Risk factors for developmental vulnerability: Insight from population-level surveillance using the Early Development Instrument.

Objectives: Population-level studies may elucidate the most promising intervention targets to prevent negative outcomes of developmental vulnerability in children. This study aims to bridge the current literature gap on identifying population-level developmental vulnerability risk factors using combined social and biological/health information. Methods: This study assessed developmental vulnerability among kindergarten children using the 2016 Early Development Instrument (EDI) and identified risk factors of developmental vulnerability using EDI data cross-linked to a population-wide administrative health dataset. A total number of 23,494 children aged 5-6 were included (48% female). Prenatal, neonatal, and early childhood risk factors for developmental vulnerability were investigated, highlighting the most important ones contributing to early development. Results: The main risk factors for developmental vulnerability were children with a history of mental health diagnosis (risk ratio = 1.46), biological sex-male (risk ratio = 1.51), and poor socioeconomic status (risk ratio = 1.58). Conclusion: Our study encompasses both social and health information in a populational-level representative sample of Alberta, Canada. The results confirm evidence established in other geographic regions and jurisdictions and demonstrate the association between perinatal risk factors and developmental vulnerability. Based on these results, we argue that the health system should adopt a multilevel prevention and intervention strategy, targeting individual, family, and community together.

Associations between Differential Aging and Lifestyle, Environment, Current, and Future Health Conditions: Findings from Canadian Longitudinal Study on Aging.

INTRODUCTION: An aging population will bring a pressing challenge for the healthcare system. Insights into promoting healthy longevity can be gained by quantifying the biological aging process and understanding the roles of modifiable lifestyle and environmental factors, and chronic disease conditions. METHODS: We developed a biological age (BioAge) index by applying multiple state-of-art machine learning models based on easily accessible blood test data from the Canadian Longitudinal Study of Aging (CLSA). The BioAge gap, which is the difference between BioAge index and chronological age, was used to quantify the differential aging, i.e., the difference between biological and chronological age, of the CLSA participants. We further investigated the associations between the BioAge gap and lifestyle, environmental factors, and current and future health conditions. RESULTS: BioAge gap had strong associations with existing adverse health conditions (e.g., cancers, cardiovascular diseases, diabetes, and kidney diseases) and future disease onset (e.g., Parkinson's disease, diabetes, and kidney diseases). We identified that frequent consumption of processed meat, pork, beef, and chicken, poor outcomes in nutritional risk screening, cigarette smoking, exposure to passive smoking are associated with positive BioAge gap ("older" BioAge than expected). We also identified several modifiable factors, including eating fruits, legumes, vegetables, related to negative BioAge gap ("younger" BioAge than expected). CONCLUSIONS: Our study shows that a BioAge index based on easily accessible blood tests has the potential to quantify the differential biological aging process that can be associated with current and future adverse health events. The identified risk and protective factors for differential aging indicated by BioAge gap are informative for future research and guidelines to promote healthy longevity.

The impact of interaction on the adoption of electric vehicles: Mediating role of experience value.

The widespread adoption of electric vehicles (EVs) largely depends on the acceptance of the public. Previous studies pay more attention to the factors affecting EV adoption from the customer perspective but lack the perspective of the interaction between sellers and customers. Based on a survey of 1,014 respondents in China, this work developed a research model analyzing the effect of interaction on the intention to purchase EVs and using experience value (EPV) as the mediating variable. The results showed that the functional experience value (FEV) was positively affected by the environment-customer interaction (ECI). The FEV, emotional experience value (EEV), and social experience value (SEV) were all positively affected by salesman-customer interaction (SCI). In addition, they all had positive impacts on purchasing intention (PI). We further analyzed the differences in the interaction between the different business models. Compared with multi-business model car companies, the ECI for single-business model car companies had a more positive impact on the PI. However, the impact of ECI for single-business model companies on PI was negative. The SCI of single-business model car companies positively impacted the PI, whereas the SCI of multi-business model car companies had no significant impact on the PI. These findings provide insight into further understanding the mechanism of interactions affecting EV adoption and help perfect future promotion strategies.

Individualized Prospective Prediction of Opioid Use Disorder.

