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BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has been shown to pose considerable clinical and economic burden; however, research quantifying the excess burden attributable to common psychiatric comorbidities of ADHD among pediatric patients is scarce. This study assessed the impact of anxiety and depression on healthcare resource utilization (HRU) and healthcare costs in pediatric patients with ADHD in the United States. METHODS: Patients with ADHD aged 6-17 years were identified in the IQVIA PharMetrics Plus database (10/01/2015-09/30/2021). The index date was the date of initiation of a randomly selected ADHD treatment. Patients with ≥ 1 diagnosis for anxiety and/or depression during both the baseline (6 months pre-index) and study period (12 months post-index) were classified in the ADHD+anxiety/depression cohort; those without diagnoses for anxiety nor depression during both periods were classified in the ADHD-only cohort. Entropy balancing was used to create reweighted cohorts. All-cause HRU and healthcare costs during the study period were compared using regression analyses. Cost analyses were also performed in subgroups by comorbid conditions. RESULTS: The reweighted ADHD-only cohort (N = 204,723) and ADHD+anxiety/depression cohort (N = 66,231) had similar characteristics (mean age: 11.9 years; 72.8% male; 56.2% had combined inattentive and hyperactive ADHD type). The ADHD+anxiety/depression cohort had higher HRU than the ADHD-only cohort (incidence rate ratios for inpatient admissions: 10.3; emergency room visits: 1.6; outpatient visits: 2.3; specialist visits: 5.3; and psychotherapy visits: 6.1; all p < 0.001). The higher HRU translated to greater all-cause healthcare costs; the mean per-patient-per-year (PPPY) costs in the ADHD-only cohort vs. ADHD+anxiety/depression cohort was $3,988 vs. $8,682 (p < 0.001). All-cause healthcare costs were highest when both comorbidities were present; among patients with ADHD who had only anxiety, only depression, and both anxiety and depression, the mean all-cause healthcare costs were $7,309, $9,901, and $13,785 PPPY, respectively (all p < 0.001). CONCLUSIONS: Comorbid anxiety and depression was associated with significantly increased risk of HRU and higher healthcare costs among pediatric patients with ADHD; the presence of both comorbid conditions resulted in 3.5 times higher costs relative to ADHD alone. These findings underscore the need to co-manage ADHD and psychiatric comorbidities to help mitigate the substantial burden borne by patients and the healthcare system.
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BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous condition with extensive psychiatric comorbidities. ADHD has been associated with substantial clinical and economic burden; however, little is known about the incremental burden specifically attributable to psychiatric comorbidities of ADHD in adults. OBJECTIVE: To assess the impact of psychiatric comorbidities, specifically anxiety and depression, on health care resource utilization (HRU) and costs in treated adults with ADHD in the United States. METHODS: A retrospective case-cohort study was conducted. Adults with ADHD were identified in the IQVIA PharMetrics Plus database (10/01/2015-09/30/2021). The index date was defined as the date of initiation of a randomly selected ADHD treatment. The baseline period was defined as the 6 months prior to the index date, and the study period as the 12 months following the index date. Patients with at least 1 diagnosis for anxiety and/or depression during both the baseline and study periods were classified in the ADHD+anxiety/depression cohort, whereas those without diagnoses for anxiety or depression at any time were classified in the ADHD-only cohort. Entropy balancing was used to create reweighted cohorts with similar baseline characteristics. All-cause HRU and health care costs were assessed during the study period and compared between cohorts using regression analyses. Cost analyses were also conducted in subgroups stratified by comorbid conditions. RESULTS: After reweighting, patients in the ADHD-only cohort (N = 276,906) and ADHD+anxiety/depression cohort (N = 217,944) had similar characteristics (mean age 34.1 years; 54.8% male). All-cause HRU was higher in the ADHD+anxiety/depression cohort than the ADHD-only cohort (incidence rate ratios for inpatient admissions: 4.5, emergency department visits: 1.8, outpatient visits: 2.0, and psychotherapy visits: 6.4; all P < 0.01). All-cause health care costs were more than 2 times higher in the ADHD+anxiety/depression cohort than the ADHD-only cohort (mean per-patient per-year [PPPY] costs in ADHD-only vs ADHD+anxiety/depression cohort: $5,335 vs $11,315; P < 0.01). Among the ADHD+anxiety/depression cohort, average all-cause health care costs were $9,233, $10,651, and $15,610 PPPY among subgroup of patients with ADHD and only anxiety, only depression, and both anxiety and depression, respectively. CONCLUSIONS: Comorbid anxiety and depression is associated with additional HRU and costs burden in patients with ADHD. Comanagement of these conditions is important and has the potential to alleviate the burden experienced by patients and the health care system.
