ABSTRACT
Approximately 1000 children are born every year in the United States with one effective cardiac pumping chamber, or single ventricle heart disease. One of the early causes of mortality in this population is pulmonary arteriovenous malformations (PAVMs), which allow blood to bypass gas exchange in the lungs. PAVMs most frequently occur in children after superior cavopulmonary anastomosis (SCPA), a procedure that redirects venous blood from the upper body to the lungs. Because plasma proteins are in part responsible for directing angiogenesis, we hypothesized that differential protein concentrations would be observed in superior caval blood among children after SCPA according to PAVM status. We performed quantitative plasma proteomics from 11 children with PAVMs and in seven children without PAVMs; an additional 11 children with Fontan circulation were included as a reference. Among children with SCPA, there were no significant differences in the plasma proteomes for those with and without PAVMs. When comparing children with Fontan circulation to those with SCPA and PAVMs, 18 proteins exhibited differential expression (10 downregulated and eight upregulated) in superior caval plasma. These results suggest that factors other than, or in addition to, plasma proteins may be responsible for single ventricle patients' susceptibility to PAVMs after SCPA. IMPACT: What is the key message of your article? We did not identify significant differences in plasma proteins when comparing those children with and without pulmonary arteriovenous malformations (PAVMs) after superior cavopulmonary anastomosis (SCPA). What does it add to the existing literature? The etiology of PAVMs in this population is likely due to factors other than, or in addition to, differences in plasma proteins. What is the impact? Further studies are needed to identify causes of PAVMs among children after SCPA.
ABSTRACT
The structure-based technologies most widely used to rank the affinities of candidate small molecule drugs for proteins range from faster but less reliable docking methods to slower but more accurate explicit solvent free energy methods. In recent years, we have advanced another technology, which is called mining minima because it "mines" out the main contributions to the chemical potentials of the free and bound molecular species by identifying and characterizing their main local energy minima. The present study provides systematic benchmarks of the accuracy and computational speed of mining minima, as implemented in the VeraChem Mining Minima Generation 2 (VM2) code, across two well-regarded protein-ligand benchmark data sets, for which there are already benchmark data for docking, free energy, and other computational methods. A core result is that VM2's accuracy approaches that of explicit solvent free energy methods at a far lower computational cost. In finer-grained analyses, we also examine the influence of various run settings, such as the treatment of crystallographic water molecules, on the accuracy, and define the costs in time and dollars of representative runs on Amazon Web Services (AWS) compute instances with various CPU and GPU combinations. We also use the benchmark data to determine the importance of VM2's correction from generalized Born to finite-difference Poisson-Boltzmann results for each energy well and find that this correction affords a remarkably consistent improvement in accuracy at a modest computational cost. The present results establish VM2 as a distinctive technology for early-stage drug discovery, which provides a strong combination of efficiency and predictivity.
Subject(s)
Proteins , Ligands , Proteins/chemistry , Proteins/metabolism , Thermodynamics , Protein Binding , Molecular Docking SimulationABSTRACT
This manuscript describes the development of a resources module that is part of a learning platform named 'NIGMS Sandbox for Cloud-based Learning' https://github.com/NIGMS/NIGMS-Sandbox. The overall genesis of the Sandbox is described in the editorial NIGMS Sandbox at the beginning of this Supplement. This module delivers learning materials on implementing deep learning algorithms for biomedical image data in an interactive format that uses appropriate cloud resources for data access and analyses. Biomedical-related datasets are widely used in both research and clinical settings, but the ability for professionally trained clinicians and researchers to interpret datasets becomes difficult as the size and breadth of these datasets increases. Artificial intelligence, and specifically deep learning neural networks, have recently become an important tool in novel biomedical research. However, use is limited due to their computational requirements and confusion regarding different neural network architectures. The goal of this learning module is to introduce types of deep learning neural networks and cover practices that are commonly used in biomedical research. This module is subdivided into four submodules that cover classification, augmentation, segmentation and regression. Each complementary submodule was written on the Google Cloud Platform and contains detailed code and explanations, as well as quizzes and challenges to facilitate user training. Overall, the goal of this learning module is to enable users to identify and integrate the correct type of neural network with their data while highlighting the ease-of-use of cloud computing for implementing neural networks. This manuscript describes the development of a resource module that is part of a learning platform named ``NIGMS Sandbox for Cloud-based Learning'' https://github.com/NIGMS/NIGMS-Sandbox. The overall genesis of the Sandbox is described in the editorial NIGMS Sandbox [1] at the beginning of this Supplement. This module delivers learning materials on the analysis of bulk and single-cell ATAC-seq data in an interactive format that uses appropriate cloud resources for data access and analyses.
