Pancreatic β-cell regeneration: advances in understanding the genes and signaling pathways involved.

Diabetes mellitus is a metabolic disorder characterized by dysfunction, loss, or insufficient mass of β cells. The main function of β cells is to produce and secrete insulin, the hormone responsible for the regulation of blood glucose levels. Type 1 diabetes (T1D) results from autoimmune destruction of β cells, while type 2 diabetes (T2D) mostly results from β-cell dysfunction or peripheral tissue resistance to insulin, often culminating in β-cell death. Thus, both forms of diabetes can benefit from restoration of β-cell mass. Currently, islet transplantation is the only way to provide new β cells to diabetic patients, but the scarcity of compatible cadaveric donors makes this approach available to only few patients; moreover, it requires lifelong immune suppression

Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas

The question of whether dedicated progenitor cells exist in adult vertebrate pancreas remains controversial. Centroacinar cells and terminal duct (CA/TD) cells lie at the junction between peripheral acinar cells and the adjacent ductal epithelium, and are frequently included among cell types proposed as candidate pancreatic progenitors. However these cells have not previously been isolated in a manner that allows formal assessment of their progenitor capacities. We have found that a subset of adult CA/TD cells are characterized by high levels of ALDH1 enzymatic activity, related to high-level expression of both Aldh1a1 and Aldh1a7. This allows their isolation by FACS using a fluorogenic ALDH1 substrate. FACS-isolated CA/TD cells are relatively depleted of transcripts associated with differentiated pancreatic cell types. In contrast, they are markedly enriched for transcripts encoding Sca1, Sdf1, c-Met, Nestin, and Sox9, markers previously associated with progenitor populations in embryonic pancreas and other tissues. FACS-sorted CA/TD cells are uniquely able to form self-renewing 'pancreatospheres' in suspension culture, even when plated at clonal density. These spheres display a capacity for spontaneous endocrine and exocrine differentiation, as well as glucose-responsive insulin secretion. In addition, when injected into cultured embryonic dorsal pancreatic buds, these adult cells display a unique capacity to contribute to both the embryonic endocrine and exocrine lineages. Finally, these cells demonstrate dramatic expansion in the setting of chronic epithelial injury. These findings suggest that CA/TD cells are indeed capable of progenitor function and may contribute to the maintenance of tissue homeostasis in adult mouse pancreas

Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation

Pancreatic β-cells are an essential source of insulin and their destruction because of autoimmunity causes type I diabetes. We conducted a chemical screen to identify compounds that would induce the differentiation of insulin-producing β-cells in vivo. To do this screen, we brought together the use of transgenic zebrafish as a model of β-cell differentiation, a unique multiwell plate that allows easy visualization of lateral views of swimming larval fish and a library of clinical drugs. We identified six hits that can induce precocious differentiation of secondary islets in larval zebrafish. Three of these six hits were known drugs with a considerable background of published data on mechanism of action. Using pharmacological approaches, we have identified and characterized two unique pathways in β-cell differentiation in the zebrafish, including down-regulation of GTP production and retinoic acid biosynthesis

Bioselection Reveals miR-99b and miR-485 as Enhancers of Adenoviral Oncolysis in Pancreatic Cancer

Oncolytic viruses are designed for cancer treatment. Cell-virus interactions are key determinants for successful viral replication. Therefore, the extensive reprogramming of gene expression that occurs in tumor cells might create a hurdle for viral propagation. We used a replication-based approach of a microRNA (miRNA) adenoviral library encoding up to 243 human miRNAs as a bioselection strategy to identify miRNAs that facilitate adenoviral oncolytic activity in pancreatic ductal adenocarcinoma. We identify two miRNAs, miR-99b and miR-85, that function as enhancers of adenoviral oncolysis by improving the intra-and extracellular yield of mature virions. An increased adenoviral activity is the consequence of enhanced E1A and late viral protein expression, which is probably mediated by the downregulation of the transcriptional repressors ELF4, MDM2, and KLF8, which we identify as miR-99b or miR-485 target genes. Arming the oncolytic adenovirus ICOVIR15 with miR-99b or miR-485 enhances its fitness and its antitumoral activity. Our results demonstrate the potential of this strategy to improve oncolytic adenovirus potency, and they highlight miR-99b and miR-485 as sensitizers of adenoviral replication