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Trastorno por Déficit de Atención con Hiperactividad , Comorbilidad , Costos de la Atención en Salud , Aceptación de la Atención de Salud , Humanos , Trastorno por Déficit de Atención con Hiperactividad/economía , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/terapia , Masculino , Femenino , Estudios Retrospectivos , Adulto , Costos de la Atención en Salud/estadística & datos numéricos , Aceptación de la Atención de Salud/estadística & datos numéricos , Estados Unidos/epidemiología , Persona de Mediana Edad , Recursos en Salud/economía , Recursos en Salud/estadística & datos numéricos , Ansiedad/epidemiología , Ansiedad/economía , Adulto Joven , Depresión/epidemiología , Depresión/economía , Estudios de Cohortes , AdolescenteRESUMEN
MOTIVATION: In recent years deep learning has become one of the central approaches in a number of applications, including many tasks in genomics. However, as models grow in depth and complexity, they either require more data or a strategic initialization technique to improve performance. RESULTS: In this project, we introduce cGen, a novel unsupervised, model-agnostic contrastive pre-training method for sequence-based models. cGen can be used before training to initialize weights, reducing the size of the dataset needed. It works through learning the intrinsic features of the reference genome and makes no assumptions on the underlying structure. We show that the embeddings produced by the unsupervised model are already informative for gene expression prediction and that the sequence features provide a meaningful clustering. We demonstrate that cGen improves model performance in various sequence-based deep learning applications, such as chromatin profiling prediction and gene expression. Our findings suggest that using cGen, particularly in areas constrained by data availability, could improve the performance of deep learning genomic models without the need to modify the model architecture.
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Deciphering the regulatory code of gene expression and interpreting the transcriptional effects of genome variation are critical challenges in human genetics. Modern experimental technologies have resulted in an abundance of data, enabling the development of sequence-based deep learning models that link patterns embedded in DNA to the biochemical and regulatory properties contributing to transcriptional regulation, including modeling epigenetic marks, 3D genome organization, and gene expression, with tissue and cell-type specificity. Such methods can predict the functional consequences of any noncoding variant in the human genome, even rare or never-before-observed variants, and systematically characterize their consequences beyond what is tractable from experiments or quantitative genetics studies alone. Recently, the development and application of interpretability approaches have led to the identification of key sequence patterns contributing to the predicted tasks, providing insights into the underlying biological mechanisms learned and revealing opportunities for improvement in future models.
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Aprendizaje Profundo , Regulación de la Expresión Génica , Transcripción Genética , Humanos , Genoma Humano , Epigénesis GenéticaRESUMEN
BACKGROUND: Psoriasis is a major global health burden affecting ~ 60 million people worldwide. Existing studies on psoriasis focused on individual-level health behaviors (e.g. diet, alcohol consumption, smoking, exercise) and characteristics as drivers of psoriasis risk. However, it is increasingly recognized that health behavior arises in the context of larger social, cultural, economic and environmental determinants of health. We aimed to identify the top risk factors that significantly impact the incidence of psoriasis at the neighborhood level using populational data from the province of Quebec (Canada) and advanced tree-based machine learning (ML) techniques. METHODS: Adult psoriasis patients were identified using International Classification of Disease (ICD)-9/10 codes from Quebec (Canada) populational databases for years 1997-2015. Data on environmental and socioeconomic factors 1 year prior to psoriasis onset were obtained from the Canadian Urban Environment Health Consortium (CANUE) and Statistics Canada (StatCan) and were input as predictors into the gradient boosting ML. Model performance was evaluated using the area under the curve (AUC). Parsimonious models and partial dependence plots were determined to assess directionality of the relationship. RESULTS: The incidence of psoriasis varied geographically from 1.6 to 325.6/100,000 person-years in Quebec. The parsimonious model (top 9 predictors) had an AUC of 0.77 to predict high psoriasis incidence. Amongst top predictors, ultraviolet (UV) radiation, maximum daily temperature, proportion of females, soil moisture, urbanization, and distance to expressways had a negative association with psoriasis incidence. Nighttime light brightness had a positive association, whereas social and material deprivation indices suggested a higher psoriasis incidence in the middle socioeconomic class neighborhoods. CONCLUSION: This is the first study to highlight highly variable psoriasis incidence rates on a jurisdictional level and suggests that living environment, notably climate, vegetation, urbanization and neighborhood socioeconomic characteristics may have an association with psoriasis incidence.
