstract Short-term preoperative methionine restriction (MetR) is a promising translatable strategy to mitigate surgical injury response. However, its application to improve post-interventional vascular remodeling remains underexplored. Here we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and pathologic vascular remodeling following vein graft surgery in male mice. RNA sequencing reveals that MetR enhances browning in arterial (thoracic aorta) perivascular adipose tissue (PVAT) and induces it in venous (caval vein) PVAT. Specifically, Ppara is highly upregulated in PVAT-adipocytes upon MetR. Furthermore, MetR dampens the postoperative pro-inflammatory response to surgery in PVAT-macrophages in vivo and in vitro. This study shows that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in MetR-induced browning of PVAT. Furthermore, we demonstrate the potential of short-term preoperative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.

This study investigated the effect of combining radiation with an angiogenesis inhibitor and vascular disrupting agent on tumor response and systemic toxicity. CDF1 mice with 200 mm3 foot implanted C3H mammary carcinomas were treated with TNP-470 (100 mg/kg every second day for 2 weeks; s.c.) and combretastatin A-4 phosphate (CA4P; 1 × 250 mg/kg, i.p.). Radiation (230-kV X-rays) was locally administered to tumors of restrained non-anesthetized mice. Response was tumor growth delay and change in mouse body weight. Radiation induced changes in serum levels of 10 cytokines up to 72-h after irradiation were measured using a Luminex assay. The results showed that TNP-470 (100 mg/kg × 7) or CA4P (250 mg/kg × 1) significantly (Student’s t-test; p < 0.05) inhibited tumor growth; the greatest effect when these two drugs were combined. TNP-470 and CA4P, alone or together, also significantly enhanced tumor response to radiation. No systemic toxicity occurred with drugs administered alone or in combination, but toxicity was observed when TNP-470 was combined with radiation. Serum cytokine levels only showed a significant transient increase in IL-6 1-h after irradiating. In conclusion, combining different acting vascular targeting agents with radiation increased anti-tumor activity. However, this benefit may sometimes be associated with a radiation-induced inflammatory response increasing systemic toxicity.

Abstract Aims Interatrial shunts are under evaluation as a treatment for heart failure (HF); however, their in vivo flow performance has not been quantitatively studied. We aimed to investigate the fluid dynamics properties of the 0.51 cm orifice diameter Ventura shunt and assess its lumen integrity with serial transesophageal echocardiography (TEE). Methods and results Computational fluid dynamics (CFD) and bench flow tests were used to establish the flow‐pressure relationship of the shunt. Open‐label patients from the RELIEVE‐HF trial underwent TEE at shunt implant and at 6 and 12 month follow‐up. Shunt effective diameter (Deff) was derived from the vena contracta, and flow was determined by the continuity equation. CFD and bench studies independently validated that the shunt's discharge coefficient was 0.88 to 0.89. The device was successfully implanted in all 97 enrolled patients; mean age was 70 ± 11 years, 97% were NYHA class III, and 51% had LVEF ≤40%. Patency was confirmed in all instances, except for one stenotic shunt at 6 months. Deff remained unchanged from baseline at 12 months (0.47 ± 0.01 cm, P = 0.376), as did the trans‐shunt mean pressure gradient (5.1 ± 3.9 mmHg, P = 0.316) and flow (1137 ± 463 mL/min, P = 0.384). TEE measured flow versus pressure closely correlated (R2 ≥ 0.98) with a fluid dynamics model. At 12 months, the pulmonary/systemic flow Qp/Qs ratio was 1.22 ± 0.12. Conclusions When implanted in patients with advanced HF, this small interatrial shunt demonstrated predictable and durable patency and performance.

Abstract A confined, non-relativistic, accelerating electron is shown to emit thermal radiation. Since laboratories face spatial constraints when dealing with rectilinear motion, focusing on a finite total travel distance combines the benefits of simple theoretical analysis with prospects for table-top experimentation. We demonstrate an accelerated moving charge along an asymptotically static worldline with fixed transit distance and non-relativistic maximum speed, emitting self-consistent analytic power, spectra, and energy. The classical radiation is Planck distributed with an associated acceleration temperature. This is the first fully parametrized, spectrum-solved, finite-distance worldline.

