RESUMEN
N7-methylguanosine (m7G) modification, routinely occurring at mRNA 5' cap or within tRNAs/rRNAs, also exists internally in messenger RNAs (mRNAs). Although m7G-cap is essential for pre-mRNA processing and protein synthesis, the exact role of mRNA internal m7G modification remains elusive. Here, we report that mRNA internal m7G is selectively recognized by Quaking proteins (QKIs). By transcriptome-wide profiling/mapping of internal m7G methylome and QKI-binding sites, we identified more than 1,000 high-confidence m7G-modified and QKI-bound mRNA targets with a conserved "GANGAN (N = A/C/U/G)" motif. Strikingly, QKI7 interacts (via C terminus) with the stress granule (SG) core protein G3BP1 and shuttles internal m7G-modified transcripts into SGs to regulate mRNA stability and translation under stress conditions. Specifically, QKI7 attenuates the translation efficiency of essential genes in Hippo signaling pathways to sensitize cancer cells to chemotherapy. Collectively, we characterized QKIs as mRNA internal m7G-binding proteins that modulate target mRNA metabolism and cellular drug resistance.
Asunto(s)
ADN Helicasas , ARN Helicasas , ADN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/genética , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , ARN Helicasas/metabolismo , Gránulos de Estrés , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Proteínas de Unión al GTP/metabolismo , ARN Mensajero/metabolismo , Gránulos Citoplasmáticos/metabolismoRESUMEN
BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).
Asunto(s)
Diabetes Mellitus Tipo 1 , Hipoglucemiantes , Insulina Aspart , Sistemas de Infusión de Insulina , Insulina Lispro , Adolescente , Adulto , Anciano , Biónica/instrumentación , Glucemia/análisis , Automonitorización de la Glucosa Sanguínea/instrumentación , Automonitorización de la Glucosa Sanguínea/métodos , Niño , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Insulina/administración & dosificación , Insulina/efectos adversos , Insulina/uso terapéutico , Insulina Aspart/administración & dosificación , Insulina Aspart/efectos adversos , Insulina Aspart/uso terapéutico , Sistemas de Infusión de Insulina/efectos adversos , Insulina Lispro/administración & dosificación , Insulina Lispro/efectos adversos , Insulina Lispro/uso terapéutico , Persona de Mediana Edad , Adulto JovenRESUMEN
Polypeptides encoded by long noncoding RNAs (lncRNAs) are a novel class of functional molecules. However, whether these hidden polypeptides participate in the TP53 pathway and play a significant biological role is still unclear. Here, we discover that TP53-regulated lncRNAs can encode peptides, two of which are functional in various human cell lines. Using ribosome profiling and RNA-seq approaches in HepG2 cells, we systematically identified more than 300 novel TP53-regulated lncRNAs and further confirmed that 15 of these TP53-regulated lncRNAs encode peptides. Furthermore, several peptides were validated by mass spectrometry. Ten of the novel translational lncRNAs are directly inducible by TP53 in response to DNA damage. We show that the TP53-inducible peptides TP53LC02 and TP53LC04, but not their lncRNAs, can suppress cell proliferation. TP53LC04 peptide also has a function associated with cell proliferation by regulating the cell cycle in response to DNA damage. This study shows that TP53-regulated lncRNAs can encode new functional peptides, leading to the expansion of the TP53 tumor-suppressor network and providing novel potential targets for cancer therapy.
Asunto(s)
ARN Largo no Codificante , Proliferación Celular/genética , Humanos , Péptidos/metabolismo , Péptidos/farmacología , ARN Largo no Codificante/metabolismo , Ribosomas/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
DNA and histone modifications have notable effects on gene expression1. Being the most prevalent internal modification in mRNA, the N6-methyladenosine (m6A) mRNA modification is as an important post-transcriptional mechanism of gene regulation2-4 and has crucial roles in various normal and pathological processes5-12. However, it is unclear how m6A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m6A deposition globally. We show that m6A modifications are enriched in the vicinity of H3K36me3 peaks, and are reduced globally when cellular H3K36me3 is depleted. Mechanistically, H3K36me3 is recognized and bound directly by METTL14, a crucial component of the m6A methyltransferase complex (MTC), which in turn facilitates the binding of the m6A MTC to adjacent RNA polymerase II, thereby delivering the m6A MTC to actively transcribed nascent RNAs to deposit m6A co-transcriptionally. In mouse embryonic stem cells, phenocopying METTL14 knockdown, H3K36me3 depletion also markedly reduces m6A abundance transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the important roles of H3K36me3 and METTL14 in determining specific and dynamic deposition of m6A in mRNA, and uncover another layer of gene expression regulation that involves crosstalk between histone modification and RNA methylation.