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Aprendizaje Automático , Psoriasis , Características de la Residencia , Factores Socioeconómicos , Humanos , Psoriasis/epidemiología , Incidencia , Quebec/epidemiología , Femenino , Masculino , Adulto , Características de la Residencia/estadística & datos numéricos , Factores de Riesgo , Persona de Mediana Edad , Anciano , Adulto JovenRESUMEN
Physical cleansing is a human universal. It serves health and survival functions. It also carries rich psychological meanings that interest scholars across disciplines. What psychological effects result from cleansing? What psychological states trigger cleansing? The present meta-analysis takes stock of all experimental studies examining the psychological consequences and antecedents of cleansing-related thoughts, feelings, and behaviors (e.g., feeling less guilty after cleansing; spontaneously cleansing oneself after thinking of unwelcomed sexual encounter). It includes 129 records, 230 experiments, and 551 effects from 42,793 participants. Effect sizes were synthesized in random-effects models using robust variance estimates with small-sample corrections, supplemented by other techniques. Outliers were excluded using leave-one-out diagnostics and sensitivity analysis. Publication bias was assessed and corrected for using eight methods. Theoretical, methodological, sample, and report moderators were coded. After excluding outliers, without bias correction, the synthesized effect size estimate was g = 0.315, 95% CI [0.277, 0.354]. Using various bias correction methods, the estimate ranged from g = 0.103 to 0.331 and always exhibited considerable heterogeneity. Effect sizes were especially large for behavioral measures and varied significantly between sample types, sample regions, and report types. Meanwhile, effects were domain-general (observed in the moral domain and beyond), bidirectional (physical cleansing â psychological variables), and robust across theoretical types, manipulation operationalizations, and study designs. Limitations included mixed replicability, suboptimal methodological rigor, and restricted sample diversity. We recommend future studies to (a) incorporate power analysis, preregistration, and replication; (b) investigate generalizability across samples; (c) strengthen discriminant validity; and (d) test competing theoretical accounts. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Higiene , Humanos , Conducta Sexual/psicologíaRESUMEN
There is increasing consumer demand for alternative animal protein products that are delicious and sustainably produced to address concerns about the impacts of mass-produced meat on human and planetary health. Cultured meat has the potential to provide a source of nutritious dietary protein that both is palatable and has reduced environmental impact. However, strategies to support the production of cultured meats at the scale required for food consumption will be critical. In this review, we discuss the current challenges and opportunities of using edible scaffolds for scaling up the production of cultured meat. We provide an overview of different types of edible scaffolds, scaffold fabrication techniques, and common scaffold materials. Finally, we highlight potential advantages of using edible scaffolds to advance cultured meat production by accelerating cell growth and differentiation, providing structure to build complex 3D tissues, and enhancing the nutritional and sensory properties of cultured meat.
