Imbalances of excitatory/inhibitory synaptic transmission occur early in the pathogenesis of Alzheimer's disease (AD), leading to hippocampal hyperexcitability and causing synaptic, network, and ...cognitive dysfunctions. G-protein-gated potassium (GirK) channels play a key role in the control of neuronal excitability, contributing to inhibitory signaling. Here, we evaluate the relationship between GirK channel activity and inhibitory hippocampal functionality in vivo. In a non-transgenic mouse model of AD, field postsynaptic potentials (fPSPs) from the CA3⁻CA1 synapse in the dorsal hippocampus were recorded in freely moving mice. Intracerebroventricular (ICV) injections of amyloid-
(A
) or GirK channel modulators impaired ionotropic (GABA
-mediated fPSPs) and metabotropic (GirK-mediated fPSPs) inhibitory signaling and disrupted the potentiation of synaptic inhibition. However, the activation of GirK channels prevented A
-induced changes in GABA
components. Our data shows, for the first time, the presence of long-term potentiation (LTP) for both the GABA
and GirK-mediated inhibitory postsynaptic responses in vivo. In addition, our results support the importance of an accurate level of GirK-dependent signaling for dorsal hippocampal performance in early amyloid pathology models by controlling the excess of excitation that disrupts synaptic plasticity processes.
En los últimos años, Wattpad se ha convertido en una de las plataformas de lectura y escritura colaborativa de referencia en la que jóvenes escritores publican sus trabajos, algunos de ellos ...enmarcados en la tradición de la fan fiction, historias derivadas de un texto fuente de la cultura de masas. El presente artículo tiene como objetivo principal explorar cómo se articulan las competencias transmedia de producción y de reflexión narrativa y estética de los adolescentes que leen y/o escriben fanfics en Wattpad. A partir de un marco teórico en el que se integran el alfabetismo transmedia, las comunidades de fan fiction como espacios de afinidad, y Wattpad como aplicación para el fomento de lectura transmedia, se ha llevado a cabo un estudio cualitativo con datos procedentes de talleres, diarios mediáticos y entrevistas con adolescentes en 5 comunidades autónomas. Los resultados destacan un juego de identidades en la producción de los relatos, en los que conviven fanfics sobre las celebridades reales que protagonizan los universos mediáticos de los jóvenes, e historias originales inspiradas en las vidas personales o inquietudes de los autores. Asimismo, se observa una tendencia hacia la hibridación de la fan fiction con lenguajes y formatos propios de las redes sociales, como Instagram, y una aplicación superficial de las competencias transmedia de narrativa y estética vinculadas a la práctica de la fan fiction.
Chronic lymphocytic leukemia (CLL) is a highly genetically heterogeneous disease. Although CLL has been traditionally considered as a mature B cell leukemia, few independent studies have shown that ...the genetic alterations may appear in CD34+ hematopoietic progenitors. However, the presence of both chromosomal aberrations and gene mutations in CD34+ cells from the same patients has not been explored.
Amplicon-based deep next-generation sequencing (NGS) studies were carried out in magnetically activated-cell-sorting separated CD19+ mature B lymphocytes and CD34+ hematopoietic progenitors (n = 56) to study the mutational status of TP53, NOTCH1, SF3B1, FBXW7, MYD88, and XPO1 genes. In addition, ultra-deep NGS was performed in a subset of seven patients to determine the presence of mutations in flow-sorted CD34+CD19- early hematopoietic progenitors. Fluorescence in situ hybridization (FISH) studies were performed in the CD34+ cells from nine patients of the cohort to examine the presence of cytogenetic abnormalities.
NGS studies revealed a total of 28 mutations in 24 CLL patients. Interestingly, 15 of them also showed the same mutations in their corresponding whole population of CD34+ progenitors. The majority of NOTCH1 (7/9) and XPO1 (4/4) mutations presented a similar mutational burden in both cell fractions; by contrast, mutations of TP53 (2/2), FBXW7 (2/2), and SF3B1 (3/4) showed lower mutational allele frequencies, or even none, in the CD34+ cells compared with the CD19+ population. Ultra-deep NGS confirmed the presence of FBXW7, MYD88, NOTCH1, and XPO1 mutations in the subpopulation of CD34+CD19- early hematopoietic progenitors (6/7). Furthermore, FISH studies showed the presence of 11q and 13q deletions (2/2 and 3/5, respectively) in CD34+ progenitors but the absence of IGH cytogenetic alterations (0/2) in the CD34+ cells. Combining all the results from NGS and FISH, a model of the appearance and expansion of genetic alterations in CLL was derived, suggesting that most of the genetic events appear on the hematopoietic progenitors, although these mutations could induce the beginning of tumoral cell expansion at different stage of B cell differentiation.
Our study showed the presence of both gene mutations and chromosomal abnormalities in early hematopoietic progenitor cells from CLL patients.
To assess the safety, aberrometric and keratometric changes, and stability of trans-epithelial topography-guided phototherapeutic keratectomy (TE-TG-PTK) with mitomycin C (MMC) using the ALLEGRO ...Topolyzer platform for the treatment of irregular astigmatism.
This is a retrospective case series including 57 eyes that underwent TE-TG-PTK + MMC using the ALLEGRO Topolyzer platform for the treatment of irregular astigmatism. CDVA, manifest refraction (MR), keratometry readings, and aberrometry readings were analyzed at 1, 3, 6, and 12 months.