Asunto(s)
Adenosina/análogos & derivados , Histonas/química , Histonas/metabolismo , Lisina/metabolismo , ARN Mensajero/química , ARN Mensajero/metabolismo , Transcripción Genética , Adenosina/metabolismo , Animales , Diferenciación Celular , Línea Celular , Células Madre Embrionarias/metabolismo , Humanos , Lisina/química , Metilación , Metiltransferasas/deficiencia , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones , ARN Polimerasa II/metabolismo , Elongación de la Transcripción Genética , Transcriptoma/genéticaRESUMEN
Non-coding RNAs (ncRNAs) are emerging as key regulators of various biological processes. Although thousands of ncRNAs have been discovered, the transcriptional mechanisms and networks of the majority of ncRNAs have not been fully investigated. In this study, we updated ChIPBase to version 3.0 (https://rnasysu.com/chipbase3/) to provide the most comprehensive transcriptional regulation atlas of ncRNAs and protein-coding genes (PCGs). ChIPBase has identified â¼151 187 000 regulatory relationships between â¼171 600 genes and â¼3000 regulators by analyzing â¼55 000 ChIP-seq datasets, which represent a 30-fold expansion. Moreover, we de novo identified â¼29 000 motif matrices of transcription factors. In addition, we constructed a novel 'Enhancer' module to predict â¼1 837 200 regulation regions functioning as poised, active or super enhancers under â¼1300 conditions. Importantly, we constructed exhaustive coexpression maps between regulators and their target genes by integrating expression profiles of â¼65 000 normal and â¼15 000 tumor samples. We built a 'Disease' module to obtain an atlas of the disease-associated variations in the regulation regions of genes. We also constructed an 'EpiInter' module to explore potential interactions between epitranscriptome and epigenome. Finally, we designed 'Network' module to provide extensive and gene-centred regulatory networks. ChIPBase will serve as a useful resource to facilitate integrative explorations and expand our understanding of transcriptional regulation.
Asunto(s)
Regulación de la Expresión Génica , ARN no Traducido , ARN no Traducido/genética , ARN no Traducido/metabolismo , Factores de Transcripción/metabolismo , Redes Reguladoras de GenesRESUMEN
OBJECTIVE: This study examined the preoperative and postoperative variables associated with 1 year and long-term insulin independence following total pancreatectomy and islet autotransplantation (TPIAT). METHODS: 46 TPIAT patients from 2010 to 2022 in a single hospital system were retrospectively analyzed. Pre- and postoperative variables were compared between short-term (1 year) and long-term (last follow-up after year 1) insulin-independent versus -dependent patients. RESULTS: Nine (20%) and seven (15%) patients achieved short- and long-term insulin independence, respectively. The patients were followed up for a median of 2.8 years (interquartile range [IQR] 1.0, 4.7). Short-term insulin independence was associated with higher median transplanted islet equivalents (IEQ) per kg (6981 vs 4493, P = .02), lower units of basal insulin on discharge (7 vs 12, P = .009), and lower rates of discharge with an insulin regimen (67% vs 100%, P = .006). Odds of short-term insulin independence increased by 80% for every 1000 increase in IEQ per kg (OR 1.80, CI 1.18-3.12, P = .005) and decreased by 32% for every additional basal unit of insulin on discharge (OR 0.68, CI 0.42-0.91, P = .003) on average. Long-term insulin independence was also associated with transplanted IEQ per kg. No patient on antihyperglycemic medication before surgery achieved insulin independence. CONCLUSION: Short- and long-term insulin independence after TPIAT is associated with higher transplanted IEQ per kg and immediate postoperative variables that can be used to inform the discussions clinicians have with their patients regarding glycemic prognosis following TPIAT.