Subject(s)
Deep Learning , Neural Networks, Computer , Humans , Biomedical Research , Algorithms , Cloud ComputingABSTRACT
Graft versus tumor relies on tumor-associated antigens (TAAs) that are presented to donor T cells via human leukocyte antigens (HLAs). The HLA evolutionary divergence (HED) between alleles of a single individual can dictate the ability to present TAAs. The impact of HED in haploidentical donor transplantation (HIDT) has not been studied. We studied the effect of HED on transplant outcomes following HIDT. We analyzed 322 consecutive recipient/donor pairs with a median follow-up of 57.2 months. Pairwise divergence of HLA class I and II showed that HLA-B, -DRB1, and -DQB1 contributing most to mean HED. The mean HED was class I 6.85 (HLA-A 7.08, -B 8.24, and -C 5.07), class II 8.58 (HLA-DRB1 10.97, -DQB1 10.06 and -DPB1 4.06). A high HED in class I mismatched recipient/donor haplotype (RD MM) was significant for worse DFS (HR 1.11, p = 0.020), and relapse (HR 1.11, p = 0.02). Also, a high HED in RD MM HLA-B haplotype had worse OS (HR 1.07, p = 0.02), DFS (HR 1.09, p = 0.002), higher relapse (HR 1.10, p = 0.003), and similar NRM to low HED. The multivariate analysis showed that high HED in RD MM HLA-B (≥7.8 vs <7.8) had worse DFS (HR 1.53, p = 0.01), higher relapse (HR 1.61, p = 0.024), and similar NRM and OS.
ABSTRACT
Background: National cancer reporting-based registry data, although robust, lacks granularity for incidence trends. Expert opinion remains conflicted regarding the possibility of melanoma overdiagnosis in the context of rising incidence without a corresponding rise in mortality. Objective: To characterize 10- and 50-year trends in melanoma incidence and mortality. Methods: Multicenter, population-based epidemiologic study utilizing the Rochester Epidemiology Project for Olmsted County, Minnesota residents diagnosed with melanoma from 01/01/1970 to 12/21/2020. Age- and sex-adjusted incidence and disease-specific mortality are calculated. Results: Two thousand three hundred ten primary cutaneous melanomas were identified. Current age- and sex-adjusted incidence rates increased 11.1-fold since 1970s (P < .001). Over the last decade, there is an overall 1.21-fold (P < .002) increase, with a 1.36-fold increase (P < .002) among females and no significant increase among males (1.09-fold increase, P < .329). Melanoma-specific mortality decreased from 26.7% in 1970s to 1.5% in 2010s, with a hazard ratio (HR) reduction of 0.73 (P < .001) per 5-year period. Increased mortality was associated with Breslow thickness (HR 1.35, P < .001), age at diagnosis (HR 1.13, P = .001) left anatomic site (HR 1.98, P = .016), and nodular histogenic subtype (HR 3.08, P < .001). Limitations: Retrospective nature and focused geographic investigation. Conclusion: Melanoma incidence has continued to increase over the past decade, most significantly in females aged 40+. Trend variations among age and sex cohorts suggests external factors beyond overdiagnosis may be responsible. Disease-specific mortality of melanoma continues to decrease over the last 50 years.
