Computación molecular y óptica

Los progresos de la informática están íntimamente ligados a los desarrollos de la arquitectura de los procesadores que, a su vez, son posibles gracias a los progresos logrados en otras ramas de la ciencia. La arquitectura de los procesadores $urgió de la conjunción de la electrónica y la noción de "máquina secuencial de programa registrado" formulada por el matemático John von Newman. Este modelo está constituido por dos partes básicas: una memoria 'central y un procesador, que a su vez posee dos partes: la unidad de procesamiento y la unidad de control

Caribbean Corals in Crisis: Record Thermal Stress, Bleaching, and Mortality in 2005

BACKGROUND The rising temperature of the world's oceans has become a major threat to coral reefs globally as the severity and frequency of mass coral bleaching and mortality events increase. In 2005, high ocean temperatures in the tropical Atlantic and Caribbean resulted in the most severe bleaching event ever recorded in the basin. METHODOLOGY/PRINCIPAL FINDINGS Satellite-based tools provided warnings for coral reef managers and scientists, guiding both the timing and location of researchers' field observations as anomalously warm conditions developed and spread across the greater Caribbean region from June to October 2005. Field surveys of bleaching and mortality exceeded prior efforts in detail and extent, and provided a new standard for documenting the effects of bleaching and for testing nowcast and forecast products. Collaborators from 22 countries undertook the most comprehensive documentation of basin-scale bleaching to date and found that over 80% of corals bleached and over 40% died at many sites. The most severe bleaching coincided with waters nearest a western Atlantic warm pool that was centered off the northern end of the Lesser Antilles. CONCLUSIONS/SIGNIFICANCE Thermal stress during the 2005 event exceeded any observed from the Caribbean in the prior 20 years, and regionally-averaged temperatures were the warmest in over 150 years. Comparison of satellite data against field surveys demonstrated a significant predictive relationship between accumulated heat stress (measured using NOAA Coral Reef Watch's Degree Heating Weeks) and bleaching intensity. This severe, widespread bleaching and mortality will undoubtedly have long-term consequences for reef ecosystems and suggests a troubled future for tropical marine ecosystems under a warming climate.This work was partially supported by salaries from the NOAA Coral Reef Conservation Program to the NOAA Coral Reef Conservation Program authors. NOAA provided funding to Caribbean ReefCheck investigators to undertake surveys of bleaching and mortality. Otherwise, no funding from outside authors' institutions was necessary for the undertaking of this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice

Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography–mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance

Sorting out fate determination.

How organ morphogenesis specifies cell fate and whether organ progenitors are predetermined or specified via niche signals are critical developmental biology questions. In this issue of Developmental Cell, Nyeng et al. (2019) modulate cell-cell adhesion in the pancreas and provide evidence that progenitors are plastic and instructed by niche signals

Wnt signaling: Implications in endoderm development and pancreas organogenesis.

The pancreas is derived from the foregut endoderm during embryonic development. After gastrulation and endoderm germ layer formation complex morphogenetic events coupled with cell differentiation programs pattern the gut tube and induce pancreas organogenesis. This results in formation of exocrine, ductal and hormone-producing endocrine cells. Among these, endocrine cells are responsible for blood glucose homeostasis and their malfunction leads to diabetes mellitus, which cannot be stopped or reversed by the current standard treatments. Thus, intense efforts to regenerate or replace the lost or dysfunctional insulin-producing beta-cells are on the way. This depends on identifying the factors that coordinate pancreas organogenesis. Here, we highlight the contribution of canonical and non-canonical Wnt signaling branches in orchestrating endoderm formation, pancreatic morphogenesis as well as endocrine cell formation and function

Cellular and molecular mechanisms coordinating pancreas development.

The pancreas is an endoderm-derived glandular organ that participates in the regulation of systemic glucose metabolism and food digestion through the function of its endocrine and exocrine compartments, respectively. While intensive research has explored the signaling pathways and transcriptional programs that govern pancreas development, much remains to be discovered regarding the cellular processes that orchestrate pancreas morphogenesis. Here, we discuss the developmental mechanisms and principles that are known to underlie pancreas development, from induction and lineage formation to morphogenesis and organogenesis. Elucidating such principles will help to identify novel candidate disease genes and unravel the pathogenesis of pancreas-related diseases, such as diabetes, pancreatitis and cancer

β-cell maturation and identity in health and disease.

The exponential increase of patients with diabetes mellitus urges for novel therapeutic strategies to reduce the socioeconomic burden of this disease. The loss or dysfunction of insulin-producing beta -cells, in patients with type 1 and type 2 diabetes respectively, put these cells at the center of the disease initiation and progression. Therefore, major efforts have been taken to restore the beta -cell mass by cell-replacement or regeneration approaches. Implementing novel therapies requires deciphering the developmental mechanisms that generate beta -cells and determine the acquisition of their physiological phenotype. In this review, we summarize the current understanding of the mechanisms that coordinate the postnatal maturation of beta -cells and define their functional identity. Furthermore, we discuss different routes by which beta -cells lose their features and functionality in type 1 and 2 diabetic conditions. We then focus on potential mechanisms to restore the functionality of those beta -cell populations that have lost their functional phenotype. Finally, we discuss the recent progress and remaining challenges facing the generation of functional mature beta -cells from stem cells for cell-replacement therapy for diabetes treatment

Analysis of the role of synaptotagmin 13 in pancreatic beta-cell function and islet architecture.