Asunto(s)
Insulina , Trasplante de Islotes Pancreáticos , Pancreatectomía , Trasplante Autólogo , Humanos , Trasplante de Islotes Pancreáticos/métodos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Insulina/uso terapéutico , Periodo Posoperatorio , Periodo Preoperatorio , Hipoglucemiantes/uso terapéutico , Glucemia/análisisRESUMEN
Although long noncoding RNAs (lncRNAs) have significant tissue specificity, their expression and variability in single cells remain unclear. Here, we developed ColorCells (http://rna.sysu.edu.cn/colorcells/), a resource for comparative analysis of lncRNAs expression, classification and functions in single-cell RNA-Seq data. ColorCells was applied to 167 913 publicly available scRNA-Seq datasets from six species, and identified a batch of cell-specific lncRNAs. These lncRNAs show surprising levels of expression variability between different cell clusters, and has the comparable cell classification ability as known marker genes. Cell-specific lncRNAs have been identified and further validated by in vitro experiments. We found that lncRNAs are typically co-expressed with the mRNAs in the same cell cluster, which can be used to uncover lncRNAs' functions. Our study emphasizes the need to uncover lncRNAs in all cell types and shows the power of lncRNAs as novel marker genes at single cell resolution.
Asunto(s)
Bases de Datos de Ácidos Nucleicos , Regulación de la Expresión Génica , ARN Largo no Codificante , Análisis de la Célula Individual , Programas Informáticos , Animales , Humanos , Anotación de Secuencia Molecular , ARN Largo no Codificante/biosíntesis , ARN Largo no Codificante/genéticaRESUMEN
As an easily disposable substrate with a microporous texture, paper is a well-suited, generic substrate to build analytical devices for studying bacteria. Using a multi-pass lasing process, cellulose-based laser-induced graphene (cLIG) with a sheet resistance of 43.7 ± 2.3 Ωsq-1 is developed and utilized in the fabrication of low-cost and environmentally-friendly paper sensor arrays. Two case studies with Pseudomonas aeruginosa and Escherichia coli demonstrate the practicality of the cLIG sensors for the electrochemical analysis of bacteria. The first study measures the time-dependent profile of phenazines released from both planktonic (up to 60 h) and on-chip-grown (up to 22 h) Pseudomonas aeruginosa cultures. While similarities do exist, marked differences in phenazine production are seen with cells grown directly on cLIG compared to the planktonic culture. Moreover, in planktonic cultures, pyocyanin levels increase early on and plateau around 20 h, while optical density measurements increase monotonically over the duration of testing. The second study monitors the viability and metabolic activity of Escherichia coli using a resazurin-based electrochemical assay. These results demonstrate the utility of cLIG paper sensors as an inexpensive and versatile platform for monitoring bacteria and could enable new opportunities in high-throughput antibiotic susceptibility testing, ecological studies, and biofilm studies.
RESUMEN
OBJECTIVE: The effects of diabetes medications on COVID-19 hospitalization outcomes have not been consistent. We sought to determine the effect of metformin, dipeptidyl peptidase-4 inhibitors (DPP-4i), and insulin on admission to the intensive care unit (ICU), need for assisted ventilation, development of renal insufficiency, and mortality in patients admitted with COVID-19 infection after controlling for clinical variables and other relevant diabetes-related medications in patients with type 2 diabetes mellitus (DM). METHODS: This was a retrospective study of patients hospitalized with COVID-19 from a single hospital system. Univariate and multivariate analyses were performed that included demographic data, glycated hemoglobin, kidney function, smoking status, insurance, Charlson comorbidity index, number of diabetes medications, and use of angiotensin-converting enzyme inhibitors and statin prior to admission and glucocorticoids during admission. RESULTS: A total of 529 patients with type 2 DM were included in our final analysis. Neither metformin nor DPP4i prescription was associated with ICU admission, need for assisted ventilation, or mortality. Insulin prescription was associated with increased ICU admission but not with need for assisted ventilation or mortality. There was no association of any of these medications with development of renal insufficiency. CONCLUSIONS: In this population, limited to type 2 DM and controlled for multiple variables that have not been consistently studied (such as a measure of general health, glycated hemoglobin, and insurance status), insulin prescription was associated with increased ICU admission. Metformin and DPP4i prescriptions did not have an association with the outcomes.
