RESUMO
Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent nine MTOR pathogenic variants. We conducted a detailed natural history study and found pathophysiological deficits among individuals with SKS in addition to the common neurodevelopmental symptoms. These symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, indicative of homeostatic imbalance. To characterize these variants, we developed cell models and characterized their functional consequences. We showed that these SKS variants display a range of mechanistic target of rapamycin (mTOR) activities and respond to the mTOR inhibitor, rapamycin, differently. For example, the R1480_C1483del variant we identified here and the previously known C1483F are more active than wild-type controls and less responsive to rapamycin. Further, we showed that SKS mutations dampened circadian rhythms and low-dose rapamycin improved the rhythm amplitude, suggesting that optimal mTOR activity is required for normal circadian function. As SKS is caused by gain-of-function mutations in MTOR, rapamycin was used to treat several patients. While higher doses of rapamycin caused delayed sleep-wake phase disorder in a subset of patients, optimized lower doses improved sleep. Our study expands the clinical and molecular spectrum of SKS and supports further studies for mechanism-guided treatment options to improve sleep-wake behavior and overall health.
RESUMO
Disrupted sleep is commonly reported during hematopoietic stem cell transplant. In this study, we use actigraphy to measure sleep parameters, and qualitative measures of quality of life, depression, and sleep in pediatric and young adult transplant recipients to describe their time course through transplant. Eight patients had evaluable actigraphy data, and 10 patients completed the surveys. The median age of the 6 male and 7 female participants was 13.94 years old. Sleep duration and efficiency measured by actigraphy were suboptimal prior to transplant, then declined to a nadir between Day +7 to +14. Self-reported sleep quality, depression, and quality of life were worst at Day +14 to +30 but improved by Day +100. Findings support efforts to improve sleep, which may improve recovery, mental health and quality of life.
Assuntos
Actigrafia , Depressão , Transplante de Células-Tronco Hematopoéticas , Qualidade de Vida , Sono , Humanos , Qualidade de Vida/psicologia , Masculino , Feminino , Transplante de Células-Tronco Hematopoéticas/psicologia , Adolescente , Criança , Depressão/psicologia , Sono/fisiologia , Adulto Jovem , Qualidade do Sono , Transtornos do Sono-Vigília/psicologia , Transtornos do Sono-Vigília/epidemiologia , Inquéritos e Questionários , AdultoRESUMO
Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.
Assuntos
Proteína de Ligação a CREB , Proteína p300 Associada a E1A , Síndrome de Rubinstein-Taybi , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/terapia , Humanos , Proteína de Ligação a CREB/genética , Proteína p300 Associada a E1A/genética , Consenso , Gerenciamento Clínico , MutaçãoRESUMO
OBJECTIVE: Investigate the accuracy of ChatGPT in the manner of medical questions related to otolaryngology. METHODS: A ChatGPT session was opened within which 93 questions were asked related to otolaryngology topics. Questions were drawn from all major domains within otolaryngology and based upon key action statements (KAS) from clinical practice guidelines (CPGs). Twenty-one "patient-level" questions were also asked of the program. Answers were graded as either "correct," "partially correct," "incorrect," or "non-answer." RESULTS: Correct answers were given at a rate of 45.5% (71.4% correct in patient-level, 37.3% CPG); partially correct answers at 31.8% (28.6% patient-level, 32.8% CPG); incorrect at 21.6% (0% patient-level, 28.4% CPG); and 1.1% non-answers (% patient-level, 1.5% CPG). There was no difference in the rate of correct answers between CPGs published before or after the period of data collection cited by ChatGPT. CPG-based questions were less likely to be correct than patient-level questions (p = 0.003). CONCLUSION: Publicly available artificial intelligence software has become increasingly popular with consumers for everything from story-telling to data collection. In this study, we examined the accuracy of ChatGPT responses to questions related to otolaryngology over 7 domains and 21 published CPGs. Physicians and patients should understand the limitations of this software as it applies to otolaryngology, and programmers in future iterations should consider giving greater weight to information published by well-established journals and written by national content experts. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:4011-4015, 2024.