OBJECTIVE: Opioid use disorder (OUD) is a chronic relapsing disorder with a problematic pattern of opioid use, affecting nearly 27 million people worldwide. Machine learning (ML)-based prediction of OUD may lead to early detection and intervention. However, most ML prediction studies were not based on representative data sources and prospective validations, limiting their potential to predict future new cases. In the current study, we aimed to develop and prospectively validate an ML model that could predict individual OUD cases based on representative large-scale health data. METHOD: We present an ensemble machine-learning model trained on a cross-linked Canadian administrative health data set from 2014 to 2018 (n = 699,164), with validation of model-predicted OUD cases on a hold-out sample from 2014 to 2018 (n = 174,791) and prospective prediction of OUD cases on a non-overlapping sample from 2019 (n = 316,039). We used administrative records of OUD diagnosis for each subject based on International Classification of Diseases (ICD) codes. RESULTS: With 6409 OUD cases in 2019 (mean [SD], 45.34 [14.28], 3400 males), our model prospectively predicted OUD cases at a high accuracy (balanced accuracy, 86%, sensitivity, 93%; specificity 79%). In accord with prior findings, the top risk factors for OUD in this model were opioid use indicators and a history of other substance use disorders. CONCLUSION: Our study presents an individualized prospective prediction of OUD cases by applying ML to large administrative health datasets. Such prospective predictions based on ML would be essential for potential future clinical applications in the early detection of OUD.

Age-dependent increase of cytoskeletal components in sensory axons in human skin.

Aging is a complex process characterized by several molecular and cellular imbalances. The composition and stability of the neuronal cytoskeleton is essential for the maintenance of homeostasis, especially in long neurites. Using human skin biopsies containing sensory axons from a cohort of healthy individuals, we investigate alterations in cytoskeletal content and sensory axon caliber during aging via quantitative immunostainings. Cytoskeletal components show an increase with aging in both sexes, while elevation in axon diameter is only evident in males. Transcriptomic data from aging males illustrate various patterns in gene expression during aging. Together, the data suggest gender-specific changes during aging in peripheral sensory axons, possibly influencing cytoskeletal functionality and axonal caliber. These changes may cumulatively increase susceptibility of aged individuals to neurodegenerative diseases.

The Impact of Social Conformity on Adopting Decision of Shared Electric Vehicles: A Choice Experiment Analysis in China.

Social conformity, a psychological phenomenon commonly shared by most individuals, has long been ignored by studies focusing on influencing preferences for shared electric vehicles (SEVs). To fill this gap, this paper divides social conformity into informational conformity and normative conformity, and analyzes their effects on individuals' choice of SEVs. Respondents were selected randomly in Jiangsu Province, and the data were collected by the choice experiment method. The data were further analyzed by logit models. Results show that social conformity has a significant positive impact on individuals' choice of SEVs, and informational conformity has a much more profound impact than normative conformity. The driving cost and the convenience of picking up and returning a vehicle also influence consumers' preferences. In addition, social conformity cannot totally dispel the negative impact of poor experience. Finally, some targeted policy recommendations are proposed.

A new form of axonal pathology in a spinal model of neuromyelitis optica.

Neuromyelitis optica is a chronic neuroinflammatory disease, which primarily targets astrocytes and often results in severe axon injury of unknown mechanism. Neuromyelitis optica patients harbour autoantibodies against the astrocytic water channel protein, aquaporin-4 (AQP4-IgG), which induce complement-mediated astrocyte lysis and subsequent axon damage. Using spinal in vivo imaging in a mouse model of such astrocytopathic lesions, we explored the mechanism underlying neuromyelitis optica-related axon injury. Many axons showed a swift and morphologically distinct 'pearls-on-string' transformation also readily detectable in human neuromyelitis optica lesions, which especially affected small calibre axons independently of myelination. Functional imaging revealed that calcium homeostasis was initially preserved in this 'acute axonal beading' state, ruling out disruption of the axonal membrane, which sets this form of axon injury apart from previously described forms of traumatic and inflammatory axon damage. Morphological, pharmacological and genetic analyses showed that AQP4-IgG-induced axon injury involved osmotic stress and ionic overload, but does not appear to use canonical pathways of Wallerian-like degeneration. Subcellular analysis demonstrated remodelling of the axonal cytoskeleton in beaded axons, especially local loss of microtubules. Treatment with the microtubule stabilizer epothilone, a putative therapy approach for traumatic and degenerative axonopathies, prevented axonal beading, while destabilizing microtubules sensitized axons for beading. Our results reveal a distinct form of immune-mediated axon pathology in neuromyelitis optica that mechanistically differs from known cascades of post-traumatic and inflammatory axon loss, and suggest a new strategy for neuroprotection in neuromyelitis optica and related diseases.