Asunto(s)
COVID-19 , Diabetes Mellitus Tipo 2 , Dipeptidasas , Inhibidores de la Dipeptidil-Peptidasa IV , Metformina , Insuficiencia Renal , Humanos , Metformina/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Dipeptidasas/uso terapéutico , Estudios Retrospectivos , Hemoglobina Glucada , COVID-19/complicaciones , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Insulina Regular Humana/uso terapéutico , Hospitales , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/complicaciones , Insuficiencia Renal/tratamiento farmacológicoRESUMEN
BACKGROUND: Data regarding changes in cortisol axis after adrenalectomy for non-cortisol secreting tumors and their correlation with adrenal insufficiency are limited. Our aim was to analyze these changes and their clinical correlations to guide management after adrenalectomy for non-Cushing's tumors. METHODS: Following IRB approval, postoperative cortisol axis changes were analyzed in patients who underwent unilateral adrenalectomy for non-Cushing's tumors. A morning serum cortisol of ≥ 10 µg/dl was accepted as a sufficient adrenal response. RESULTS: 223 adrenalectomies were analyzed. In 63% of patients, POD1 serum cortisol was ≥ 10 µg/dl and in 37% < 10 µg/dl. No patient with a POD1 cortisol ≥ 10 µg/dl developed AI symptoms, whereas symptoms of AI were observed in 4% of those with < 10 µg/dl. In patients with a POD1 cortisol of < 10 µg/dl, the rate of steroid replacement therapy initiation was 100%, 8%, and 25% when the decision was based on serum cortisol, clinical symptoms, and serum cortisol plus ACTH stimulation test results, respectively. In 90% of asymptomatic patients, hypocortisolemia resolved uneventfully within a week on repeat morning cortisol testing. 75% of patients with hypocortisolemia on POD1 demonstrated an adequate cortisol response to ACTH stimulation test. CONCLUSION: Although postoperative hypocortisolemia was observed in 37% of patients undergoing unilateral adrenalectomy for non-cortisol secreting tumors, majority did not develop symptoms of adrenal insufficiency. All three steroid initiation approaches appeared safe, with management based on clinical symptoms or selective ACTH stimulation testing sparing more patients from steroids compared to steroid initiation based on POD 1 cortisol levels alone.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Insuficiencia Suprarrenal , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/cirugía , Insuficiencia Suprarrenal/diagnóstico , Insuficiencia Suprarrenal/etiología , Insuficiencia Suprarrenal/cirugía , Adrenalectomía , Hormona Adrenocorticotrópica , Humanos , HidrocortisonaRESUMEN
OBJECTIVE: Hyperglycemia often occurs after the transition from intravenous insulin infusion (IVII) to subcutaneous insulin. Weight-based basal insulin initiated earlier in the course of IVII in the medical intensive care unit (MICU), and a weight-based basal-bolus regimen after IVII, can potentially improve post-IVII glycemic control by 48 hours. METHODS: This prospective study included 69 patients in MICU who were on IVII for ≥24 hours. Exclusions were end-stage renal disease, type 1 diabetes mellitus, and the active use of vasopressors. The intervention group received weight-based basal insulin (0.2-0.25 units/kg) with IVII and weight-based bolus insulin after IVII. The control group received current care. The primary end points were glucose levels at specific time intervals up to 48 hours after IVII. RESULTS: There were 25 patients in the intervention group and 44 in the control group. The mean age of the patients was 59 ± 15 years, 32 (47%) were men, and 52 (78%) had prior diabetes mellitus. The 2 groups were not different (acute kidney injury/chronic kidney disease, pre-existing diabetes mellitus, illness severity, or nothing by mouth status after IVII), except for the steroid use, which was higher in the control group than in the intervention group (34% vs 12%, respectively). Glucose levels were not lower until 36 to 48 hours after IVII (166.8 ± 39.1 mg/dL vs 220.0 ± 82.9 mg/dL, P < .001). When controlling for body mass index, nutritional status, hemoglobin A1C, and steroid use, glucose level was lower starting at 12 to 24 hours out (166.87 mg/dL vs 207.50 mg/dL, P = .015). The frequency of hypoglycemia was similar between the 2 groups (5.0% vs 7.1%). The study did not reach target enrollment. CONCLUSION: The addition of weight-based basal insulin during, and basal-bolus insulin immediately after, IVII in MICU results in better glycemic control at 24 hours after IVII with no increased hypoglycemia.