Abstract Background Precise estimates of risk-adjusted increases in postoperative length of stay (LOS) associated with postoperative complications across a range of complications and operations are not available in the existing literature. Methods Associations between preoperative characteristics, postoperative complications and postoperative LOS were tested using medians, interquartile ranges, and nonparametric rank sum tests in a retrospective cohort study using the 2005–2018 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) dataset. A negative binomial model was used with postoperative LOS as the dependent variable and preoperative characteristics and postoperative complications as independent variables. The model was applied to estimate each patient’s postoperative LOS with and without each postoperative complication to measure the association between each complication and risk-adjusted change in postoperative LOS. Results A total of 4,495,582 patients were included. After risk-adjustment, occurrence of each postoperative complication was associated with significantly increased postoperative LOS (between + 3.9 and + 20.1 days, p

Abstract Introduction The Department of Health and Human Services recently recommended rescheduling cannabis from Schedule I to Schedule III, which might have broad effects on public health outcomes related to cannabis. In this changing environment, understanding national patterns in how people obtain information about cannabis is critical to informing public health outreach and education. Methods We surveyed American adults (≥ 18 years) between June 22nd-26th, 2023 using the AmeriSpeak panel. We assessed past year cannabis use, intentions for cannabis use, and where participants got their information about cannabis. We investigated differences by past year use and explored associations between demographic and cannabis use characteristics with information sources using logistic regression. Results Participants (n = 1,161) were 48.3±27.3 years of age (mean±standard deviation), 51% female, and 27% reported past year cannabis use. The most common information sources used were friends/family (35.6%) and websites (33.7%), while the least common information sources were health/medical care providers (9.3%), employees at place of purchase (8.6%), and government agencies (4.7%). Past year cannabis use was positively associated with all information sources except government agencies and popular media articles. A higher proportion of those using cannabis medically (with or without recreational use) obtained information from a healthcare provider (16.4% vs. 5.2%, p = 0.006). Conclusions As cannabis accessibility increases and legality continues changing, there is a strong need for better clinician education, improved public health outreach, and improved communication between patients and clinicians about cannabis.

Abstract Background Single-cell RNA sequencing (scRNAseq) offers powerful insights, but the surge in sample sizes demands more computational power than local workstations can provide. Consequently, high-performance computing (HPC) systems have become imperative. Existing web apps designed to analyze scRNAseq data lack scalability and integration capabilities, while analysis packages demand coding expertise, hindering accessibility. Results In response, we introduce scRNAbox, an innovative scRNAseq analysis pipeline meticulously crafted for HPC systems. This end-to-end solution, executed via the SLURM workload manager, efficiently processes raw data from standard and Hashtag samples. It incorporates quality control filtering, sample integration, clustering, cluster annotation tools, and facilitates cell type-specific differential gene expression analysis between two groups. We demonstrate the application of scRNAbox by analyzing two publicly available datasets. Conclusion ScRNAbox is a comprehensive end-to-end pipeline designed to streamline the processing and analysis of scRNAseq data. By responding to the pressing demand for a user-friendly, HPC solution, scRNAbox bridges the gap between the growing computational demands of scRNAseq analysis and the coding expertise required to meet them.

Abstract Background Therapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD. Methods Longitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology. Results Plasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF. Conclusions Our data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD.

Abstract Hairy cell leukemia is an uncommon B‐cell malignancy with excellent response to purine analogs and to targeted therapies such as ibrutinib and vemurafenib. However, purine analogs are known to be highly immunosuppressive and the infection burden in this patient population with current therapies is unknown. We therefore conducted a retrospective cohort study following 149 patients. Median follow‐up time was 6.9 years. Thirty‐six percent developed an opportunistic or serious infection requiring hospitalization. Most cases were bacterial and most coincided with neutropenia and/or CD4 T‐lymphopenia. No single treatment agent was significantly associated with increased or decreased incidence of infection. Reassuringly, the cumulative incidence of infections plateaued 2 months after initial treatment suggesting clinically significant immune recovery. Only one patient in our cohort passed away due to infection. Estimated 10‐year overall survival was 99% suggesting that infections may not cause as much mortality as was seen prior to current therapies.