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Carne , Andamios del Tejido , Animales , Andamios del Tejido/química , Humanos , Ingeniería de Tejidos/métodosRESUMEN
The integration of intramuscular fat-or marbling-into cultured meat will be critical for meat texture, mouthfeel, flavor, and thus consumer appeal. However, culturing muscle tissue with marbling is challenging since myocytes and adipocytes have different media and scaffold requirements for optimal growth and differentiation. Here, we present an approach to engineer multicomponent tissue using myogenic and adipogenic microtissues. The key innovation in our approach is the engineering of myogenic and adipogenic microtissues using scaffolds with customized physical properties; we use these microtissues as building blocks that spontaneously adhere to produce multicomponent tissue, or marbled cultured meat. Myocytes are grown and differentiated on gelatin nanofiber scaffolds with aligned topology that mimic the aligned structure of skeletal muscle and promotes the formation of myotubes in both primary rabbit skeletal muscle and murine C2C12 cells. Pre-adipocytes are cultured and differentiated on edible gelatin microbead scaffolds, which are customized to have a physiologically-relevant stiffness, and promote lipid accumulation in both primary rabbit and murine 3T3-L1 pre-adipocytes. After harvesting and stacking the individual myogenic and adipogenic microtissues, we find that the resultant multicomponent tissues adhere into intact structures within 6-12 h in culture. The resultant multicomponent 3D tissue constructs show behavior of a solid material with a Young's modulus of â¼ 2 ± 0.4 kPa and an ultimate tensile strength of â¼ 23 ± 7 kPa without the use of additional crosslinkers. Using this approach, we generate marbled cultured meat with â¼ mm to â¼ cm thickness, which has a protein content of â¼ 4 ± 2 g/100 g that is comparable to a conventionally produced Wagyu steak with a protein content of â¼ 9 ± 4 g/100 g. We show the translatability of this layer-by-layer assembly approach for microtissues across primary rabbit cells, murine cell lines, as well as for gelatin and plant-based scaffolds, which demonstrates a strategy to generate edible marbled meats derived from different species and scaffold materials.
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Gelatina , Fibras Musculares Esqueléticas , Animales , Ratones , Conejos , Diferenciación Celular , Carne , Músculo EsqueléticoRESUMEN
Talc is a hydrous magnesium sheet silicate used in cosmetic powders, ceramics, paints, rubber, and many other products. We conducted a systematic review of the potential carcinogenicity of genitally applied talc in humans. Our systematic review methods adhere to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and incorporated aspects from the US Institute of Medicine (IOM, now the National Academy of Medicine) and several US EPA frameworks for systematic reviews, evaluating and integrating the epidemiological, animal, and mechanistic literature on talc and cancer. We conducted a comprehensive literature search. Detailed data abstraction and study quality evaluation, adapting the Toxic Substances Control Act (TSCA) framework, were central to our analysis. The literature search and selection process identified 40 primary studies that assessed exposure to talc and female reproductive cancer risks in humans (n = 36) and animals (n = 4). The results of our evaluation emphasize the importance of considering biological plausibility and study quality in systematic review. Integrating all streams of evidence according to the IOM framework yielded classifications of suggestive evidence of no association between perineal application of talcum powders and risk of ovarian cancer at human-relevant exposure levels. We also concluded that there is suggestive evidence of no association between genital talc application and endometrial cancer, and insufficient evidence to determine whether a causal association exists between genital talc application and cervical cancer based on a smaller but largely null body of literature.
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BACKGROUND: Peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) is the first oral immunotherapy indicated for children aged 4 to 17 years with peanut allergy. There are limited real-world data on patients treated with PTAH. OBJECTIVE: To characterize pediatric patients treated with PTAH and associated treatment patterns in US clinical practice. METHODS: US-based physicians with allergy and immunology training treating patients with peanut allergy aged 4 to 17 years with PTAH were recruited from an existing physician panel and completed an online case report form (October to December 2021) with data abstracted from patient medical charts. Physician practice circumstances, patient characteristics, and PTAH treatment patterns were reported. Time to reach the 300-mg dose and treatment persistence were assessed using Kaplan-Meier analysis. RESULTS: A geographically balanced sample of 43 physicians contributed data for 118 demographically diverse pediatric patients. Patients had heterogeneous diagnostic test results, with a wide range of peanut-specific immunoglobulin E levels; 6.8% received an oral food challenge. During the updosing phase, there were no temporary interruptions and 5.1% of the patients required downdosing. Patients reached the 300-mg dose at a median of 21.3 weeks post-initiation. The rate of PTAH persistence at 24 weeks was 93.4%. Only 1 patient discontinued treatment because of treatment-related systemic allergic symptoms, and the remaining discontinuations were for reasons other than treatment-related symptoms. Prophylactic antihistamines were used by 33.9% of the patients to prevent PTAH adverse effects. CONCLUSION: PTAH was prescribed in demographically diverse patients with a wide range of peanut-specific immunoglobulin E levels. Treatment persistence with PTAH was high in this study population, with a small number of patients experiencing treatment modification.