Assuntos
Otolaringologia , Otolaringologia/normas , Humanos , Inquéritos e Questionários , Guias de Prática Clínica como AssuntoRESUMO
STUDY OBJECTIVES: Obstructive sleep apnea (OSA) adversely affects normal blood pressure (BP) and may disrupt circadian BP patterns. We sought to examine 24-hour circadian BP rhythms in children with OSA and healthy controls. METHODS: Children 5-14 years with OSA and healthy controls underwent 24-hour BP monitoring and actigraphy to quantify sleep. Shape invariant statistical models compared circadian BP patterns (e.g. times of BP peaks, time arrived at peak BP velocity [TAPV]) in the OSA and control groups. RESULTS: The analytic sample included 219 children (mild OSA: nâ =â 52; moderate-to-severe OSA (MS-OSA): nâ =â 50; controls: nâ =â 117). In the morning, the MS-OSA group had earlier TAPV for DBP than controls (51 minutes, pâ <â 0.001). TAPV in the evening was earlier for the MS-OSA group than controls (SBP: 95 minutes, pâ <â 0.001; DBP: 28 minutes, pâ =â 0.028). At mid-day, SBP and DBP velocity nadirs were earlier for the MS-OSA group than controls (SBP: 57 minutes, pâ <â 0.001; DBP: 38 minutes, pâ <â 0.01). The MS-OSA group reached most BP values significantly earlier than controls; the largest differences were 118 minutes (SBP) and 43 minutes (DBP) (pâ <â 0.001). SBP and DBP were elevated in the MS-OSA group (hours 18-21 and 7--12, respectively, pâ <â 0.01) compared to controls. The MS-OSA group was prone to "non-dipping" compared to controls (SBP: odds ratio [OR]â =â 2.16, 95% CI: 1.09, 4.29; DBP: ORâ =â 3.45, 95% CI: 1.21, 10.23). CONCLUSIONS: Children with MS-OSA had changes in circadian BP patterns, namely earlier TAPV and BP peaks and nadirs than controls. Circadian disturbances in BP rhythms may be key to mapping the natural history of BP dysregulation in children with OSA.
Assuntos
Hipertensão , Apneia Obstrutiva do Sono , Humanos , Criança , Pressão Sanguínea/fisiologia , Ritmo Circadiano/fisiologia , Apneia Obstrutiva do Sono/complicações , Sono/fisiologia , Monitorização Ambulatorial da Pressão ArterialRESUMO
OBJECTIVES: Obstructive sleep apnea (OSA) is characterized by chronic systemic inflammation; however, the mechanisms underlying these pathologic consequences are incompletely understood. Our objective was to determine the effects of short- versus long-term exposure to intermittent hypoxia (IH) on pro-inflammatory mediators within vulnerable organs impacted by OSA. STUDY DESIGN: Experimental animal study. METHODS: A total of 8-10 week old C57BL/6J mice were exposed to normoxic or IH conditions for 7 days (short-term) or 6 weeks (long-term) under 12 h light, 12 h dark cycles. After exposure, multiple tissues were collected over a 24 h period. These tissues were processed and evaluated for gene expression and protein levels of pro-inflammatory mediators from peripheral tissues. RESULTS: We observed a global decrease in immune response pathways in the heart, lung, and liver compared with other peripheral organs after short-term exposure to IH. Although there were tissue-specific alterations in the gene expression of pro-inflammatory mediators, with down-regulation in the lung and up-regulation in the heart, we also observed reduced protein levels of pro-inflammatory mediators in the serum, lung, and heart following short-term exposure to IH. Long-term exposure to IH resulted in an overall increase in the levels of inflammatory mediators in the serum, lung, and heart. CONCLUSIONS: We demonstrated novel, longitudinal changes in the inflammatory cascade in a mouse model of OSA. The duration of exposure to IH led to significant variability of inflammatory responses within blood and cardiopulmonary tissues. Our findings further elucidate how inflammatory responses change over the course of the disease in vulnerable organs. LEVEL OF EVIDENCE: NA Laryngoscope, 134:S1-S11, 2024.