Asunto(s)
Hiperglucemia , Insulina , Adulto , Anciano , Glucemia , Humanos , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Infusiones Intravenosas , Insulina/uso terapéutico , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
OBJECTIVE: To determine the prevalence of obesity and assess the cardiometabolic risk profile and treatments associated with obesity management in the type 1 diabetes mellitus adult population. METHODS: We reviewed the records of all patients with type 1 diabetes mellitus seen in our institution's outpatient endocrinology clinic between 2015 and 2018. We stratified the patients into 4 weight categories on the basis of body mass index (BMI) (normal, overweight, obesity class I, and combined obesity class II and III) and evaluated their associated clinical characteristics and relevant medications. RESULTS: Of 451 patients, 64% had a BMI of >25 kg/m2, and 25% had a BMI of ≥30 kg/m2. Over 40% of patients with a BMI of >30 kg/m2 had a history of cardiovascular disease. The off-label use of the glucagon-like peptide 1 receptor agonist was 12% and the sodium glucose cotransporter 2 inhibitor use was 5% in those with obesity. Only 2 patients were prescribed phentermine and 3 had undergone bariatric surgery. Hemoglobin A1C and low-density lipoprotein did not significantly differ between the normal weight and obesity groups. The obesity groups had significantly higher levels of median triglycerides and lower high-density lipoprotein than the normal weight group. CONCLUSION: Obesity was prevalent in a population of patients with type 1 diabetes mellitus seen in a specialty clinic. Those with obesity had a higher prevalence of cardiovascular disease than their normal weight counterparts. The use of weight loss medications was scarce. Studies exploring the safety and efficacy of obesity-targeted therapy in the type 1 diabetes mellitus population are needed.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Adulto , Índice de Masa Corporal , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Obesidad/terapia , Prevalencia , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: Closed-loop insulin pump systems (artificial pancreas) represent the cutting edge of insulin delivery technology. There are only a few systems currently approved for use in the USA: the MiniMed 670G/770G (which share an algorithm), t:slim X2 Control IQ, and the Omnipod 5. We review these systems and look into the future of the technology. RECENT FINDINGS: All of the approved closed-loop insulin pump systems have demonstrated in multicenter prospective trials improvements in time in range, hemoglobin A1c, and time spent in hypoglycemia. The newer systems have also improved time spent in automation. Comparisons between the systems with regard to glycemic control are difficult to make due to differences in clinical trial design, but there are notable differences in the user experience between systems. The past few years have been a time of exponential development in the field of closed-loop insulin pump systems. However, more research is needed to provide full automation of these systems without any need for information from the user.
Asunto(s)
Diabetes Mellitus Tipo 1 , Páncreas Artificial , Glucemia , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Sistemas de Infusión de Insulina , Estudios Multicéntricos como Asunto , Estudios ProspectivosRESUMEN
OBJECTIVE: The transition of diabetes care from home to hospital, within the hospital, and upon discharge is fraught with gaps that can adversely affect patient safety and length of stay. We aimed to highlight the variability in care during these transitions and point out areas where research is needed. METHODS: A PubMed search was performed with a combination of search terms that pertained to diabetes, hyperglycemia, hospitalization, locations in the hospital, discharge to home or a nursing facility, and diabetes medications. Studies with at least 50 patients that were written in the English language were included. RESULTS: With the exception of transitioning from intravenous insulin infusion to subcutaneous insulin and perhaps admission to the regular floors, few studies pointedly focused on transitions of care, leading us to extrapolate recommendations based on data from disparate areas of care in the hospital. There is evidence at every stage of care, starting from the entry into the hospital and ending with discharge home or to a facility, that patients benefit from having protocols in place guiding overall care. CONCLUSION: Pockets of care exist in hospitals where methods of effective diabetes management have been studied and implemented. However, there is no sustained continuum of care. Protocols and care teams that follow patients from one physical location to the other may result in improved clinical outcomes during and following a hospital stay.