Neural labeling and manipulation by neonatal intraventricular viral injection in mice.

This step-by-step protocol provides a fast and easy technique to label and/or genetically manipulate neural cells, achieved by intraventricular injection of viral vectors into neonatal mice under ultrasound guidance. Successful injection of adeno-associated viral vectors (AAV) induces neural transduction as fast as 3 days post injection (dpi) in both the central and peripheral nervous systems. Virally driven expression persists until early adulthood. The same setup enables injection of other viral vectors as well as intramuscular injection. For complete details on the use and execution of this protocol, please refer to Wang et al. (2021) and Brill et al. (2016).

Feasibility of resource utilization of the refractory evaporation concentrate of gas field wastewater exhibiting high salinity: Application of UV/Fenton, desulfurization, distillation and crystallization process after pre-treatment.

The evaporation concentrate of gas field wastewater (EC-GFW) is a new type of refractory actual wastewater produced by the three-effect evaporation of gas field wastewater, exhibiting extremely high salinity and complex organic components. This study proposed a set of processes consisting of AOPs, precipitation, distillation, and crystallization for the systematic treatment of EC-GFW. In this paper, the optimal conditions for the processes after pre-treatment were investigated. The optimal operating parameters of UV/Fenton process were determined to be 180 min of reaction time, 4 of initial pH, 0.6 mol/L of H2O2 dosage, 10:1 of n(H2O2): n(Fe2+) value, and 30 W of UV power. Fenton's reagent was added in two steps (0 min and 90 min) for effective utilization. The results showed that the TOC (Total organic carbon) removal efficiency during the two-stage oxidation reached 93% with TOC in the effluent of 132 mg/L. Then, 82.3% of sulfate ions were removed by the desulfurization process using 50 g/L of CaCl2 within 10 min at a pH of 5 before distillation. It was found that the TOC in the influent of distillation played a decisive role in the quality of the effluent and purity of the crystalline salt, which was expected to be controlled lower than 132 mg/L. The final condensate could utilize to reuse, 99% of main pollutants of which have been removed, reducing the pressure of water supply on site. Simultaneously, the industrial-grade NaCl with extensive application prospect can be recovered. The harmless disposal and resource utilization of EC-GFW was achieved on a laboratory scale, providing the data support and theoretical guidance for treating EC-GFW at gas field project site.

Development of 18F-Labeled Vinyl Sulfone-PSMAi Conjugates as New PET Agents for Prostate Cancer Imaging.

Radiolabeled prostate-specific membrane antigen (PSMA) ligands have been rapidly adopted as part of patient care for prostate cancer. In this study, a new series of 18F-labeled PSMA-targeting agents was developed based on the high-affinity Glu-ureido-Lys scaffold and 18F-vinyl sulfones (VSs), the tumor uptake and tumor/major organ contrast of which could be tuned by pharmacokinetic linkers within the molecules. In particular, 18F-PEG3-VS-PSMAi showed the highest tumor uptake (12.1 ± 2.2%ID/g at 0.5 h p.i.) and 18F-PEG2-VS-PSMAi showed the highest tumor-to-liver ratio (T/L = 3.7 ± 1.0, 4.8 ± 1.2, and 6.3 ± 1.1 at 0.5, 1.5, and 3 h p.i. respectively). Significantly, compared with the FDA-approved 68Ga-PSMA-11, the newly developed 18F-PEG3-VS-PSMAi has an almost double tumor uptake (P < 0.0001) when tested in the same animal model. In conclusion, 18F-VS-labeled PSMA ligands are promising PET agents with prominent tumor uptake and high contrast. The lead agents 18F-PEG2-VS-PSMAi and 18F-PEG3-VS-PSMAi warrant further evaluation in prostate cancer patients.