Assuntos
Hipóxia , Apneia Obstrutiva do Sono , Camundongos , Animais , Camundongos Endogâmicos C57BL , Hipóxia/patologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Modelos Animais de DoençasRESUMO
Circadian Rhythm Sleep-Wake Disorders (CRSWDs) are important sleep disorders whose unifying feature is a mismatch between the preferred or required times for sleep and wakefulness and the endogenous circadian drives for these. Their etiology, presentation, and treatment can be different in pediatric patients as compared to adults. Evaluation of these disorders must be performed while viewed through the lens of a patient's comorbid conditions. Newer methods of assessment promise to provide greater diagnostic clarity and critical insights into how circadian physiology affects overall health and disease states. Effective clinical management of CRSWDs is multimodal, requiring an integrated approach across disciplines. Therapeutic success depends upon appropriately timed nonpharmacologic and pharmacologic interventions. A better understanding of the genetic predispositions for and causes of CRSWDs has led to novel clinical opportunities for diagnosis and improved therapeutics.
Assuntos
Transtornos do Sono do Ritmo Circadiano , Transtornos do Sono-Vigília , Adulto , Humanos , Criança , Transtornos do Sono do Ritmo Circadiano/diagnóstico , Transtornos do Sono do Ritmo Circadiano/terapia , Sono/fisiologia , Predisposição Genética para Doença , Ritmo Circadiano/fisiologiaRESUMO
OBJECTIVES: To develop and validate a consensus international pediatric sleep endoscopy scale (IPSES) for pediatric drug-induced sleep endoscopy (DISE). METHODS: Existing published DISE ratings scales were reviewed in order to develop a consensus rating scale synthesizing the most common features and adding new elements to address areas of controversy. Samples of 30 de-identified DISE video recordings were reviewed to develop and refine the scale. After the consensus scale was defined, a separate sample of 25 de-identified DISE videos were scored with the new consensus scale by the development group and a panel of independent raters. A weighted kappa statistic was used to quantify the inter-rater and intra-rater reliability of the consensus scale at each anatomic level. RESULTS: Among all raters, intra-rater reliability was most variable for the nasal airway (kappa range 0.33-0.94) and best for the lateral oropharynx (kappa range 0.68-0.95). Inter-rater reliability ranged from 0.43 for the nasal airway to 0.57 at the soft palate. CONCLUSION: The IPSES is a reliable consensus scale that reflects the most common features of existing scales and can be adopted as a universal scoring scale for pediatric DISE.
Assuntos
Apneia Obstrutiva do Sono , Humanos , Criança , Reprodutibilidade dos Testes , Endoscopia , Palato Mole , SonoRESUMO
Intermittent hypoxia (IH) is a major clinical feature of obstructive sleep apnea (OSA). The mechanisms that become dysregulated after periods of exposure to IH are unclear, particularly in the early stages of disease. The circadian clock governs a wide array of biological functions and is intimately associated with stabilization of hypoxia-inducible factors (HIFs) under hypoxic conditions. In patients, IH occurs during the sleep phase of the 24-hour sleep-wake cycle, potentially affecting their circadian rhythms. Alterations in the circadian clock have the potential to accelerate pathological processes, including other comorbid conditions that can be associated with chronic, untreated OSA. We hypothesized that changes in the circadian clock would manifest differently in those organs and systems known to be impacted by OSA. Using an IH model to represent OSA, we evaluated circadian rhythmicity and mean 24-hour expression of the transcriptome in 6 different mouse tissues, including the liver, lung, kidney, muscle, heart, and cerebellum, after a 7-day exposure to IH. We found that transcriptomic changes within cardiopulmonary tissues were more affected by IH than other tissues. Also, IH exposure resulted in an overall increase in core body temperature. Our findings demonstrate a relationship between early exposure to IH and changes in specific physiological outcomes. This study provides insight into the early pathophysiological mechanisms associated with IH.