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Arachis , Hipersensibilidad al Cacahuete , Niño , Humanos , Polvos , Alérgenos , Desensibilización Inmunológica/métodos , Inmunoglobulina E , Administración OralRESUMEN
We conducted a systematic review to assess the potential pulmonary carcinogenicity of inhaled talc in humans. Our systematic review methods adhere to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and incorporated aspects from the US Institute of Medicine (IOM) and several United States (US) Environmental Protection Agency (EPA) frameworks for systematic reviews. A comprehensive literature search was conducted. Detailed data abstraction and study quality evaluation, adapting the US Toxic Substances Control Act (TSCA) framework, were central to our analysis. The literature search and selection process identified 23 primary studies that assessed exposure to talc and pulmonary cancer risks in humans (n = 19) and animals (n = 3). Integrating all streams of evidence according to the IOM framework yielded classifications of suggestive evidence of no association between inhaled talc and lung cancer and pleural mesothelioma at human-relevant exposure levels.
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Talco , Animales , Estados Unidos , Humanos , Talco/toxicidadRESUMEN
Hydrophilic amendments can enhance soil moisture content, which, in turn, can improve crop health under drought conditions. Understanding how different hydrogels interact with specific crops is necessary for optimal application. The soil conditioning abilities of a trehalose hydrogel and polyacrylate-based hydrogel were evaluated for tomatoes (Solanum lycopersicum) subjected to drought. Tomato plants were transplanted into individual pots with soil that contained trehalose hydrogel (0.4 wt%), polyacrylate-based hydrogel (0.4 wt%), or no hydrogel and subjected to a well-watered treatment or to pronounced soil drought, with or without rewatering. The health of tomato plants was monitored by measuring leaf total chlorophyll (a + b) concentration, leaf water potential (Ψleaf), stomatal conductance (g s) and relative growth rate (RGR). The polyacrylate-based hydrogel, but not the trehalose hydrogel, improved tomato plant function under drought conditions, as indicated by improved g s and RGR relative to the well-watered control. However, when subjected to a second drought, neither hydrogel was effective, and neither prolonged survival. The more hydrophilic polyacrylate-based hydrogel demonstrated promise in improving the growth of tomato plants under drought when included as a soil amendment at 0.4 wt%. This research is important for understanding the effects of these hydrogels as soil conditioners in drought prone systems.
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Cultured meat has potential to diversify methods for protein production, but innovations in production efficiency will be required to make cultured meat a feasible protein alternative. Microcarriers provide a strategy to culture sufficient volumes of adherent cells in a bioreactor that are required for meat products. However, cell culture on inedible microcarriers involves extra downstream processing to dissociate cells prior to consumption. Here, we present edible microcarriers that can support the expansion and differentiation of myogenic cells in a single bioreactor system. To fabricate edible microcarriers with a scalable process, we used water-in-oil emulsions as templates for gelatin microparticles. We also developed a novel embossing technique to imprint edible microcarriers with grooved topology in order to test if microcarriers with striated surface texture can promote myoblast proliferation and differentiation in suspension culture. In this proof-of-concept demonstration, we showed that edible microcarriers with both smooth and grooved surface topologies supported the proliferation and differentiation of mouse myogenic C2C12 cells in a suspension culture. The grooved edible microcarriers showed a modest increase in the proliferation and alignment of myogenic cells compared to cells cultured on smooth, spherical microcarriers. During the expansion phase, we also observed the formation of cell-microcarrier aggregates or 'microtissues' for cells cultured on both smooth and grooved microcarriers. Myogenic microtissues cultured with smooth and grooved microcarriers showed similar characteristics in terms of myotube length, myotube volume fraction, and expression of myogenic markers. To establish feasibility of edible microcarriers for cultured meat, we showed that edible microcarriers supported the production of myogenic microtissue from C2C12 or bovine satellite muscle cells, which we harvested by centrifugation into a cookable meat patty that maintained its shape and exhibited browning during cooking. These findings demonstrate the potential of edible microcarriers for the scalable production of cultured meat in a single bioreactor.