Bioequivalence assessment of high-capacity polymeric micelle nanoformulation of paclitaxel and Abraxane® in rodent and non-human primate models using a stable isotope tracer assay.

The in vivo fate of nanoformulated drugs is governed by the physicochemical properties of the drug and the functionality of nanocarriers. Nanoformulations such as polymeric micelles, which physically encapsulate poorly soluble drugs, release their payload into the bloodstream during systemic circulation. This results in three distinct fractions of the drug-nanomedicine: encapsulated, protein-bound, and free drug. Having a thorough understanding of the pharmacokinetic (PK) profiles of each fraction is essential to elucidate mechanisms of nanomedicine-driven changes in drug exposure and PK/PD relationships pharmacodynamic activity. Here, we present a comprehensive preclinical assessment of the poly (2-oxazoline)-based polymeric micelle of paclitaxel (PTX) (POXOL hl-PM), including bioequivalence comparison to the clinically approved paclitaxel nanomedicine, Abraxane®. Physicochemical characterization and toxicity analysis of POXOL hl-PM was conducted using standardized protocols by the Nanotechnology Characterization Laboratory (NCL). The bioequivalence of POXOL hl-PM to Abraxane® was evaluated in rats and rhesus macaques using the NCL's established stable isotope tracer ultrafiltration assay (SITUA) to delineate the plasma PK of each PTX fraction. The SITUA study revealed that POXOL hl-PM and Abraxane® had comparable PK profiles not only for total PTX but also for the distinct drug fractions, suggesting bioequivalence in given animal models. The comprehensive preclinical evaluation of POXOL hl-PM in this study showcases a series of widely applicable standardized studies by NCL for assessing nanoformulations prior to clinical investigation.

Completion of neuronal remodeling prompts myelination along developing motor axon branches.

Neuronal remodeling and myelination are two fundamental processes during neurodevelopment. How they influence each other remains largely unknown, even though their coordinated execution is critical for circuit function and often disrupted in neuropsychiatric disorders. It is unclear whether myelination stabilizes axon branches during remodeling or whether ongoing remodeling delays myelination. By modulating synaptic transmission, cytoskeletal dynamics, and axonal transport in mouse motor axons, we show that local axon remodeling delays myelination onset and node formation. Conversely, glial differentiation does not determine the outcome of axon remodeling. Delayed myelination is not due to a limited supply of structural components of the axon-glial unit but rather is triggered by increased transport of signaling factors that initiate myelination, such as neuregulin. Further, transport of promyelinating signals is regulated via local cytoskeletal maturation related to activity-dependent competition. Our study reveals an axon branch-specific fine-tuning mechanism that locally coordinates axon remodeling and myelination.

FAP-Targeted Photodynamic Therapy Mediated by Ferritin Nanoparticles Elicits an Immune Response against Cancer Cells and Cancer Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) are present in many types of tumors and play a pivotal role in tumor progression and immunosuppression. Fibroblast-activation protein (FAP), which is overexpressed on CAFs, has been indicated as a universal tumor target. However, FAP expression is not restricted to tumors, and systemic treatment against FAP often causes severe side effects. To solve this problem, a photodynamic therapy (PDT) approach was developed based on ZnF16Pc (a photosensitizer)-loaded and FAP-specific single chain variable fragment (scFv)-conjugated apoferritin nanoparticles, or αFAP-Z@FRT. αFAP-Z@FRT PDT efficiently eradicates CAFs in tumors without inducing systemic toxicity. When tested in murine 4T1 models, the PDT treatment elicits anti-cancer immunity, causing suppression of both primary and distant tumors, i.e. abscopal effect. Treatment efficacy is enhanced when αFAP-Z@FRT PDT is used in combination with anti-PD1 antibodies. Interestingly, it is found that the PDT treatment not only elicits a cellular immunity against cancer cells, but also stimulates an anti-CAFs immunity. This is supported by an adoptive cell transfer study, where T cells taken from 4T1-tumor-bearing animals treated with αFAP PDT retard the growth of A549 tumors established on nude mice. Overall, our approach is unique for permitting site-specific eradication of CAFs and inducing a broad spectrum anti-cancer immunity.