With unprecedented and growing interest in data science education, there are limited educator materials that provide meaningful opportunities for learners to practice statistical thinking, as defined by Wild and Pfannkuch, with messy data addressing real-world challenges. As a solution, Nolan and Speed advocated for bringing applications to the forefront in undergraduate statistics curriculum with the use of in-depth case studies to encourage and develop statistical thinking in the classroom. Limitations to this approach include the significant time investment required to develop a case study—namely, to select a motivating question and to create an illustrative data analysis—and the domain expertise needed. As a result, case studies based on realistic challenges, not toy examples, are scarce. To address this, we developed the Open Case Studies (opencasestudies.org) project, which offers a new statistical and data science education case study model. This educational resource provides self-contained, multimodal, peer-reviewed, and open-source guides (or case studies) from real-world examples for active experiences of complete data analyses. We developed an educator’s guide describing how to most effectively use the case studies, how to modify and adapt components of the case studies in the classroom, and how to contribute new case studies (opencasestudies.org/OCS_Guide).

Abstract To examine temporal changes in patient characteristics, the incidence rate of surgical intervention, and the three-year mortality rate for patients undergoing surgical intervention for mitral valve stenosis (MS) from 2001 to 2021 in Denmark. Utilizing Danish nationwide registries, we identified all adult patients undergoing first-time surgical intervention for MS (2001–2021). Temporal changes in the incidence rate of surgical intervention across calendar periods were investigated (2001–2005, 2006–2010, 2011–2015, and 2016–2021). Using Kaplan-Meier estimates, we computed temporal changes in three-year all-cause mortality across calendar periods. With multivariable Cox regression analysis, we assessed the adjusted rates of mortality. We included 256 patients (median age 60.3 years, 31.3% males). A stepwise decrease in the burden of chronic heart failure was identified (2001–2005: 54%, and 2016–2021: 20%, p-value

Abstract Background Oral immunotherapy (OIT) has become the standard of care for children with food allergy (FA) and has substantially improved their quality of life. The effect of OIT on the quality of life in adults, however, has been studied to a much lesser degree. Methods Patients with food allergy aged ≥ 18 years who underwent OIT at Shamir Medical Center completed the Food Allergy Quality of Life Questionnaire-Adult Form (FAQLQ-AF) before and at the end of treatment. Adults with FA not undergoing OIT who completed the FAQLQ-AF at 2 time points, served as controls. Results A total of 44 adults, median age 23.4 years, who underwent OIT for milk (n = 19), egg (n = 2), peanut (n = 9), sesame (n = 6), and tree nuts (n = 8), and 11 controls were studied. The median OIT starting dose was 23.8 mg protein. 33 patients (75%) reached full desensitization within a median of 10.3 months. The FAQLQ-AF baseline scores were comparable between the study and control groups for all items except for Food Allergy related Health (FAH) item in which the study group had a significantly better score (p = 0.02). At the second time point, the study group had significantly better scores in all items (Allergen Avoidance and Dietary Restrictions (AADR), p = 0.02; and Emotional Impact (EI), Risk of Allergen Exposure (RAE), FAH and the Total Score, p

Abstract Background The worldwide market for continuing medical education (CME) was severely affected by the COVID-19 pandemic, which precipitated an increase in web-based CME course attendance. Virtual education methods may be effective for engaging learners and changing behaviors. However, more information is needed about physician preferences for in-person vs. livestreamed CME courses in the postpandemic era. Because of the paucity of data regarding this topic, the current study was designed to evaluate CME participant characteristics, preferences, engagement, and satisfaction with traditional in-person vs. virtual educational methods. Methods A cross-sectional study was performed of attendees of two large internal medicine CME courses held in 2021. Both CME courses were offered via in-person and livestream options, and were taught by Mayo Clinic content experts. Participants, who consisted of practicing physicians seeking CME, completed a 41-question survey after CME course completion. Statistical comparisons were performed by using Fisher exact tests for all survey items, except for those with ordinal response sets, which were compared with Cochran-Armitage trend tests. Results A total of 146 participants completed the survey (response rate, 30.2%). Among the 77 respondents who attended in-person courses, the most frequent reasons indicated were the opportunity to travel (66%) and collaboration/networking with others (25%). Among the 68 respondents who attended the livestream courses, the most frequent reasons indicated included COVID-19–related concerns (65%), convenience (46%), and travel costs (34%). The percentage of respondents who indicated that they would choose the same mode of attendance if given the option again was higher for those who attended in person than for those who attended via livestream (91% vs. 65%, P