ABSTRACT
Chimeric antigen receptor (CAR) T cells have been used to successfully treat various blood cancers, but adverse effects have limited their potential. Here, we developed chimeric adaptor proteins (CAPs) and CAR tyrosine kinases (CAR-TKs) in which the intracellular ζ T cell receptor (TCRζ) chain was replaced with intracellular protein domains to stimulate signaling downstream of the TCRζ chain. CAPs contain adaptor domains and the kinase domain of ZAP70, whereas CAR-TKs contain only ZAP70 domains. We hypothesized that CAPs and CAR-TKs would be more potent than CARs because they would bypass both the steps that define the signaling threshold of TCRζ and the inhibitory regulation of upstream molecules. CAPs were too potent and exhibited high tonic signaling in vitro. In contrast, CAR-TKs exhibited high antitumor efficacy and significantly enhanced long-term tumor clearance in leukemia-bearing NSG mice as compared with the conventional CD19-28ζ-CAR-T cells. CAR-TKs were activated in a manner independent of the kinase Lck and displayed slower phosphorylation kinetics and prolonged signaling compared with the 28ζ-CAR. Lck inhibition attenuated CAR-TK cell exhaustion and improved long-term function. The distinct signaling properties of CAR-TKs may therefore be harnessed to improve the in vivo efficacy of T cells engineered to express an antitumor chimeric receptor.
Subject(s)
Receptors, Antigen, T-Cell , Receptors, Chimeric Antigen , Signal Transduction , T-Lymphocytes , Animals , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/metabolism , Receptors, Chimeric Antigen/genetics , Humans , Signal Transduction/immunology , Mice , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Receptors, Antigen, T-Cell/genetics , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , ZAP-70 Protein-Tyrosine Kinase/metabolism , ZAP-70 Protein-Tyrosine Kinase/genetics , ZAP-70 Protein-Tyrosine Kinase/immunology , Immunotherapy, Adoptive/methods , Mice, Inbred NOD , Cell Line, Tumor , PhosphorylationABSTRACT
In November 2021, two grassroots organizations in Boston, Massachusetts-a housing and health justice organization and a student-led nonprofit-established an initiative to provide persons experiencing homelessness (PEH) near the Massachusetts Avenue and Melnea Cass Boulevard ("Mass&Cass") intersection in Boston with access to free COVID-19 education and other wrap-around services. They partnered with hospitals, public health organizations, and advocacy groups to make this happen. This community-driven initiative serves as a model for how to enact a sustainable pipeline for PEH to receive health resources and information, with the voices of those directly impacted at the center. (Am J Public Health. 2024;114(9):870-873. https://doi.org/10.2105/AJPH.2024.307713).
Subject(s)
COVID-19 , Ill-Housed Persons , Humans , Boston , COVID-19/prevention & control , COVID-19/epidemiology , SARS-CoV-2 , Health ResourcesABSTRACT
Following conventional graft-versus-host disease (GVHD) prophylaxis, the development of acute and/or chronic GVHD is associated with lower relapse rates. However, the effects of GVHD on relapse and non-relapse mortality following post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis have not been well studied. To this end, we analyzed the impact of acute and chronic GVHD following PTCy-based haploidentical donor transplantation (HIDT). The analysis included 335 consecutive HIDT recipients transplanted at a single institution between 2005 and 2021. Landmark analysis (LA) and time-dependent multivariable analysis (MVA) were utilized to study the impact of GVHD development on transplant outcome. Landmarks were defined as Day +100 for acute GVHD and one-year for chronic GVHD. Recipient characteristics included a median age of 50 (19-80) years, most commonly transplanted for acute leukemia[/MDS [242]. PBSC was the graft source in 81%, and regimen intensity was myeloablative in 49%. Median follow-up was 65 (23-207) months. In landmark analysis, development of grade 3 to 4 acute GVHD (versus 0-1) was associated with inferior 3-year overall survival (OS 47% versus 64%, P = .041), due to higher NRM (25% versus 10%, P = .013). In contrast, development of grade 2 acute GVHD had no significant effect on NRM or survival. When restricted to acute leukemia/MDS patients, development of grade II acute GVHD was associated with improved OS (79% versus 58%, P = .027) and a trend towards lower relapse (24% versus 36%, P = .08). Development of moderate-to-severe chronic GVHD resulted in significantly higher NRM (15% versus 4%, P = .010), but had no impact on relapse, DFS or OS. In Cox multivariate analysis (MVA), grade 3 to 4 acute GVHD and moderate-to-severe chronic GVHD were both associated with significantly higher NRM (HR 3.38, P < .001 and HR3.35, P < .001, respectively). In addition, grade 3 to 4 acute GVHD predicted worse OS (HR 1.80, P = .007) and DFS (HR 1.55, P = .041). In contrast, relapse was not impacted by acute or chronic GVHD in MVA. Grade 2 acute GVHD was not associated with transplant outcome in MVA. In summary, both grade 3 to 4 acute and moderate-to-severe chronic GVHD were associated with higher NRM after PTCy-based HIDT, without an effect on relapse risk. Methods of early identification of such patients in order to augment GVHD prophylaxis are clearly needed.