RXH-Reactive 18F-Vinyl Sulfones as Versatile Agents for PET Probe Construction.

Efficient radiolabeling reactions are important chemical tools in biomedical research especially in probe construction. Herein, three 18F-labeled vinyl sulfones were prepared. In particular, 18F-PEG1-VS (((2-(2-(fluoro-18F)ethoxy)ethyl)sulfonyl)ethane) could not only allow chemoselective labeling of bioactive molecules containing -XH (X = S, NH) groups, but also react with red blood cells both in vitro and in living mice for potential cell tracking applications. In addition, these hydrophilic agents were found to cross the blood brain barrier (BBB) efficiently and localize at the cerebellum region. In summary, 18F-labeled vinyl sulfones provide a versatile platform for PET probe construction.

Genetically modified macrophages accomplish targeted gene delivery to the inflamed brain in transgenic Parkin Q311X(A) mice: importance of administration routes.

Cell-based drug delivery systems have generated an increasing interest in recent years. We previously demonstrated that systemically administered macrophages deliver therapeutics to CNS, including glial cell line-derived neurotrophic factor (GDNF), and produce potent effects in Parkinson's disease (PD) mouse models. Herein, we report fundamental changes in biodistribution and brain bioavailability of macrophage-based formulations upon different routes of administration: intravenous, intraperitoneal, or intrathecal injections. The brain accumulation of adoptively transferred macrophages was evaluated by various imaging methods in transgenic Parkin Q311(X)A mice and compared with those in healthy wild type littermates. Neuroinflammation manifested in PD mice warranted targeting macrophages to the brain for each route of administration. The maximum amount of cell-carriers in the brain, up to 8.1% ID/g, was recorded followed a single intrathecal injection. GDNF-transfected macrophages administered through intrathecal route provided significant increases of GDNF levels in different brain sub-regions, including midbrain, cerebellum, frontal cortex, and pons. No significant offsite toxicity of the cell-based formulations in mouse brain and peripheral organs was observed. Overall, intrathecal injection appeared to be the optimal administration route for genetically modified macrophages, which accomplished targeted gene delivery, and significant expression of reporter and therapeutic genes in the brain.

Tetrazine-TCO Ligation: A Potential Simple Approach to Improve Tumor Uptake through Enhanced Blood Circulation.

Targeted imaging via peptides has been extensively investigated for both diagnostic and therapeutic applications. However, peptides can be cleared out from the blood circulation quickly, leading to only moderate to low accumulation in regions of interest. Previously, 18F-sTCO-DiPhTz-RGDyK demonstrated relatively high blood retention with increased tumor uptake at the late time point (5.3 ± 0.4 and 8.9 ± 0.5%ID/g tumor uptake at 1 h p.i. and 4 h p.i., respectively). In this study, we aim to develop a novel platform based on TCO/tetrazine ligation that could be used not only to label the peptides with F-18 for PET but also to lead to increased or persistent tumor uptake potentially due to enhanced blood circulation of the labeled peptides. We first constructed systems containing different combinations of TCOs/tetrazines and found that the tetrazine moiety played a more important role to facilitate the enhanced blood circulation compared with TCO moiety. Four clinically relevant peptides including NT20.3, RGD, BBN, and exendin-4 were then evaluated, and the increased tumor uptake at a late time point was demonstrated by the combination of 18F-sTCO-DiPhTz system to NT20.3, RGD, and exendin-4. The plasma binding components of the PET agents were investigated by electrophoresis and autoradiography and indicated that transferrin and hemopexin could be the major proteins in blood plasma for binding with 18F-sTCO-DiPhTz conjugates. In summary, we have discovered a TCO/tetrazine system that could not only be used for PET probe construction but also potentially improve the tumor uptake and retention of fast-clearing peptides. Although additional binding experiments are still needed for some of the constructs, the promising preliminary result suggested that this strategy may be used to convert fast-clearing bioligands into relatively long circulating agents with enhanced tumor uptake/retention for either imaging or therapy applications.