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Reactores Biológicos , Técnicas de Cultivo de Célula , Animales , Bovinos , Ratones , Emulsiones , Técnicas de Cultivo de Célula/métodos , Diferenciación Celular , Carne , Células CultivadasRESUMEN
STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To investigate the size of prepsoas surgical corridors, developed between the iliopsoas and prespinal vessels, at all disk levels between L1 and S1 granted by left and right lateral antepsoas (ATP) approaches. Secondary aims include evaluation of presurgery radiographic prepsoas windows between L1 and S1 with respect to the intraoperative findings. SUMMARY OF BACKGROUND DATA: The ATP technique is an evolving alternative to the transpsoas and direct anterior exposures for lumbar fusion. However, the vascular morphometric data of the ATP approach remain underexplored, especially at L5-S1. MATERIALS AND METHODS: Patients indicated for ATP lumbar-lumbosacral fusion between September 2018 and February 2020 were enrolled (n=121). Data were collected prospectively, including the following (in mm): intraoperative manual measurements of the premobilization psoas-vessel (pre-PV) window, the final postmobilization psoas-vessel (post-PV) window, and the preoperative radiographic psoas-to-vessel distance at the respective studied disk levels. RESULTS: A total of 121 patients (75 female, mean age: 55.3 yr, 81.8% right-sided approach) underwent a total of 279 levels of spinal fusion. Irrespective of the ATP access laterality, we noted ample postmobilization psoas-vessel (post-PV differential) corridors: largest at L4-L5 (36-38 mm) followed by L5-S1 (31-35 mm), L3-L4 (32-33 mm), L2-L3 (28-30 mm), and L1-L2 (20-24 mm). Similarly, the relative increases of the psoas-vessel corridors (post-PV and pre-PV differentials, averaged: 31 mm at L5-S1, 32 mm at L4-L5, 26 mm at L3-L4, 25 mm at L2-L3, and 14 mm at L1-L2) were also significant in both lateral approaches. In right flank approaches, the right vascular structures projected more dorsally compared with left-sided vasculature ( P <0.05). CONCLUSION: The ATP access offers generous bilateral prepsoas surgical windows to L1-S1 intervertebral disks, allowing for a safe anterior column release, decompression, instrumentation, and fusion.
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Disco Intervertebral , Fusión Vertebral , Adenosina Trifosfato , Femenino , Humanos , Disco Intervertebral/cirugía , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/cirugía , Región Lumbosacra/diagnóstico por imagen , Región Lumbosacra/cirugía , Persona de Mediana Edad , Fusión Vertebral/métodosRESUMEN
Epigenomic profiling has enabled large-scale identification of regulatory elements, yet we still lack a systematic mapping from any sequence or variant to regulatory activities. We address this challenge with Sei, a framework for integrating human genetics data with sequence information to discover the regulatory basis of traits and diseases. Sei learns a vocabulary of regulatory activities, called sequence classes, using a deep learning model that predicts 21,907 chromatin profiles across >1,300 cell lines and tissues. Sequence classes provide a global classification and quantification of sequence and variant effects based on diverse regulatory activities, such as cell type-specific enhancer functions. These predictions are supported by tissue-specific expression, expression quantitative trait loci and evolutionary constraint data. Furthermore, sequence classes enable characterization of the tissue-specific, regulatory architecture of complex traits and generate mechanistic hypotheses for individual regulatory pathogenic mutations. We provide Sei as a resource to elucidate the regulatory basis of human health and disease.
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Sitios de Carácter Cuantitativo , Secuencias Reguladoras de Ácidos Nucleicos , Cromatina/genética , Epigenómica , Genética Humana , Humanos , Sitios de Carácter Cuantitativo/genética , Secuencias Reguladoras de Ácidos Nucleicos/genéticaRESUMEN
Chirality and molecular conformation are central components of life: biological systems rely on stereospecific interactions between discrete (macro)molecular conformers, and the impacts of stereochemistry and rigidity on the properties of small molecules and biomacromolecules have been intensively studied. Nevertheless, how these features affect the properties of synthetic macromolecules has received comparably little attention. Here we leverage iterative exponential growth and ring-opening metathesis polymerization to produce water-soluble, chiral bottlebrush polymers (CBPs) from two enantiomeric pairs of macromonomers of differing rigidity. Remarkably, CBPs with conformationally flexible, mirror image side chains show several-fold differences in cytotoxicity, cell uptake, blood pharmacokinetics and liver clearance; CBPs with comparably rigid, mirror image side chains show no differences. These observations are rationalized with a simple model that correlates greater conformational freedom with enhanced chiral recognition. Altogether, this work provides routes to the synthesis of chiral nanostructured polymers and suggests key roles for stereochemistry and conformational rigidity in the design of future biomaterials.