The Acquisition of Phrasal Verbs by Catalan Learners of English. Preference for One-Word verbs rather than Two-word combinations

English phrasal verbs have been considered one of the most difficult structures for ESL students to master as a counterpart is rarely found in the L1. Existing literature on the field seems to provide evidence for avoidance inducing factors such as the structural differences between L1-L2 and the highly idiomatic nature of phrasal verbs (Dagut and Laufer 1985; Gaston, 2004; Hulstijn and Marchena,1989; Laufer and Eliasson, 1993; Liao and Fukuya, 2004). Additionally, the semantic component of phrasal verbs has been given a short shrift. This paper aims to examine whether there is avoidance in advanced Catalan ESL learners and whether avoidance of phrasal verbs is triggered by semantic reasons.Durant el procés d' adquisició de l'anglès com a segona llengua o com a llengua estrangera, una de les majors dificultats per els estudiants són els anomenats phrasal verbs. Aquest tipus d'estructures només es troben en la família de llengües germàniques i per tant no es troba una forma equivalent en les llengües no-germàniques. Està demostrat en els estudis sobre aquest tema que els estudiants tendeixen a evitar aquest tipus de verbs optant per aquella forma similar a la llengua materna. Les raons per les quals els phrasal verbs resulten difícils són bàsicament per diferències estructurals entre la llengua materna i la llengua estrangera i també la semàntica dels phrasal verbs que es caracteritza per ser altament figurativa. Aquest treball examina la producció de phrasal verbs per part d'estudiants avançats d'anglès i si hi ha alguna relació en la semàntica d'aquests verbs i la conseqüent evitació

Implication of breast cancer phenotype for patients with leptomeningeal carcinomatosis

Abstract Background We aimed to study the implications of breast cancer (BC) subtypes for the development and prognosis of leptomeningeal carcinomatosis (LC). Patients and methods Data from the breast cancer patients diagnosed with LC between 2005 and 2010 were retrieved. Patients were classified in luminal A, B, HER2 positive and triple negative (TN) and their BC diagnosis, treatment, and outcome were analyzed according to each subtype. Pearson's chi-square and Fisher's exact test were used for categorical variables. Survival analyses were performed by Kaplan–Meier method and compared with the log-rank test. Results A total of 38 BC patients were identified, with a median age of 54.8 years (range 36–79). The proportion of luminal A, B, HER2 positive and TN was 18.4%, 31.6%, 26.3% and 23.7%, respectively. LC was the first evidence of metastatic disease in 5 BC patients. Twenty patients received the systemic chemotherapy, with 16 (80%) whole brain radiotherapy (WBRT). Nine patients received only WBRT. TN patients had the shorter interval between metastatic breast cancer diagnosis and the development of LC. Median survival after the diagnosis of LC (OSLC) was 2.6 months (range 1.2–6.4), and did not differ across breast cancer subtypes. In univariate analysis, performance status (ECOG = 0–2) and chemotherapy were prognostic for OSLC, but only the treatment stood as an independent prognostic factor in multivariate analysis. Conclusions Breast cancer subtype influences the timing of LC appearance, but not OSLC. Patients with LC from breast cancer should be offered systemic treatment, as it appears to associate with the improved outcome. New therapeutic strategy, including, targeted and intrathecal therapy are deserved for BC patients with LC

Centroacinar cells are progenitors that contribute to endocrine pancreas regeneration

Diabetes is associated with a paucity of insulin-producing β-cells. With the goal of finding therapeutic routes to treat diabetes, we aim to find molecular and cellular mechanisms involved in β-cell neogenesis and regeneration. To facilitate discovery of such mechanisms, we use a vertebrate organism where pancreatic cells readily regenerate. The larval zebrafish pancreas contains Notch-responsive progenitors that during development give rise to adult ductal, endocrine, and centroacinar cells (CACs). Adult CACs are also Notch responsive and are morphologically similar to their larval predecessors. To test our hypothesis that adult CACs are also progenitors, we took two complementary approaches: 1) We established the transcriptome for adult CACs. Using gene ontology, transgenic lines, and in situ hybridization, we found that the CAC transcriptome is enriched for progenitor markers. 2) Using lineage tracing, we demonstrated that CACs do form new endocrine cells after β-cell ablation or partial pancreatectomy. We concluded that CACs and their larval predecessors are the same cell type and represent an opportune model to study both β-cell neogenesis and β-cell regeneration. Furthermore, we show that in cftr loss-of-function mutants, there is a deficiency of larval CACs, providing a possible explanation for pancreatic complications associated with cystic fibrosis

