TFAP2C regulates transcription in human naive pluripotency by opening enhancers.

Naive and primed pluripotent human embryonic stem cells bear transcriptional similarity to pre- and post-implantation epiblast and thus constitute a developmental model for understanding the pluripotent stages in human embryo development. To identify new transcription factors that differentially regulate the unique pluripotent stages, we mapped open chromatin using ATAC-seq and found enrichment of the activator protein-2 (AP2) transcription factor binding motif at naive-specific open chromatin. We determined that the AP2 family member TFAP2C is upregulated during primed to naive reversion and becomes widespread at naive-specific enhancers. TFAP2C functions to maintain pluripotency and repress neuroectodermal differentiation during the transition from primed to naive by facilitating the opening of enhancers proximal to pluripotency factors. Additionally, we identify a previously undiscovered naive-specific POU5F1 (OCT4) enhancer enriched for TFAP2C binding. Taken together, TFAP2C establishes and maintains naive human pluripotency and regulates OCT4 expression by mechanisms that are distinct from mouse

Neuro-Ophthalmologic Evaluation as a Biomarker for Diagnosis and Progression in Parkinson Disease

Objectives: The purpose of current neuro-ophthalmologic research is to evaluate visual dysfunction and its correlation with structural changes in the retina of patients with Parkinson’s disease and to examine whether there is an association between retinal thinning and disease progression

The Networked Forge: New Environments for Libre Software Development

Libre (free, open source) software forges (sites hosting the development infrastructure for a collection of projects) have been stable in architecture, services and concept since they become popular during the late 1990s. During this time several problems that cannot be solved without dramatic design changes have become evident. To overcome them, we propose a new concept, the “networked forge”, focused on addressing the core characteristics of libre software development and the needs of developers. The key of this proposal is to re-engineer forges as a net of distributed components which can be composed and configured according to the needs of users, using a combination of web 2.0, semantic web and mashup technologies. This approach is flexible enough to accommodate different development processes, while at the same time interoperates with current facilitie

Reparación completa quirúrgica en adultos con situación Fallot no operada o solamente paliada: ¿ficción o realidad?

Introducción-objetivos: Los pacientes con situación Fallot sin operar o solamente paliados excepcionalmente sobreviven hasta la edad adulta. Si las arterias pulmonares tienen un calibre aceptable, creemos que la reparación completa quirúrgica es viable. A continuación, revisamos nuestra experiencia. Métodos: Estudio retrospectivo de 27 adultos con situación Fallot no operada o solo paliada y reparación completa quirúrgica entre 1991-2014. Resultados: Edad media ± desviación estándar: 35,6 ± 10,6 años, 59% varones, paliación previa 18,5%. Diagnóstico principal: ventrículo derecho bicameral + comunicación interventricular (48%), tetralogía de Fallot clásica (30%). Grado funcional NYHA: I-26%, II-30%, III-44%. Arritmia: 22%. Hematocrito medio: 49 ± 11%. Asociaban agenesia arteria pulmonar izquierda (11%), insuficiencia aórtica severa (11%). Las pruebas complementarias mostraban gradientes elevados entre ventrículo derecho-arteria pulmonar y buena contractilidad biventricular. Operados por esternotomía media con extracorpórea, hipotermia moderada y pinzamiento aórtico. Cierre de comunicación interventricular desde la aurícula derecha: 63%. Reconstrucción del tracto de salida derecho conservando la válvula pulmonar (78%), interponiendo bioprótesis (15%) y con parche transanular (7%). Cirugía asociada en 5 pacientes (18,5%): tricúspide (1), aórtica (4). Sin mortalidad hospitalaria. Seguimiento medio 8,4 ± 6,3 años (máximo 19,75). Un paciente fallece tardíamente. Reoperación en 3 pacientes (11%) por lesiones residuales. Actualmente grado funcional i65%, ii31%, iii4%, estando el 92% en ritmo sinusal. Conclusiones: La reparación completa del adulto con situación Fallot consigue mejoría clínica al eliminar la cianosis, cerrar los cortocircuitos intracardiacos y disminuir la sobrecarga de presión del ventrículo derecho. Esta reparación tiene resultados excelentes y permite superiores tasas de conservación del anillo pulmonar respecto a las series infantiles

Transcriptome and proteome profiling of primary human gastric interstitial cells of Cajal predicts pacemaker networks