Improving Tumor-to-Background Contrast through Hydrophilic Tetrazines: The Construction of 18 F-Labeled PET Agents Targeting Nonsmall Cell Lung Carcinoma.

Bioorthogonal reactions have been widely used in the biomedical field. 18 F-TCO/Tetrazine ligation is the most reactive radiolabelled inverse electron demand Diels-Alder reaction, but its application had been limited due to modest contrast ratios of the resulting conjugates. Herein, we describe the use of hydrophilic tetrazines to improve tumor-to-background contrast of neurotensin receptor targeted PET agents. PET agents were constructed using a rapid Diels-Alder reaction of the radiolabeled trans-cyclooctene (18 F-sTCO) with neurotensin (NT) conjugates of a 3,6-diaryltetrazine, 3-methyl-6-aryltetrazine, and a derivative of 3,6-di(2-hydroxyethyl)tetrazine. Although cell binding assays demonstrated all agents have comparable binding affinity, the conjugate derived from 3,6-di(2-hydroxyethyl)tetrazine demonstrated the highest tumor to muscle contrast, followed by conjugates of the 3-methyl-6-aryltetrazine and 3,6-diaryltetrazine.

CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling.

Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins are key to the development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating semaphorin 3A (Sema3A) signaling; however, nothing is known about its role in synapse pruning. Here, using newly generated crmp2-/- mice we demonstrate that CRMP2 has a moderate effect on Sema3A-dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and the corpus callosum. Surprisingly, crmp2-/- mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which is consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). We demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2-/- mice display ASD-related social behavior changes in the early postnatal period as well as in adults. Together, we demonstrate that CRMP2 mediates Sema3F-dependent synapse pruning and its dysfunction shares histological and behavioral features of ASD.

A Novel PET Probe for Brown Adipose Tissue Imaging in Rodents.

PURPOSE: Brown adipose tissue (BAT) has emerged as a promising target to counteract obesity and its associated metabolic disorders. However, the detection of this tissue remains one of the major roadblocks. PROCEDURES: In this study, we assess the use of BODIPY 1 as a positron emission tomography (PET) imaging agent to image BAT depots in vivo in two mouse phenotypes: obesity-resistant BALB/c mice and the obesity-prone C57BL/6 mice. [18F]BODIPY 1 is a radioactive dye that processed both radioactivity for PET imaging and fluorescence signal for in vitro mechanism study. RESULTS: Through the co-staining of cancer cells with BODIPY 1 and MitoTracker, we found BODIPY 1 mainly accumulated in cell mitochondria in vitro. Fluorescence imaging of primary brown and white adipocytes further confirmed BODIPY 1 had significantly higher accumulation in primary brown adipocytes compared with primary white adipocytes. We evaluated [18F]BODIPY 1 for BAT imaging in both obesity-resistant BALB/c mice and obesity-prone C57BL/6 mice. Indeed, [18F]BODIPY 1 was efficiently taken up by BAT in both mouse genotypes (6.40 ± 1.98 %ID/g in obesity-resistant BALB/c mice (n = 8) and 5.37 ± 0.82 %ID/g in obesity-prone C57BL/6 mice (n = 7)). Although norepinephrine stimulation could increase the absolute BAT uptake, the enhancement is not significant in both genotypes (p > 0.05) at current sample size. These results suggest BAT uptake of [18F]BODIPY 1 may be independent of BAT thermogenic activity. As a comparison, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET imaging was performed in obesity-resistant BALB/c mice. Significantly increased uptake was observed in adrenergically activated BAT (10.08 ± 2.52 %ID/g, n = 3) but not in inactive BAT (3.803 ± 0.70 %ID/g; n = 3). Because [18F]BODIPY 1 maintained its fluorescent property, BAT tissue was excised and studied using fluorescence microscopy. Strong fluorescence signal was observed in BAT mouse that was injected with BODIPY 1. CONCLUSIONS: Unlike [18F]FDG, [18F]BODIPY 1 showed prominent accumulation in BAT under both inactive and stimulated status. [18F]BODIPY 1 may serve as a valuable BAT PET agent to possibly assess BAT mitochondria density, thus BAT thermogenic capacity after further evaluation.