ABSTRACT
Forests play a key role in the mitigation of global warming and provide many other vital ecosystem goods and services. However, as forest continues to vanish at an alarming rate from the surface of the planet, the world desperately needs knowledge on what contributes to forest preservation and restoration. Migration, a hallmark of globalization, is widely recognized as a main driver of forest recovery and poverty alleviation. Here, we show that remittance from migrants reinforces forest recovery that would otherwise be unlikely with mere migration, realizing the additionality of payments for ecosystem services for China's largest reforestation policy, the Conversion of Cropland to Forest Program (CCFP). Guided by the framework that integrates telecoupling and coupled natural and human systems, we investigate forest-livelihood dynamics under the CCFP through the lens of rural out-migration and remittance using both satellite remote sensing imagery and household survey data in two representative sites of rural China. Results show that payments from the CCFP significantly increases the probability of sending remittance by out-migrants to their origin households. We observe substantial forest regeneration and greening surrounding households receiving remittance but forest decline and browning in proximity to households with migrants but not receiving remittance, as measured by forest coverage and the Enhanced Vegetation Index derived from space-borne remotely sensed data. The primary mechanism is that remittance reduces the reliance of households on natural capital from forests, particularly fuelwood, allowing forests near the households to recover. The shares of the estimated ecological and economic additionality induced by remittance are 2.0% (1.4%â¼3.8%) and 9.7% (5.0%â¼15.2%), respectively, to the baseline of the reforested areas enrolled in CCFP and the payments received by the participating households. Remittance-facilitated forest regeneration amounts to 12.7% (6.0%â¼18.0%) of the total new forest gained during the 2003-2013 in China. Our results demonstrate that remittance constitutes a telecoupling mechanism between rural areas and cities over long distances, influencing the local social-ecological gains that the forest policy intended to stimulate. Thus, supporting remittance-sending migrants in cities can be an effective global warming mitigation strategy.
Subject(s)
Conservation of Natural Resources , Forests , Transients and Migrants , China , Conservation of Natural Resources/methods , Conservation of Natural Resources/economics , Transients and Migrants/statistics & numerical data , Humans , Forestry/economics , Forestry/methods , EcosystemABSTRACT
BACKGROUND: This study aims to compare the performance of ChatGPT-3.5 (GPT-3.5) and ChatGPT-4 (GPT-4) on the American Society for Surgery of the Hand (ASSH) Self-Assessment Examination (SAE) to determine their potential as educational tools. METHODS: This study assessed the proportion of correct answers to text-based questions on the 2021 and 2022 ASSH SAE between untrained ChatGPT versions. Secondary analyses assessed the performance of ChatGPT based on question difficulty and question category. The outcomes of ChatGPT were compared with the performance of actual examinees on the ASSH SAE. RESULTS: A total of 238 questions were included in the analysis. Compared with GPT-3.5, GPT-4 provided significantly more correct answers overall (58.0% versus 68.9%, respectively; P = 0.013), on the 2022 SAE (55.9% versus 72.9%; P = 0.007), and more difficult questions (48.8% versus 63.6%; P = 0.02). In a multivariable logistic regression analysis, correct answers were predicted by GPT-4 (odds ratio [OR], 1.66; P = 0.011), increased question difficulty (OR, 0.59; P = 0.009), Bone and Joint questions (OR, 0.18; P < 0.001), and Soft Tissue questions (OR, 0.30; P = 0.013). Actual examinees scored a mean of 21.6% above GPT-3.5 and 10.7% above GPT-4. The mean percentage of correct answers by actual examinees was significantly higher for correct (versus incorrect) ChatGPT answers. CONCLUSIONS: GPT-4 demonstrated improved performance over GPT-3.5 on the ASSH SAE, especially on more difficult questions. Actual examinees scored higher than both versions of ChatGPT, but the margin was cut in half by GPT-4.