Causes of corneal irregularity included non-infectious leucoma (n=23), infectious leucoma (n=7), adenoviral keratitis (n=20), corneal haze (n=2), post-penetrant keratoplasty (PKP) (n=1), and others (n=4). Overall, 76% of the eyes (n=40) gained lines of vision; patients gained 1, and 2 or more lines of vision in 76%, and 38% of cases, respectively. Only 1 patient (2%) lost 5 lines of vision. Mean preoperative CDVA (LogMAR) was 0.37 ±0.31 and improved to 0.14 ±0.18 (p<0.001) at final follow-up (12 months). CDVA remained unchanged in 10 eyes (21%). No significant changes were observed in mean keratometry (Kmean) and keratometric astigmatism readings. Regarding aberrometry, only changes in coma proved to be significant 6 months after surgery (P<0.01). No intraoperative/postoperative complications were reported.
At final follow-up, significant improvements were observed in CDVA and coma. TE-TG-PTK + MMC proved to be an effective and safe procedure for the treatment of corneal irregular astigmatism due to several causes.
Consumption of fruits and vegetables is associated with a lower overall mortality. The aim of this study was to identify causes of death through which this association is established. More than ...450,000 participants from the European Prospective Investigation into Cancer and Nutrition study were included, of which 25,682 were reported deceased after 13 years of follow-up. Information on lifestyle, diet and vital status was collected through questionnaires and population registries. Hazard ratios (HR) with 95 % confidence intervals (95 % CI) for death from specific causes were calculated from Cox regression models, adjusted for potential confounders. Participants reporting consumption of more than 569 g/day of fruits and vegetables had lower risks of death from diseases of the circulatory (HR for upper fourth 0.85, 95 % CI 0.77-0.93), respiratory (HR for upper fourth 0.73, 95 % CI 0.59-0.91) and digestive system (HR for upper fourth 0.60, 95 % CI 0.46-0.79) when compared with participants consuming less than 249 g/day. In contrast, a positive association with death from diseases of the nervous system was observed. Inverse associations were generally observed for vegetable, but not for fruit consumption. Associations were more pronounced for raw vegetable consumption, when compared with cooked vegetable consumption. Raw vegetable consumption was additionally inversely associated with death from neoplasms and mental and behavioral disorders. The lower risk of death associated with a higher consumption of fruits and vegetables may be derived from inverse associations with diseases of the circulatory, respiratory and digestive system, and may depend on the preparation of vegetables and lifestyle factors.
Epigenetic modifications, characterized by changes in gene expression without altering the DNA sequence, play a crucial role in the development and progression of cancer by significantly influencing ...gene activity and cellular function. This insight has led to the development of a novel class of therapeutic agents, known as epigenetic drugs. These drugs, including histone deacetylase inhibitors, histone acetyltransferase inhibitors, histone methyltransferase inhibitors, and DNA methyltransferase inhibitors, aim to modulate gene expression to curb cancer growth by uniquely altering the epigenetic landscape of cancer cells. Ongoing research and clinical trials are rigorously evaluating the efficacy of these drugs, particularly their ability to improve therapeutic outcomes when used in combination with other treatments. Such combination therapies may more effectively target cancer and potentially overcome the challenge of drug resistance, a significant hurdle in cancer therapy. Additionally, the importance of nutrition, inflammation control, and circadian rhythm regulation in modulating drug responses has been increasingly recognized, highlighting their role as critical modifiers of the epigenetic landscape and thereby influencing the effectiveness of pharmacological interventions and patient outcomes. Epigenetic drugs represent a paradigm shift in cancer treatment, offering targeted therapies that promise a more precise approach to treating a wide spectrum of tumors, potentially with fewer side effects compared to traditional chemotherapy. This progress marks a step towards more personalized and precise interventions, leveraging the unique epigenetic profiles of individual tumors to optimize treatment strategies.
OBJECTIVE Age at menopause is an important determinant of future health outcomes, but little is known about its relationship with type 2 diabetes. We examined the associations of menopausal age and ...reproductive life span (menopausal age minus menarcheal age) with diabetes risk. RESEARCH DESIGN AND METHODS Data were obtained from the InterAct study, a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition. A total of 3,691 postmenopausal type 2 diabetic case subjects and 4,408 subcohort members were included in the analysis, with a median follow-up of 11 years. Prentice weighted Cox proportional hazards models were adjusted for age, known risk factors for diabetes, and reproductive factors, and effect modification by BMI, waist circumference, and smoking was studied. RESULTS Mean (SD) age of the subcohort was 59.2 (5.8) years. After multivariable adjustment, hazard ratios (HRs) of type 2 diabetes were 1.32 (95% CI 1.04–1.69), 1.09 (0.90–1.31), 0.97 (0.86–1.10), and 0.85 (0.70–1.03) for women with menopause at ages <40, 40–44, 45–49, and ≥55 years, respectively, relative to those with menopause at age 50–54 years. The HR per SD younger age at menopause was 1.08 (1.02–1.14). Similarly, a shorter reproductive life span was associated with a higher diabetes risk (HR per SD lower reproductive life span 1.06 1.01–1.12). No effect modification by BMI, waist circumference, or smoking was observed (P interaction all > 0.05). CONCLUSIONS Early menopause is associated with a greater risk of type 2 diabetes.
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