Eye movements in patients with post-COVID condition

Eye movement control is impaired in some neurological conditions, but the impact of COVID-19 on eye movements remains unknown. This study aims to investigate differences in oculomotor function and pupil response in individuals who suffer post-COVID-19 condition (PCC) with cognitive deficits. Saccades, smooth pursuit, fixation, vergence and pupillary response were recorded using an eye tracker. Eye movements and pupil response parameters were computed. Data from 16 controls, 38 COVID mild (home recovery) and 19 COVID severe (hospital admission) participants were analyzed. Saccadic latencies were shorter in controls (183¿±¿54 ms) than in COVID mild (236¿±¿83 ms) and COVID severe (227¿±¿42 ms) participants (p¿=¿0.017). Fixation stability was poorer in COVID mild participants (Bivariate Contour Ellipse Area of 0.80¿±¿1.61°2 vs 0.36¿±¿0.65 °2 for controls, p¿=¿0.019), while percentage of pupil area reduction/enlargement was reduced in COVID severe participants (39.7¿±¿12.7%/31.6¿±¿12.7% compared to 51.7¿±¿22.0%/49.1¿±¿20.7% in controls, p¿<¿0.015). The characteristics of oculomotor alterations found in PCC may be useful to understand different pathophysiologic mechanisms.Project PID2020-112527RB-I00 funded by MCIN/AEI/10.13039/501100011033; La Marató de TV3 Foundation (202111-30-31-32).Peer ReviewedPostprint (published version

Eliminación de peces introducidos como medida de restauración de lagos de alta montaña

E. Carrillo, J. Ninot, T. Buchaca and M. Ventura. Blanes, LIFE+ LIMNOPIRINEUS Technical OfficeEntre los objetivos del proyecto LIFE+ LimnoPirineus (2014-2019) figuraban la restauración ecológica de ocho lagos pirenaicos y la recuperación o mejora de las poblaciones de diversas especies de interés comunitario de estos lagos, mediante la erradicación o el control intensivo de peces introducidos de hasta cuatro especies. En la mayor parte de lagos el objetivo operativo ha sido la erradicación, mientras que tan solo en uno de ellos el objetivo pasaba simplemente por llevar a cabo un control intensivo hasta alcanzar al menos una reducción del 75 % de la población inicial. A finales de 2019, estos objetivos se han alcanzado completamente para cinco de los lagos de actuación, mientras que en los otros tres lagos están cerca de alcanzarse, cosa que sucederá probablemente antes de finales de 2020. Se han puesto a punto métodos de extracción de peces basados en la combinación de hasta tres técnicas de captura principales: redes, trampas y pesca eléctrica. Se demuestra que la erradicación de los peces es factible en muchos lagos de alta montaña con una inversión suficiente en medios materiales y humanos, y con una adecuada planificación de las operaciones. Cuando no es factible la erradicación, el control intensivo mediante un esfuerzo sostenible en el tiempo es también una alternativa que cabe considerar a medio plazo.Peer reviewe

Real-time smart multisensing wearable platform for monitoring sweat biomarkers during exercise

Sweat secreted by the human eccrine sweat glands can provide valuable biomarker information during exercise in hot and humid conditions. Real-time noninvasive biomarker recordings are therefore useful for evaluating the physiological conditions of an athlete such as their hydration status during endurance exercise. In this work, we describe a platform that in- cludes different sweat biomonitoring prototypes of cost-effective, smart wearable devices for continuous biomonitoring of sweat during exercise. One prototype is based on conformable and disposable soft sensing patches with an integrated multi-sensor array requiring the integration of different sensors and printed sensors with their corresponding functionalization protocols on the same substrate. The second is based on silicon based sensors and paper microfluidics. Both platforms integrate a multi-sensor array for measuring sodium, potassium, and pH in sweat. We show preliminary results obtained from the multi-sensor prototypes placed on two athletes during exercise. We also show that the machine learning algorithms can predict the percentage of body weight loss during exercise from biomarkers such as heart rate and sweat sodium concentration collected over multiple subjects