ABSTRACT
Background: High-altitude populations exhibit distinct cellular, respiratory, and cardiovascular phenotypes, some of which provide adaptive advantages to hypoxic conditions compared to populations with sea-level ancestry. Studies performed in populations with a history of high-altitude residence, such as Tibetans, support the idea that many of these phenotypes may be shaped by genomic features that have been positively selected for throughout generations. We hypothesize that such traits observed in Tibetans at high altitude also occur in Tibetans living at intermediate altitude, even in the absence of severe sustained hypoxia. Methodology: We studied individuals of high-altitude ancestry (Tibetans, n = 17 females; n = 12 males) and sea-level ancestry (Han Chinese, n = 6 females; n = 10 males), both who had been living at â¼1300 m (â¼4327 ft) for at least 18 months. We measured hemoglobin concentration ([Hb]), hypoxic ventilatory response (HVR), and hypoxic heart rate response (HHRR) with end-tidal CO2 (PetCO2) held constant (isocapnia) or allowed to decrease with hypoxic hyperventilation (poikilocapnia). We also quantified the contribution of CO2 on ventilation and heart rate by calculating the differences of isocapnic versus poikilocapnic hypoxic conditions (Δ VËI/ΔPetCO2 and ΔHR/ΔPetCO2, respectively). Results: Male Tibetans had lower [Hb] compared to Han Chinese males (p < 0.05), consistent with reports for individuals from these populations living at high altitude and sea level. Measurements of ventilation (resting ventilation, HVR, and PetCO2) were similar for both groups. Heart rate responses to hypoxia were similar in both groups during isocapnia; however, HHRR in poikilocapnia was reduced in the Tibetan group (p < 0.03), and the heart rate response to CO2 in hypoxia was lower in Tibetans relative to Han Chinese (p < 0.01). Conclusion: These results suggest that Tibetans living at intermediate altitude have blunted cardiac responses in the context of hypoxia. Hence, only some of the phenotypes observed in Tibetans living at high altitude are observed in Tibetans living at intermediate altitude. Whereas blunted cardiac responses to hypoxia is revealed at intermediate altitudes, manifestation of other physiological adaptations to high altitude may require exposure to more severe levels of hypoxia.
ABSTRACT
Invasive grasses cause devastating losses to biodiversity and ecosystem function directly and indirectly by altering ecosystem processes. Escape from natural enemies, plant-plant competition, and variable resource availability provide frameworks for understanding invasion. However, we lack a clear understanding of how natural stressors interact in their native range to regulate invasiveness. In this study, we reduced diverse guilds of natural enemies and plant competitors of the highly invasive buffelgrass across a precipitation gradient throughout major climatic shifts in Laikipia, Kenya. To do this, we used a long-term ungulate exclosure experiment design across a precipitation gradient with nested treatments that (1) reduced plant competition through clipping, (2) reduced insects through systemic insecticide, and (3) reduced fungal associates through fungicide application. Additionally, we measured the interaction of ungulates on two stem-boring insect species feeding on buffelgrass. Finally, we measured a multiyear smut fungus outbreak. Our findings suggest that buffelgrass exhibits invasive qualities when released from a diverse group of natural stressors in its native range. We show natural enemies interact with precipitation to alter buffelgrass productivity patterns. In addition, interspecific plant competition decreased the basal area of buffelgrass, suggesting that biotic resistance mediates buffelgrass dominance in the home range. Surprisingly, systemic insecticides and fungicides did not impact buffelgrass production or reproduction, perhaps because other guilds filled the niche space in these highly diverse systems. For example, in the absence of ungulates, we showed an increase in host-specific stem-galling insects, where these insects compensated for reduced ungulate use. Finally, we documented a smut outbreak in 2020 and 2021, corresponding to highly variable precipitation patterns caused by a shifting Indian Ocean Dipole. In conclusion, we observed how reducing natural enemies and competitors and certain interactions increased properties related to buffelgrass invasiveness.