Assuntos
Apneia Obstrutiva do Sono , Transcriptoma , Animais , Camundongos , Transcriptoma/genética , Apneia Obstrutiva do Sono/genética , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/patologia , Ritmo Circadiano/genética , Modelos Animais de Doenças , Hipóxia/metabolismoRESUMO
Neurons in the hypothalamic preoptic area (POA) regulate multiple homeostatic processes, including thermoregulation and sleep, by sensing afferent input and modulating sympathetic nervous system output. The POA has an autonomous circadian clock and may also receive circadian signals indirectly from the suprachiasmatic nucleus. We have previously defined a subset of neurons in the POA termed QPLOT neurons that are identified by the expression of molecular markers (Qrfp, Ptger3, LepR, Opn5, Tacr3) that suggest receptivity to multiple stimuli. Because Ptger3, Opn5, and Tacr3 encode G-protein coupled receptors (GPCRs), we hypothesized that elucidating the G-protein signaling in these neurons is essential to understanding the interplay of inputs in the regulation of metabolism. Here, we describe how the stimulatory Gs-alpha subunit (Gnas) in QPLOT neurons regulates metabolism in mice. We analyzed Opn5cre; Gnasfl/fl mice using indirect calorimetry at ambient temperatures of 22°C (a historical standard), 10°C (a cold challenge), and 28°C (thermoneutrality) to assess the ability of QPLOT neurons to regulate metabolism. We observed a marked decrease in nocturnal locomotion of Opn5cre; Gnasfl/fl mice at both 28°C and 22°C, but no overall differences in energy expenditure, respiratory exchange, or food and water consumption. To analyze daily rhythmic patterns of metabolism, we assessed circadian parameters including amplitude, phase, and MESOR. Loss-of-function GNAS in QPLOT neurons resulted in several subtle rhythmic changes in multiple metabolic parameters. We observed that Opn5cre; Gnasfl/fl mice show a higher rhythm-adjusted mean energy expenditure at 22°C and 10°C, and an exaggerated respiratory exchange shift with temperature. At 28°C, Opn5cre; Gnasfl/fl mice have a significant delay in the phase of energy expenditure and respiratory exchange. Rhythmic analysis also showed limited increases in rhythm-adjusted means of food and water intake at 22°C and 28°C. Together, these data advance our understanding of Gαs-signaling in preoptic QPLOT neurons in regulating daily patterns of metabolism.
Assuntos
Regulação da Temperatura Corporal , Hipotálamo , Animais , Camundongos , Regulação da Temperatura Corporal/fisiologia , Ritmo Circadiano/fisiologia , Metabolismo Energético , Homeostase , Hipotálamo/metabolismo , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Opsinas/metabolismo , TemperaturaRESUMO
OBJECTIVE: To develop an expert consensus statement regarding persistent pediatric obstructive sleep apnea (OSA) focused on quality improvement and clarification of controversies. Persistent OSA was defined as OSA after adenotonsillectomy or OSA after tonsillectomy when adenoids are not enlarged. METHODS: An expert panel of clinicians, nominated by stakeholder organizations, used the published consensus statement methodology from the American Academy of Otolaryngology-Head and Neck Surgery to develop statements for a target population of children aged 2-18 years. A medical librarian systematically searched the literature used as a basis for the clinical statements. A modified Delphi method was used to distill expert opinion and compose statements that met a standardized definition of consensus. Duplicate statements were combined prior to the final Delphi survey. RESULTS: After 3 iterative Delphi surveys, 34 statements met the criteria for consensus, while 18 statements did not. The clinical statements were grouped into 7 categories: general, patient assessment, management of patients with obesity, medical management, drug-induced sleep endoscopy, surgical management, and postoperative care. CONCLUSION: The panel reached a consensus for 34 statements related to the assessment, management and postoperative care of children with persistent OSA. These statements can be used to establish care algorithms, improve clinical care, and identify areas that would benefit from future research.
Assuntos
Apneia Obstrutiva do Sono , Tonsilectomia , Criança , Humanos , Adenoidectomia/métodos , Endoscopia/métodos , Cuidados Pós-Operatórios , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/cirurgia , Tonsilectomia/efeitos adversos , Tonsilectomia/métodosRESUMO
PURPOSE: Thyroid cancer recurrence following curative thyroidectomy is associated with increased morbidity and mortality, but current surveillance strategies are inadequate for early detection. Prior studies indicate that tissue glycosylation is altered in thyroid cancer, but the utility of serum glycosylation in thyroid cancer surveillance remains unexplored. We therefore assessed the potential utility of altered serum glycomic profile as a tumor-specific target for disease surveillance in recurrent thyroid cancer. EXPERIMENTAL DESIGN: We employed banked serum samples from patients with recurrent thyroid cancer post thyroidectomy and healthy controls. N-glycans were enzymatically released from serum glycoproteins, labeled via permethylation, and analyzed by MALDI-TOF mass spectrometry. Global level and specific subtypes of glycan structures were compared between patients and controls. RESULTS: We evaluated 28 independent samples from 13 patients with cancer recurrence and 15 healthy controls. Global features of glycosylation, including N-glycan class and terminal glycan modifications were similar between groups, but three of 35 individual glycans showed significant differences. The three glycans were biosynthetically related biantennary core fucosylated N-glycans that only varied by the degree of galactosylation (G0F, G1F, and G2F; G: galactose, F: fucose). The ratio of G0F:G1F that captures reduced galactosylation was observed in patients samples but not in healthy controls (p = 0.004) and predicted thyroid cancer recurrence (AUC = 0.82, CI 95% = 0.64-0.99). CONCLUSIONS: Altered N-glycomic profile was associated with thyroid cancer recurrence. This serum-based biomarker would be useful as an effective surveillance tool to improve the care and prognosis of thyroid cancer after prospective validation.