In rodents, development of islets of Langerhans starts with the specification of the endocrine lineage during secondary transition of pancreas morphogenesis. In this process, endocrine cells leave the ductal epithelium and form clusters which became functional islets upon maturation after birth. Previously, we identified Synaptotagmin 13 (Syt13) as a novel endocrine lineage determinant during mouse pancreas development. 3D culture from Syt13-kock-out mice reveals a mitotic spindle positioning function of this protein. Additionally, in mice lacking of Syt13, endocrine cells differentiate but they do not go through a proper delamination to leave the epithelium, indicating that spindle position could be necessary for this process. In mature islets expression of Syt13 is restricted to β-cells. Due to the prenatal lethality of Syt13 knock-out mice it is not possible to analyze its role in mature β-cell function and islet structure. Therefore, we are generating Syt13 conditional knock-out mouse using different Cre lines (Ngn3, Pdx1 and Insulin). Preliminary data from hypomorphic mice with reduced levels of Syt13 show an alteration in islet structure with an increase in α-cell number. Moreover, immunostaining of human pancreas reveals expression of this protein in β-cells implicating a potential role of Syt13 in islet function. This is supported by a correlation of single nucleotide polymorphism (SNP) analysis of the Syt13 intron with changes in insulin secretion in a cohort of patients with increased risk of diabetes, highlighting the importance of Syt13 in human β-cell function. Addressing the role of Syt13 regarding the pancreatic β-cell function and islet architecture will provide patomechanism of diabetes and will allow to regenerate β-cell mass and/or function

Establishment of a high-resolution 3D modeling system for studying pancreatic epithelial cell biology in vitro.

Objective: Translation of basic research from bench-to-bedside relies on a better understanding of similarities and differences between mouse and human cell biology, tissue formation, and organogenesis. Thus, establishing ex vivo modeling systems of mouse and human pancreas development will help not only to understand evolutionary conserved mechanisms of differentiation and morphogenesis but also to understand pathomechanisms of disease and design strategies for tissue engineering.Methods: Here, we established a simple and reproducible Matrigel-based three-dimensional (3D) cyst culture model system of mouse and human pancreatic progenitors (PPs) to study pancreatic epithelialization and endocrinogenesis ex vivo. In addition, we reanalyzed previously reported single-cell RNA sequencing (scRNA-seq) of mouse and human pancreatic lineages to obtain a comprehensive picture of differential expression of key transcription factors (TFs), cell-cell adhesion molecules and cell polarity components in PPs during endocrinogenesis.Results: We generated mouse and human polarized pancreatic epithelial cysts derived from PPs. This system allowed to monitor establishment of pancreatic epithelial polarity and lumen formation in cellular and sub-cellular resolution in a dynamic time-resolved fashion. Furthermore, both mouse and human pancreatic cysts were able to differentiate towards the endocrine fate. This differentiation system together with scRNA-seq analysis revealed how apical-basal polarity and tight and adherens junctions change during endocrine differentiation.Conclusions: We have established a simple 3D pancreatic cyst culture system that allows to tempo-spatial resolve cellular and subcellular processes on the mechanistical level, which is otherwise not possible in vivo

Synaptotagmin-13 is a neuroendocrine marker in brain, intestine and pancreas.

Synaptotagmin-13 (Syt13) is an atypical member of the vesicle trafficking synaptotagmin protein family. The expression pattern and the biological function of this Ca2+-independent protein are not well resolved. Here, we have generated a novel Syt13-Venus fusion (Syt13-VF) fluorescence reporter allele to track and isolate tissues and cells expressing Syt13 protein. The reporter allele is regulated by endogenous cis-regulatory elements of Syt13 and the fusion protein follows an identical expression pattern of the endogenous Syt13 protein. The homozygous reporter mice are viable and fertile. We identify the expression of the Syt13-VF reporter in different regions of the brain with high expression in tyrosine hydroxylase (TH)-expressing and oxytocin-producing neuroendocrine cells. Moreover, Syt13-VF is highly restricted to all enteroendocrine cells in the adult intestine that can be traced in live imaging. Finally, Syt13-VF protein is expressed in the pancreatic endocrine lineage, allowing their specific isolation by flow sorting. These findings demonstrate high expression levels of Syt13 in the endocrine lineages in three major organs harboring these secretory cells. Collectively, the Syt13-VF reporter mouse line provides a unique and reliable tool to dissect the spatio-temporal expression pattern of Syt13 and enables isolation of Syt13-expressing cells that will aid in deciphering the molecular functions of this protein in the neuroendocrine system