Asunto(s)
Hiperglucemia , Pacientes Internos , Hospitalización , Humanos , Insulina , Alta del PacienteRESUMEN
BACKGROUND: Thyroid uptake and scan (TUS) is a clinical tool used for differentiation of thyrotoxicosis etiologies. Although guidelines recommend ordering a TUS for evaluation of low TSH levels, no specific value is defined. This study aimed to determine a TSH cutoff at which TUSs yield a greater likelihood of successful determination of etiology to avoid unnecessary testing. METHODS: This was a retrospective study on 137 patients seen by an endocrinologist who underwent TUS for evaluation of low TSH (<0.4 µU/mL). A receiver operating curve analysis was performed to determine the TSH cutoff with maximal sensitivity and specificity for prediction of diagnostic utility. RESULTS: Ninety percent of TUSs (n = 123) led to a diagnosis, while 10% (n = 14) were inconclusive or normal. Diagnoses included Graves' diseases (52%), toxic multinodular goiter (19%), thyroiditis (12%), and solitary toxic adenoma (7%). The median TSH value was 0.008 µU/mL (IQR 0.005, 0.011), and the median free T4 value was 1.7 µU/mL (IQR 1.3, 2.8). The ROC analysis produced an area under the curve of 0.86. The optimal TSH cutoff value was 0.02 µU/mL (sensitivity 80%, specificity 93%) for prediction of diagnostic yield. CONCLUSION: This study demonstrates that TSH is a useful predictor of the utility of TUS in yielding an etiology of thyrotoxicosis. Our analysis showed that TUS had a greater likelihood of determining an etiology when TSH was ≤0.02 µU/mL. This information can help clinicians avoid unnecessary cost and patient time burden when TUS is unlikely to aid in determining the etiology of thyrotoxicosis.
Asunto(s)
Técnicas de Diagnóstico Endocrino/normas , Radiofármacos/farmacocinética , Enfermedades de la Tiroides/sangre , Enfermedades de la Tiroides/diagnóstico , Tirotropina/sangre , Adulto , Femenino , Bocio/sangre , Bocio/diagnóstico , Enfermedad de Graves/sangre , Enfermedad de Graves/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Sensibilidad y Especificidad , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/diagnóstico , Tiroiditis/sangre , Tiroiditis/diagnóstico , Tirotoxicosis/sangre , Tirotoxicosis/diagnósticoRESUMEN
More than 100 distinct chemical modifications to RNA have been characterized so far. However, the prevalence, mechanisms and functions of various RNA modifications remain largely unknown. To provide transcriptome-wide landscapes of RNA modifications, we developed the RMBase v2.0 (http://rna.sysu.edu.cn/rmbase/), which is a comprehensive database that integrates epitranscriptome sequencing data for the exploration of post-transcriptional modifications of RNAs and their relationships with miRNA binding events, disease-related single-nucleotide polymorphisms (SNPs) and RNA-binding proteins (RBPs). RMBase v2.0 was expanded with â¼600 datasets and â¼1 397 000 modification sites from 47 studies among 13 species, which represents an approximately 10-fold expansion when compared with the previous release. It contains â¼1 373 000 N6-methyladenosines (m6A), â¼5400 N1-methyladenosines (m1A), â¼9600 pseudouridine (Ψ) modifications, â¼1000 5-methylcytosine (m5C) modifications, â¼5100 2'-O-methylations (2'-O-Me), and â¼2800 modifications of other modification types. Moreover, we built a new module called 'Motif' that provides the visualized logos and position weight matrices (PWMs) of the modification motifs. We also constructed a novel module termed 'modRBP' to study the relationships between RNA modifications and RBPs. Additionally, we developed a novel web-based tool named 'modMetagene' to plot the metagenes of RNA modification along a transcript model. This database will help researchers investigate the potential functions and mechanisms of RNA modifications.