Abstract The CUT and homeodomain are ubiquitous DNA binding elements often tandemly arranged in multiple transcription factor families. However, how the CUT and homeodomain work concertedly to bind DNA remains unknown. Using ONECUT2, a driver and therapeutic target of advanced prostate cancer, we show that while the CUT initiates DNA binding, the homeodomain thermodynamically stabilizes the ONECUT2-DNA complex through allosteric modulation of CUT. We identify an arginine pair in the ONECUT family homeodomain that can adapt to DNA sequence variations. Base interactions by this ONECUT family-specific arginine pair as well as the evolutionarily conserved residues are critical for optimal DNA binding and ONECUT2 transcriptional activity in a prostate cancer model. The evolutionarily conserved base interactions additionally determine the ONECUT2-DNA binding energetics. These findings provide insights into the cooperative DNA binding by CUT-homeodomain proteins.

Abstract Time-integrated radiography using MeV Bremsstrahlung X-ray sources is the norm for imaging during system-level testing of components and structures under dynamic condition. One source of error in the analysis of the time-integrated radiography data sets stems from motion blur which smears out sharp interfaces to a greater degree with longer exposure times, which become necessary to provide sufficient signal-to-noise with low X-ray penetration of objects of interest. To quantify motion blur, a 1D shock wave through PMMA was investigated experimentally at The Dynamic Compression Sector at The Advanced Photon Source (DCS@APS) with tapered broadband and 25.46 ± 1.06 keV narrowband X-rays. Four cameras with different exposure times were used for each experiment to compare the effect that exposure time has on motion blur. In addition, our methodology to accurately simulate motion blur in terms of transmission and shape is presented and compared to our experimental results and quantified. There is a high level of agreement between the experimental and simulation results across the range of data sets investigated in this study with a percent difference range of 0.29–1.31% for the four shots. The methodology of this work serves as a steppingstone towards a physically validated model that could be used in conjunction with experimental results to deconvolve physical parameters, densities, and interfaces of interest in a way that would not be possible with experimental results alone.

Abstract Genome-wide association studies (GWAS) identify genetic variants underlying complex traits but are limited by stringent genome-wide significance thresholds. We present GRIN (Gene set Refinement through Interacting Networks), which increases confidence in the expanded gene set by retaining genes strongly connected by biological networks when GWAS thresholds are relaxed. GRIN was validated on both simulated interrelated gene sets as well as multiple GWAS traits. From multiple GWAS summary statistics of suicide attempt, a complex phenotype, GRIN identified additional genes that replicated across independent cohorts and retained biologically interrelated genes despite a relaxed significance threshold. We present a conceptual model of how these retained genes interact through neurobiological pathways that may influence suicidal behavior, and identify existing drugs associated with these pathways that would not have been identified under traditional GWAS thresholds. We demonstrate GRIN’s utility in boosting GWAS results by increasing the number of true positive genes identified from GWAS results.

Abstract Neuromyelitis optica spectrum disorders (NMOSD) comprise autoimmune diseases imposing substantial disability. We compared an NMOSD-targeted disability assessment of mobility, vision, and self-care domains (individually and composite) with the multiple sclerosis-targeted Expanded Disability Status Scale (EDSS) to assess NMOSD disease burden. An overall cohort (n = 505) and a subset of these patients with an enriched dataset (n = 198) were analyzed from the CIRCLES longitudinal, observational database of patients with AQP4-IgG–seropositive or –seronegative NMOSD in North America. Multinomial modeling was used to identify temporal correlates of disability improvement, stability, and worsening. Prior on-study relapse correlated with worsening mobility (OR, 3.08; 95% CI: 1.61–5.90), vision (OR, 3.99; 95% CI: 2.03–7.86), self-care disability (OR, 1.90; 95% CI: 1.07–3.38), and mean composite index disability (OR, 4.20; 95% CI: 1.71–10.34). Higher vision disability was associated with Black race, shorter time on-study, and AQP4-IgG–seropositive status in patients ≥ 18 years (p