ABSTRACT
STATEMENT OF PROBLEM: Maxillofacial prosthodontists were advanced digital technology (ADT) adopters early in the new Millennium. The past two decades saw a range of digital enablers emerge including digital imaging (internal and surface), digital surgical planning, digital functional assessment, subtractive and additive manufacturing, navigation, and robotics among others. Artificial Intelligence (AI) is the latest ADT arrival that will be a challenging disruptive technology. ADT has served as a profound change agent in maxillofacial prosthodontics. The intent was to explore the process and level of ADT engagement in maxillofacial prosthodontics. PURPOSE: The purpose was twofold. Firstly, to explore maxillofacial prosthodontic engagement of ADT. Secondly, to develop a discussion document to assist the American Academy of Maxillofacial Prosthetics (AAMP) with establishing a collective awareness and considered opinion on the future of maxillofacial prosthodontics in the digital era. MATERIAL AND METHODS: AAMP member interest in ADT was assessed through analysis of AAMP annual congress programs and publications in the Journal of Prosthetic Dentistry (JPD). The history of the maxillofacial prosthodontic journey to the digital era was undertaken with a selective literature review. The perceptions maxillofacial prosthodontists hold on ADT engagement was assessed through a survey of AAMP members. Developing an understanding of the influence AI was conducted with a review of pertinent literature. RESULTS: From 2011-2020, an annual mean of 38% of papers published in the JPD involved clinical use of ADT. From 2017-2019, 44% of invited presentations at AAMP annual congresses included clinical use of ADT. The journey to the digital era distinguished three periods with formative and consolidation periods influencing the innovation digital era. The AAMP member survey had a 59% response rate and studied 10 domains through 31 questions. Of the respondents, 89% thought ADT important to the future of maxillofacial prosthodontics. CONCLUSIONS: The discussion document will assist the AAMP in developing a collective consciousness and considered opinion on ADT in the future of maxillofacial prosthodontics. Members of the AAMP have a developed interest in clinical applications of ADT. A great challenge is that no formal education, training, or clinical competency requirements for ADT could be identified. Clinical competency requirements are important to prepare maxillofacial prosthodontics for the inevitability of a digital era future. The discussion document poses the fundamental question of whether maxillofacial prosthodontists will remain as passive end users of ADT and AI or will they become engaged knowledge workers that have determined clinical competency in ADT and AI in patient care. Without this knowledge worker role, maxillofacial prosthodontists may experience difficulty being part of the inevitable ADT-AI driven future.
Subject(s)
Artificial Intelligence , Prosthodontics , Humans , North America , Digital Technology , Maxillofacial Prosthesis , Forecasting , Computer-Aided DesignABSTRACT
Congenital diaphragmatic hernia (CDH) is a complex and highly variable disease process that should be treated at institutions with multidisciplinary teams designed for their care. Treatment in the neonatal period focuses on pulmonary hypoplasia, pulmonary hypertension, and cardiac dysfunction. Extracorporeal membrane oxygenation (ECMO) can be considered in patients refractory to medical management. Repair of CDH early during the ECMO course seems to improve mortality compared with other times for surgical intervention. The choice of surgical approach to CDH repair should consider the patient's physiologic status and the surgeon's familiarity with the operative approaches available, recognizing the pros/cons of each technique.
Subject(s)
Extracorporeal Membrane Oxygenation , Hernias, Diaphragmatic, Congenital , Humans , Infant , Infant, Newborn , Extracorporeal Membrane Oxygenation/methods , Hernias, Diaphragmatic, Congenital/surgery , Hernias, Diaphragmatic, Congenital/therapy , Herniorrhaphy/methodsABSTRACT
Rationale: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia, and primary immunodeficiency disorders), but most cases remain idiopathic. Objectives: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. Methods: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived cells, cell cultures, and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. Measurements and Main Results: We identified biallelic pathogenic variants in WAP four-disulfide core domain 2 (WFDC2) in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2-deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and, thus, secretion of mature WFDC2. Conclusions: WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis.