Asunto(s)
Bases de Datos Genéticas , Perfilación de la Expresión Génica , Procesamiento Postranscripcional del ARN , Análisis de Secuencia de ARN , 5-Metilcitosina/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Animales , Sitios de Unión , Enfermedad/genética , Variación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Ratones , MicroARNs/metabolismo , Anotación de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Seudouridina/metabolismo , ARN Largo no Codificante/química , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/metabolismo , Ratas , Interfaz Usuario-ComputadorRESUMEN
Although thousands of pseudogenes have been annotated in the human genome, their transcriptional regulation, expression profiles and functional mechanisms are largely unknown. In this study, we developed dreamBase (http://rna.sysu.edu.cn/dreamBase) to facilitate the investigation of DNA modification, RNA regulation and protein binding of potential expressed pseudogenes from multidimensional high-throughput sequencing data. Based on â¼5500 ChIP-seq and DNase-seq datasets, we identified genome-wide binding profiles of various transcription-associated factors around pseudogene loci. By integrating â¼18 000 RNA-seq data, we analysed the expression profiles of pseudogenes and explored their co-expression patterns with their parent genes in 32 cancers and 31 normal tissues. By combining microRNA binding sites, we demonstrated complex post-transcriptional regulation networks involving 275 microRNAs and 1201 pseudogenes. We generated ceRNA networks to illustrate the crosstalk between pseudogenes and their parent genes through competitive binding of microRNAs. In addition, we studied transcriptome-wide interactions between RNA binding proteins (RBPs) and pseudogenes based on 458 CLIP-seq datasets. In conjunction with epitranscriptome sequencing data, we also mapped 1039 RNA modification sites onto 635 pseudogenes. This database will provide insights into the transcriptional regulation, expression, functions and mechanisms of pseudogenes as well as their roles in biological processes and diseases.
Asunto(s)
Bases de Datos Genéticas , Seudogenes , ADN/genética , ADN/metabolismo , Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Unión Proteica/genética , ARN/genética , ARN/metabolismo , Procesamiento Postranscripcional del ARN , Proteínas de Unión al ARN/metabolismo , Análisis de Secuencia de ARNRESUMEN
Objective: It is unclear whether acute weight loss or the chronic trajectory of weight loss after bariatric surgery is associated with long-term type 2 diabetes mellitus (T2DM) glycemic improvement. This ancillary study of the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial aimed to answer this question. Methods: In STAMPEDE, 150 patients with T2DM were randomized to bariatric surgery, and 96 had 5-year follow-up. Data post-Roux-en-Y gastric bypass (RYGB, n = 49) and sleeve gastrectomy (SG, n = 47) were analyzed. We defined percent weight loss in the first year as negative percent decrease from baseline weight to lowest weight in the first year. Percent weight regain was positive percent change from lowest weight in the first year to fifth year. Weight change was then correlated with cardiometabolic (CM) and glycemic outcomes at 5 years using Spearman rank correlations and multivariate analysis. Results: In both RYGB and SG, less weight loss in the first year positively correlated with higher 5-year glycated hemoglobin (HbA1c) (RYGB, ß = +0.13; P<.001 and SG, ß = 0.14; P<.001). In SG, greater weight regain from nadir positively correlated with higher HbA1c (ß = 0.06; P = .02), but not in RYGB. Reduced first-year weight loss was also correlated with increased 5-year triglycerides (ß = 1.81; P = .01), but not systolic blood pressure. Weight regain did not correlate with CM outcomes. Conclusion: Acute weight loss may be more important for T2DM glycemic control following both RYGB and SG as compared with weight regain. Clinicians should aim to assist patients with achieving maximal weight loss in the first year post-op to maximize long-term health of patients. Abbreviations: BMI = body mass index; HbA1c = glycated hemoglobin; RYGB = Roux-en-Y gastric bypass; SBP = systolic blood pressure; SG = sleeve gastrectomy; STAMPEDE = Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently; T2DM = type 2 diabetes mellitus; TG = triglyceride.