Highlights Ir-doped NiFe2O4 (NFI) spinel with TiO2 heterojunction overlayer brought about outstanding chlorine evolution reaction in circumneutral pH. Electroanalyses including operando X-ray absorption spectroscopy uncovered the active role of TiO2 for Cl− chemisorption. NFI/TiO2 anode boosted both NH4 +-to-N2 conversion and H2 generation in wastewater, and the practical applicability was confirmed with scaled-up anodes and real wastewater.

Abstract Background Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood. Methods APOEε4 carriers and APOEε3 homozygotes enrolled in the Women’s Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank. Results A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P

Abstract Mechanistic predictions of ecological niches are fundamentally based on energy and mass exchange processes that, to be realistic, must be linked to microclimate and incorporate behaviour and physiology. Estimates of leaf temperature and associated transpiration and net photosynthesis rates are fundamental in ecology, agriculture and global change biology. Equations for calculating leaf energy budgets have been available for over 60 years and complex models of stomatal behaviour have been developed. However, user‐friendly ways of estimating leaf temperature under realistic microclimatic regimes, including soil moisture effects, remain limited. Here we show that the integrated microclimate and ectotherm functions of the NicheMapR package for the R programming environment can be used to make fast and effective estimates of leaf temperature and associated rates of water loss and photosynthesis for a wide range of leaf functional types, root depths and microhabitats. Stomatal conductance may be constant or simulated to change dynamically (a) as a function of vapour pressure deficit and CO2 concentration, (b) as a function of soil water potential and (c) as a thermoregulatory mechanism to avoid heat stress. We tested the approach against hourly leaf temperature observations in summer from an arid shrubland in Australia, a temperate woodland in Montana USA, along an elevational gradient in Colorado USA, and at a botanical garden in Florida, USA. National or global gridded data sets can provide the required forcing data but local observational data or some combination of local and gridded data can be used. The global ERA5 and NCEP datasets allow historical leaf energy budget calculations to be made anywhere in the world and a Shiny app has been developed to facilitate use of the model with these datasets. Situated leaf energy budget calculations can be used to design informative field programs to collect much needed detailed temporal data on leaf temperature under natural settings, enabling better predictions and interpretations of how plants respond to environmental change.

Abstract Background Unhealthy alcohol use represents a significant risk for morbidity and mortality among people living with HIV (PLWH), in part through its impact on HIV management. Chronic pain, a common comorbidity, exacerbates suboptimal engagement in the HIV care continuum and has reciprocal detrimental effects on alcohol outcomes. There are no integrated, accessible approaches that address these comorbid conditions among PLWH to date. This paper describes a research study protocol of an integrated telehealth intervention to reduce unhealthy drinking and chronic pain among PLWH (Motivational and Cognitive-Behavioral Management for Alcohol and Pain [INTV]). Methods Two-hundred and fifty PLWH with unhealthy drinking and chronic pain will be recruited nationally via online advertisement. Informed consent and baseline assessments occur remotely, followed by 15 days of ecological momentary assessment to assess alcohol use, chronic pain, functioning, and mechanisms of behavior change. Next, participants will be randomized to either the INTV or Control (CTL) condition. Individuals in both conditions will meet with a health counselor through videoconferencing following randomization, and those in the INTV condition will receive 6 additional sessions. At 3- and 6-months post-baseline, participants will complete outcome assessments. It is hypothesized that the INTV condition will result in reduced unhealthy alcohol use and pain ratings compared to the CTL condition. Conclusion This protocol paper describes a randomized controlled trial which tests the efficacy of a novel, integrated telehealth approach to reduce unhealthy alcohol use and chronic pain for PLWH, two common comorbid conditions that influence the HIV treatment cascade. ClinicalTrials.gov identifier NCT05503173.