Assuntos
Adenocarcinoma , Neoplasias da Glândula Tireoide , Humanos , Glicômica/métodos , Recidiva Local de Neoplasia , Biomarcadores , Polissacarídeos , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
STUDY OBJECTIVES: Genetics impacts sleep, yet, the molecular mechanisms underlying sleep regulation remain elusive. In this study, we built machine learning models to predict sleep genes based on their similarity to genes that are known to regulate sleep. METHODS: We trained a prediction model on thousands of published datasets, representing circadian, immune, sleep deprivation, and many other processes, using a manually curated list of 109 sleep genes. RESULTS: Our predictions fit with prior knowledge of sleep regulation and identified key genes and pathways to pursue in follow-up studies. As an example, we focused on the NF-κB pathway and showed that chronic activation of NF-κB in a genetic mouse model impacted the sleep-wake patterns. CONCLUSION: Our study highlights the power of machine learning in integrating prior knowledge and genome-wide data to study genetic regulation of complex behaviors such as sleep.
Assuntos
NF-kappa B , Sono , Animais , Camundongos , Ritmo Circadiano/genética , Regulação da Expressão Gênica , NF-kappa B/genética , Sono/genética , Sono/fisiologia , Privação do Sono/genéticaRESUMO
OBJECTIVE: To compare findings of same-day cine magnetic resonance imaging (MRI) and drug-induced sleep endoscopy (DISE) and examine how each technique uniquely contributes to the evaluation of persistent obstructive sleep apnea following adenotonsillectomy. STUDY DESIGN: Retrospective cohort study. SETTING: Quaternary care center. METHODS: Chart review was performed for consecutive patients who underwent same-day cine MRI and DISE between 2015 and 2020. Descriptive statistics are reported, and Cohen kappa coefficients were calculated to evaluate the agreement between cine MRI and DISE for obstruction at the adenoids, lingual tonsils, and tongue base. RESULTS: There were 137 patients, the mean age was 10.4 years (95% CI, 3.2-16.7), and 62.8% were male. The most common sites of obstruction on DISE were the tongue base (86.9%), velum (78.7%), epiglottis (74.5%), inferior turbinate (68.6%), and lingual tonsil (61.3%). The most common sites of obstruction on cine MRI were the hypopharynx (56.3%), tongue base (44.8%), lingual tonsil (38.0%), and macroglossia (37.6%). There was moderate agreement for adenoid hypertrophy (κ = 0.53) and poor agreement for lingual tonsil hypertrophy (κ = 0.15) and tongue base obstruction (κ = 0.09). DISE identified more instances of multilevel obstruction when compared with cine MRI (94.9% vs 48.2%). CONCLUSION: DISE offered a better examination of nasal and supraglottic obstruction and is sensitive to partial vs complete collapse, while cine MRI offered better soft tissue resolution for lymphoid tissue hypertrophy and provided a global view of primary and secondary airway obstruction. Cine MRI and DISE are complementary modalities in the evaluation of children with persistent obstructive sleep apnea.