Subject(s)
Bronchiectasis , Nasal Polyps , Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Young Adult , Bronchiectasis/genetics , Bronchiectasis/physiopathology , Nasal Polyps/genetics , WAP Four-Disulfide Core Domain Protein 2ABSTRACT
Translational research requires data at multiple scales of biological organization. Advancements in sequencing and multi-omics technologies have increased the availability of these data, but researchers face significant integration challenges. Knowledge graphs (KGs) are used to model complex phenomena, and methods exist to construct them automatically. However, tackling complex biomedical integration problems requires flexibility in the way knowledge is modeled. Moreover, existing KG construction methods provide robust tooling at the cost of fixed or limited choices among knowledge representation models. PheKnowLator (Phenotype Knowledge Translator) is a semantic ecosystem for automating the FAIR (Findable, Accessible, Interoperable, and Reusable) construction of ontologically grounded KGs with fully customizable knowledge representation. The ecosystem includes KG construction resources (e.g., data preparation APIs), analysis tools (e.g., SPARQL endpoint resources and abstraction algorithms), and benchmarks (e.g., prebuilt KGs). We evaluated the ecosystem by systematically comparing it to existing open-source KG construction methods and by analyzing its computational performance when used to construct 12 different large-scale KGs. With flexible knowledge representation, PheKnowLator enables fully customizable KGs without compromising performance or usability.
Subject(s)
Biological Science Disciplines , Knowledge Bases , Pattern Recognition, Automated , Algorithms , Translational Research, BiomedicalABSTRACT
The presence of an HLA-DPB1 nonpermissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) using post-transplantation cyclophosphamide (PTCy). With the development of a revised model (TCE-Core) that further separates TCE-3 "group 3" alleles into "core" (C) and "noncore" (NC) alleles, a formerly permissive mismatch (PMM) resulting from group 3 alleles in both donor and recipient is now considered a C-NPMM if 1 or more of those alleles is NC. We aimed to study the additional effect of HLA-DPB1 C-NPMM according to the TCE-Core algorithm, as well as the directional vector of the mismatch, on outcomes following HIDT. To this end, we analyzed 242 consecutive HIDT recipients with acute leukemia or myelodysplastic syndrome who underwent transplantation between 2005 and 2021 (median age, 51 years; range, 19 to 80 years). The median follow-up was 62 months (range, 23 to 199 months). Of the 136 HIDTs classified as PMM by TCE-3, 73 were reclassified as a C-NPMM by the TCE-Core algorithm, of which 36 were in the graft-versus host (GVH) vector (37 were host-versus-graft [HVG] only). Given comparable survival between conventional NPMM and C-NPMM, GVH/bidirectional were analyzed together (nonpermissive). HVG-only C-NPMM were combined with HLA-DPB1-matched and PMM (permissive) because of similar outcomes. The presence of a TCE-Core-defined nonpermissive HLA-DP mismatch resulted in superior 5-year overall survival (OS) (66% versus 47%) and disease-free survival (DFS) (60% versus 43%). Compared to the conventional TCE-3 algorithm, TCE-Core identified a higher percentage of nonpermissive transplants (38% versus 23%) and better discriminated outcomes between nonpermissive and permissive status, with a larger difference in survival outcomes using TCE-Core compared to TCE-3 (OS Δ, 18.3% versus 12.7%; DFS Δ, 16.5% versus 8.5%). In multivariable analysis (MVA), a nonpermissive TCE-Core mismatch led to improved OS (hazard ratio [HR], .54; P = .003) and DFS (HR, .62; P = .013), largely due to decreased relapse risk (HR, .63; P = .049). In contrast, nonrelapse mortality (NRM) and graft-versus-host disease (GVHD) outcomes were not significantly impacted. In summary, the presence of nonpermissive TCE-Core HLA-DP mismatch strongly predicts survival following PTCy-based HIDT, owing to a reduction in relapse risk without a corresponding increase in GVHD or NRM. As a donor selection tool, TCE-Core appears to better discriminate HIDT outcomes while at the same time identifying a larger percentage of the potential donor pool.