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Polímeros/química , Conformación Molecular , EstereoisomerismoRESUMEN
Carbohydrate-binding proteins (lectins) play vital roles in cell recognition and signaling, including pathogen binding and innate immunity. Thus, targeting lectins, especially those on the surface of immune cells, could advance immunology and drug discovery. Lectins are typically oligomeric; therefore, many of the most potent ligands are multivalent. An effective strategy for lectin targeting is to display multiple copies of a single glycan epitope on a polymer backbone; however, a drawback to such multivalent ligands is they cannot distinguish between lectins that share monosaccharide binding selectivity (e.g., mannose-binding lectins) as they often lack molecular precision. Here, we describe the development of an iterative exponential growth (IEG) synthetic strategy that enables facile access to synthetic glycomacromolecules with precisely defined and tunable sizes up to 22.5 kDa, compositions, topologies, and absolute configurations. Twelve discrete mannosylated "glyco-IEGmers" are synthesized and screened for binding to a panel of mannoside-binding immune lectins (DC-SIGN, DC-SIGNR, MBL, SP-D, langerin, dectin-2, mincle, and DEC-205). In many cases, the glyco-IEGmers had distinct length, stereochemistry, and topology-dependent lectin-binding preferences. To understand these differences, we used molecular dynamics and density functional theory simulations of octameric glyco-IEGmers, which revealed dramatic effects of glyco-IEGmer stereochemistry and topology on solution structure and reveal an interplay between conformational diversity and chiral recognition in selective lectin binding. Ligand function also could be controlled by chemical substitution: by tuning the side chains of glyco-IEGmers that bind DC-SIGN, we could alter their cellular trafficking through alteration of their aggregation state. These results highlight the power of precision synthetic oligomer/polymer synthesis for selective biological targeting, motivating the development of next-generation glycomacromolecules tailored for specific immunological or other therapeutic applications.
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COVID-19/prevención & control , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Capacitación en Servicio/métodos , Atención Perioperativa/educación , Equipo de Protección Personal/estadística & datos numéricos , Humanos , Control de Infecciones/métodos , Grupo de Atención al Paciente/organización & administración , Complicaciones Posoperatorias/prevención & controlRESUMEN
Despite the strong genetic basis of psychiatric disorders, the underlying molecular mechanisms are largely unmapped. RNA-binding proteins (RBPs) are responsible for most post-transcriptional regulation, from splicing to translation to localization. RBPs thus act as key gatekeepers of cellular homeostasis, especially in the brain. However, quantifying the pathogenic contribution of noncoding variants impacting RBP target sites is challenging. Here, we leverage a deep learning approach that can accurately predict the RBP target site dysregulation effects of mutations and discover that RBP dysregulation is a principal contributor to psychiatric disorder risk. RBP dysregulation explains a substantial amount of heritability not captured by large-scale molecular quantitative trait loci studies and has a stronger impact than common coding region variants. We share the genome-wide profiles of RBP dysregulation, which we use to identify DDHD2 as a candidate schizophrenia risk gene. This resource provides a new analytical framework to connect the full range of RNA regulation to complex disease.
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Trastornos Mentales/genética , Fosfolipasas/genética , Proteínas de Unión al ARN/genética , Regiones no Traducidas 3' , Aprendizaje Profundo , Regulación de la Expresión Génica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Mutación , Proteínas del Factor Nuclear 90/genética , Factores de Elongación de Péptidos/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , ARN Helicasas/genética , Procesamiento Postranscripcional del ARN , Ribonucleoproteína Nuclear Pequeña U5/genética , Esquizofrenia/genética , Transactivadores/genéticaRESUMEN
A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10-4). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10-5). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1-5.0, P = 5.4 × 10-3). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1-1.2, P = 8.8 × 10-5). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.