Assuntos
Obstrução das Vias Respiratórias , Apneia Obstrutiva do Sono , Humanos , Criança , Masculino , Feminino , Imagem Cinética por Ressonância Magnética , Estudos Retrospectivos , Polissonografia/métodos , Apneia Obstrutiva do Sono/diagnóstico por imagem , Apneia Obstrutiva do Sono/cirurgia , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/cirurgia , Endoscopia/métodos , Hipertrofia , SonoRESUMO
Biomaterials have been widely used as substitutes for diseased tissue in surgery and have gained great success and attention. At present, the biocompatibility of biomaterials such as PET woven fabrics is often evaluated both in vitro and in vivo. However, the current experimental methods cannot reveal the relationship between material surfaces and cell adhesion, and few research works have focused on the mechanisms of how the surface morphology of biomaterials affects cell adhesion and proliferation. Thus, it is meaningful to find out how the altered surfaces could affect cell adhesion and growth. In this study, we employed Ar low-temperature plasma treatment technology to create nano-grooves on the warp yarn of PET woven fabrics and seeded human umbellar vein endothelial cells (HUVEC) on these fabrics. We then assessed the O-glycan and N-glycan profiles of the cells grown on different structures of the polyester woven fabrics. The result showed that the surface morphology of polyester woven fabrics could affect the O-glycan profile but not the N-glycan profile of cultured HUVEC. Taken together, the study describes the effects of the surface morphology of biomaterial on the biosynthesis of cellular glycans and may provide new insights into the design and manufacture of biomaterials used as blood vessels based on the expression profiles of O-glycans on cultured cells.
RESUMO
The VP8* domain of spike protein VP4 in group A and C rotaviruses, which cause epidemic gastroenteritis in children, exhibits a conserved galectin-like fold for recognizing glycans during cell entry. In group B rotavirus, which causes significant diarrheal outbreaks in adults, the VP8* domain (VP8*B) surprisingly lacks sequence similarity with VP8* of group A or group C rotavirus. Here, by using the recently developed AlphaFold2 for ab initio structure prediction and validating the predicted model by determining a 1.3-Å crystal structure, we show that VP8*B exhibits a novel fold distinct from the galectin fold. This fold with a ß-sheet clasping an α-helix represents a new fold for glycan recognition based on glycan array screening, which shows that VP8*B recognizes glycans containing N-acetyllactosamine moiety. Although uncommon, our study illustrates how evolution can incorporate structurally distinct folds with similar functionality in a homologous protein within the same virus genus.
Assuntos
Rotavirus , Proteínas do Capsídeo/metabolismo , Criança , Cristalografia por Raios X , Galectinas/metabolismo , Humanos , Polissacarídeos/metabolismo , Rotavirus/química , Rotavirus/metabolismoRESUMO
Glycans are critical to every facet of biology and medicine, from viral infections to embryogenesis. Tools to study glycans are rapidly evolving; however, the majority of our knowledge is deeply dependent on binding by glycan binding proteins (e.g., lectins). The specificities of lectins, which are often naturally isolated proteins, have not been well-defined, making it difficult to leverage their full potential for glycan analysis. Herein, we use a combination of machine learning algorithms and expert annotation to define lectin specificity for this important probe set. Our analysis uses comprehensive glycan microarray analysis of commercially available lectins we obtained using version 5.0 of the Consortium for Functional Glycomics glycan microarray (CFGv5). This data set was made public in 2011. We report the creation of this data set and its use in large-scale evaluation of lectin-glycan binding behaviors. Our motif analysis was performed by integrating 68 manually defined glycan features with systematic probing of computational rules for significant binding motifs using mono- and disaccharides and linkages. Combining machine learning with manual annotation, we create a detailed interpretation of glycan-binding specificity for 57 unique lectins, categorized by their major binding motifs: mannose, complex-type N-glycan, O-glycan, fucose, sialic acid and sulfate, GlcNAc and chitin, Gal and LacNAc, and GalNAc. Our work provides fresh insights into the complex binding features of commercially available lectins in current use, providing a critical guide to these important reagents.
Assuntos
Fucose , Lectinas , Lectinas/metabolismo , Análise em Microsséries , Polissacarídeos/metabolismo , Aprendizado de MáquinaRESUMO
At least one-third of adults in the United States experience intermittent hypoxia (IH) due to health or living conditions. The majority of these adults suffer with sleep breathing conditions and associated circadian rhythm disorders. The impact of IH on the circadian clock is not well characterized. In the current study, we used an IH mouse model to understand the impact of IH on the circadian gene expression of the canonical clock genes in the central (the brain) and peripheral (the liver) tissues. Gene expression was measured using a Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). CircaCompare was used to evaluate the differential rhythmicity between normoxia and IH. Our observations suggested that the circadian clock in the liver was less sensitive to IH compared to the circadian clock in the brain.