Subject(s)
Recurrence , Transplantation, Haploidentical , Humans , Middle Aged , Adult , Female , Male , Aged , Young Adult , HLA-DP beta-Chains/genetics , HLA-DP beta-Chains/metabolism , Aged, 80 and over , Hematopoietic Stem Cell Transplantation , Myelodysplastic Syndromes/therapy , Myelodysplastic Syndromes/mortality , Alleles , Graft vs Host Disease/immunologyABSTRACT
The more science advances, the more questions are asked. This compounding growth can make it difficult to keep up with current research directions. Furthermore, this difficulty is exacerbated for junior researchers who enter fields with already large bases of potentially fruitful research avenues. In this paper, we propose a novel task and a recommender system for research directions, RecSOI, that draws from statements of ignorance (SOIs) found in the research literature. By building researchers' profiles based on textual elements, RecSOI generates personalized recommendations of potential research directions tailored to their interests. In addition, RecSOI provides context for the recommended SOIs, so that users can quickly evaluate how relevant the research direction is for them. In this paper, we provide an overview of RecSOI's functioning, implementation, and evaluation, demonstrating its effectiveness in guiding researchers through the vast landscape of potential research directions.
Subject(s)
Biomedical Research , Research , HumansABSTRACT
Advances in high-throughput technologies have enhanced our ability to describe microbial communities as they relate to human health and disease. Alongside the growth in sequencing data has come an influx of resources that synthesize knowledge surrounding microbial traits, functions, and metabolic potential with knowledge of how they may impact host pathways to influence disease phenotypes. These knowledge bases can enable the development of mechanistic explanations that may underlie correlations detected between microbial communities and disease. In this review, we survey existing resources and methodologies for the computational integration of broad classes of microbial and host knowledge. We evaluate these knowledge bases in their access methods, content, and source characteristics. We discuss challenges of the creation and utilization of knowledge bases including inconsistency of nomenclature assignment of taxa and metabolites across sources, whether the biological entities represented are rooted in ontologies or taxonomies, and how the structure and accessibility limit the diversity of applications and user types. We make this information available in a code and data repository at: https://github.com/lozuponelab/knowledge-source-mappings. Addressing these challenges will allow for the development of more effective tools for drawing from abundant knowledge to find new insights into microbial mechanisms in disease by fostering a systematic and unbiased exploration of existing information.
ABSTRACT
The development of chronic graft-versus-host disease (GVHD) in 1-year survivors after matched related or unrelated hematopoietic cell transplantation was shown to be associated with higher nonrelapse mortality (NRM) and worse overall survival (OS). The impact of chronic GVHD requiring immunosuppression (IS) for recipients of haploidentical transplantation (HIDT) with post-transplantation cyclophosphamide (PTCy) who have survived to 1 year post-transplantation has not been studied previously and was investigated for this analysis. A total of 322 adult patients who underwent HIDT at our center were included in this study. The effect of IS-free status on post-transplantation outcomes was assessed. The median follow-up for survivors was 63.9 months (range, 18.3 to 165 months). A total of 163 patients (65%) were IS-free at 1 year post-HIDT. Baseline characteristics of this group were similar to those of patients still requiring IS, except for higher percentages of female donor-male recipient pairs (28% versus 15%; P =.03) and female donors (48% versus 30%; P =.008). Logistic regression to identify patients more likely to be on IS at 1 year post-HIDT identified the use of a female donor as a significant risk factor (odds ratio, 2.11; P = .009). In a Cox regression analysis, patients requiring IS at 1 year post-transplantation had higher NRM (hazard ratio [HR], 4.18; 95% confidence interval [CI], 1.80 to 6.72; P < .001) and showed a trend toward worse disease-free survival (DFS) (HR, 1.59; 95% CI, .95 to 2.66; P =.08), with no impact on OS (HR, 1.44; 95% CI, .90 to 2.31; P = .13) or relapse (HR, .77; 95% CI, .37 to 1.61; P = .49). These results indicate that use of a female donor is a significant risk factor for requiring IS at 1 year post-HIDT. Additionally, chronic GVHD requiring IS at 1-year post-HIDT no significant effect on relapse but is associated with higher NRM and a trend toward worse DFS.