Background/Aims Interstitial cells of Cajal (ICC) are specialized gastrointestinal (GI) pacemaker cells required for normal GI motility. Dysfunctions in ICC have been reported in patients with GI motility disorders, such as gastroparesis, who exhibit debilitating symptoms and greatly reduced quality of life. While the proteins, calcium-activated chloride channel anoctamin-1 (ANO1) and the receptor tyrosine kinase (KIT), are known to be expressed by human ICC, relatively little is known about the broad molecular circuitry underpinning human ICC functions. The present study therefore investigates the transcriptome and proteome of ANO1-expressing, KITlow/CD45–/CD11B– ICC obtained from primary human gastric tissue. Methods Excess human gastric tissue resections were obtained from sleeve gastrectomy patients. ICC were purified using fluorescence-activated cell sorting (FACSorting). Then, ICC were characterized by using immunofluorescence, real-time polymerase chain reaction, RNA-sequencing and mass spectrometry. Results Compared to unsorted cells, real-time polymerase chain reaction showed the KITlow/CD45–/CD11B– ICC had: a 9-fold (P 10-fold, P 4-fold, P < 0.05). RNA-sequencing and gene ontology analyses of the KITlow/ CD45–/CD11B– cells revealed a transcriptional profile consistent with ICC function. Similarly, mass spectrometry analyses of the KITlow/ CD45–/CD11B– cells presented a proteomic profile consistent with ICC activities. STRING-based protein interaction analyses using the RNA-sequencing and proteomic datasets predicted protein networks consistent with ICC-associated pacemaker activity and ion transport. Conclusion These new and complementary datasets provide a valuable molecular framework for further understanding how ICC pacemaker activity regulates smooth muscle contraction in both normal GI tissue and GI motility disorders

〈初期軍記〉における戦闘被害の表現-女の描かれ方をめぐって-

軍記・語り物研究会第374回例会(平成19年7月22日・於:法政大学)共同討議「初期軍記」研究の検証と展開-新たな「状況」と「変容」を探る-における基調報

Combination Therapy With Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Older Patients With Type 2 Diabetes: A Real-World Evidence Study

Objectives: Scientific literature about the combination of glucagon-like peptide-1 receptor agonists (GLP1ra) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in older patients is scarce. We sought to assess the real-world efficacy and safety of SGLT2 inhibitors and GLP-1ra combination therapy in older patients (>65 years of age). Methods: This was an observational, prospective, multicenter study based on clinical practice. Patients were stratified according to tertiles of baseline glycated hemoglobin (A1C) levels and to treatment schedule. Results: We included 113 patients (65.5% men, mean age 70.4±8.8 years). The body mass index was 36.5 (±6.6) kg/m2. The baseline A1C level was 8.0% (±1.2%). At the 6-month follow up, we found a significant reduction in A1C levels (–1.1%; p<0.0001), body mass index (–2.1 kg/m2; p<0.00003) and systolic blood pressure (–13 mmHg; p<0.000005). Patients who had the highest baseline A1C levels (≥8.4%) showed greater improvement in A1C levels (p<0.0001), weight (p<0.0001) and quality-of-life scores (p<0.0001). The greatest reduction in A1C levels and weight was seen in patients who started both drugs simultaneously (p<0.0001). The second greatest reduction was seen when GLP-1ra was added to previous treatment with an SGLT2i (p<0.0001). Also of note was a decrease in systolic blood pressure in patients for whom an SGLT2i was added to previous GLP-1ra treatment (p<0.0001). Of the patients, 34.3% achieved the combined endpoint of A1C levels <7% and weight loss ≥5% without hypoglycemia. Conclusions: This study’s findings provide evidence of clinically meaningful reductions in A1C level, body weight and systolic blood pressure in older patients with type 2 diabetes who are taking combined regimens. The dropout and hypoglycemia rates were minimal, and treatment was tolerated well

Early biomarkers of diabetic kidney disease. A focus on albuminuria and a new combination of antidiabetic agents

Aims: We aimed to determine the efficacy and safety of sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists to prevent worsening urinary albumin-to-creatinine ratio as an early biomarker of diabetes kidney disease. Methods: A total of 178 patients with type 2 diabetes and obesity received combination treatment with SGLT2i added to GLP1ra (n = 76), GLP1ra added to SGLT2i (n = 50) or GLP1ra plus SGLT2i from start (n = 52), according to investigators´ best clinical judgement. Major outcomes assessed at 26 weeks were changes in urine albumintocreatinine-ratio (UACR), estimated glomerular filtration rate (eGFR), glycated haemoglobin, body weight and systolic blood pressure. Results: All patients (58.6% men, mean age 61.9 ± 10.0 years) completed the study. Baseline HbA1c, weight and eGFR levels were 8.2 ± 0.9%, 109.9 ± 19 kg and 83.3 ± 19.6 mL/min/m2 , respectively. At 26 weeks, we found significant reductions in HbA1c (1.16%), weight (5.17 kg) and systolic blood pressure (8.13 mmHg). The reduction in UACR was 15.14 mg/g (95% CI 8.50-22.4) (-24.6 ± 64.7%), which was greatest in the group of patients with SGLT2i added on to GLP1ra therapy (116.7 mg/g; 95% CI: 54-296.5 mg/g; P < .001. Patients with urinary albumin-to-creatinine ratio ≥30 mg/g, showed a higher declines (63.18 mg/g [95% CI 44.5-104.99]) (-56 ± 65.9%). The greatest reduction in urinary albumin-to-creatinine ratio was obtained when SGLT2i was added to GLP1ra (116.7 mg/g). The eGFR did not significantly change along the study period. Conclusion: Our results show the beneficial effect of GLP1ra and SGLT2i combination therapy on early biomarkers of diabetes kidney disease such as albuminuria and in other significant outcomes for diabetes control