Asunto(s)
Cirugía Bariátrica , Trayectoria del Peso Corporal , Enfermedades Cardiovasculares , Derivación Gástrica , Obesidad Mórbida , Diabetes Mellitus Tipo 2 , Humanos , Distribución AleatoriaRESUMEN
The abnormal transcriptional regulation of non-coding RNAs (ncRNAs) and protein-coding genes (PCGs) is contributed to various biological processes and linked with human diseases, but the underlying mechanisms remain elusive. In this study, we developed ChIPBase v2.0 (http://rna.sysu.edu.cn/chipbase/) to explore the transcriptional regulatory networks of ncRNAs and PCGs. ChIPBase v2.0 has been expanded with â¼10 200 curated ChIP-seq datasets, which represent about 20 times expansion when comparing to the previous released version. We identified thousands of binding motif matrices and their binding sites from ChIP-seq data of DNA-binding proteins and predicted millions of transcriptional regulatory relationships between transcription factors (TFs) and genes. We constructed 'Regulator' module to predict hundreds of TFs and histone modifications that were involved in or affected transcription of ncRNAs and PCGs. Moreover, we built a web-based tool, Co-Expression, to explore the co-expression patterns between DNA-binding proteins and various types of genes by integrating the gene expression profiles of â¼10 000 tumor samples and â¼9100 normal tissues and cell lines. ChIPBase also provides a ChIP-Function tool and a genome browser to predict functions of diverse genes and visualize various ChIP-seq data. This study will greatly expand our understanding of the transcriptional regulations of ncRNAs and PCGs.
Asunto(s)
Inmunoprecipitación de Cromatina , Bases de Datos Genéticas , Redes Reguladoras de Genes , Proteínas/genética , ARN no Traducido/genética , Análisis de Secuencia de ADN , Factores de Transcripción/metabolismo , Animales , Sitios de Unión , Proteínas de Unión al ADN/metabolismo , Perfilación de la Expresión Génica , Genómica , Humanos , Metadatos , Anotación de Secuencia Molecular , ARN no Traducido/metabolismo , Elementos Reguladores de la Transcripción , Análisis de Secuencia de ARN , Programas Informáticos , Transcripción GenéticaRESUMEN
BACKGROUND AND PURPOSE: The NLRP3 (nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a crucial component of the inflammatory response in early brain injury after subarachnoid hemorrhage (SAH). In this study, we investigated a role of dihydrolipoic acid (DHLA) in lysosomal rupture, NLRP3 activation, and determined the underlying pathway. METHODS: SAH was induced by endovascular perforation in male Sprague-Dawley rats. DHLA was administered intraperitoneally 1 hour after SAH. Small interfering RNA for lysosome-associated membrane protein-1 and CaMKIIα (calcium/calmodulin-dependent protein kinase II α) was administered through intracerebroventricular 48 hours before SAH induction. SAH grade evaluation, short- and long-term neurological function testing, Western blot, and immunofluorescence staining experiments were performed. RESULTS: DHLA treatment increased the expression of lysosome-associated membrane protein-1 and decreased phosphorylated CaMKIIα and NLRP3 inflammasome, thereby alleviating neurological deficits after SAH. Lysosome-associated membrane protein-1 small interfering RNA abolished the neuroprotective effects of DHLA and increased the level of phosphorylated CaMKIIα, p-TAK1 (phosphorylated transforming growth factor-ß-activated kinase), p-JNK (phosphorylated c-Jun-N-terminal kinase), and NLRP3 inflammasome. CaMKIIα small interfering RNA downregulated the expression of p-TAK1, p-JNK, and NLRP3 and improved the neurobehavior after SAH. CONCLUSIONS: DHLA treatment improved neurofunction and alleviated inflammation through the lysosome-associated membrane protein-1/CaMKII/TAK1 pathway in early brain injury after SAH. DHLA may provide a promising treatment to alleviate early brain injury after SAH.