Implantation of CPT1AM-expressing adipocytes reduces obesity and glucose intolerance in mice

Obesity and its associated metabolic comorbidities are a rising global health and social issue, with novel therapeutic approaches urgently needed. Adipose tissue plays a key role in the regulation of energy balance and adipose tissue-derived mesenchymal stem cells (AT-MSCs) have gained great interest in cell therapy. Carnitine palmitoyltransferase 1A (CPT1A) is the gatekeeper enzyme for mitochondrial fatty acid oxidation. Here, we aimed to generate adipocytes expressing a constitutively active CPT1A form (CPT1AM) that can improve the obese phenotype in mice after their implantation. AT-MSCs were differentiated into mature adipocytes, subjected to lentivirus-mediated expression of CPT1AM or the GFP control, and subcutaneously implanted into mice fed a high-fat diet (HFD). CPT1AM-implanted mice showed lower body weight, hepatic steatosis and serum insulin and cholesterol levels alongside improved glucose tolerance. HFD-induced increases in adipose tissue hypertrophy, fibrosis, inflammation, endoplasmic reticulum stress and apoptosis were reduced in CPT1AM-implanted mice. In addition, the expression of mitochondrial respiratory chain complexes was enhanced in the adipose tissue of CPT1AM-implanted mice. Our results demonstrate that implantation of CPT1AM-expressing AT-MSC-derived adipocytes into HFD-fed mice improves the obese metabolic phenotype, supporting the future clinical use of this ex vivo gene therapy approach

Elevated VCAM-1, MCP-1 and ADMA serum levels related to pulmonary fibrosis of interstitial lung disease associated with rheumatoid arthritis

Introduction: Early diagnosis of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA) constitutes a challenge for the clinicians. Pulmonary vasculopathy is relevant in the development of interstitial lung disease. Accordingly, we aimed to explore the role of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and asymmetric dimethylarginine (ADMA), key molecules in the vasculopathy, as potential biomarkers of pulmonary fibrosis in RA-ILD+. Methods: We included 21 RA-ILD+ patients and two comparative groups: 25 RA-ILD- patients and 21 idiopathic pulmonary fibrosis (IPF) patients. Serum levels of the molecules were determined by ELISA, and mRNA expression was quantified by qPCR. Results: VCAM-1, MCP-1 and ADMA serum levels were increased in RA-ILD+ patients in relation to RA-ILD- and IPF patients. Additionally, RA-ILD+ patients exhibited increased CCL2 (gene encoding MCP-1) and decreased PRMT1 (gene related to ADMA synthesis) mRNA expression in relation to RA-ILD- patients. A lower expression of VCAM1, CCL2, and PRMT1 was observed in RA-ILD+ patients when compared with those with IPF. Furthermore, MCP-1 serum levels and PRMT1 mRNA expression were positively correlated with RA duration, and ADMA serum levels were positively associated with C-reactive protein in RA-ILD+ patients. Conclusion: Our study suggests that VCAM-1, MCP-1 and ADMA could be considered as useful biomarkers to identify ILD in RA patients, as well as to discriminate RA-ILD+ from IPF, contributing to the early diagnosis of RA-ILD+.Funding: VP-C is supported by funds of PI18/00042 from Instituto de Salud Carlos III (ISCIII), co-funded by European Regional Development Fund (ERDF). SR-M is supported by funds of RETICS Program (RD16/0012/0009) from ISCIII, co-funded by ERDF; FG is supported by funds of the RICORS Program (RD21/ 0002/0025) from ISCIII, co-funded by the European Union; OG is staff personnel of Xunta de Galicia (Servizo Galego de Saude (SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and ERDF [RD16/0012/0014 (RIER) and PI17/00409]. He is beneficiary of project funds from the Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, project 734899—Olive-Net. RL-M is a recipient of a Miguel Servet type II Program fellowship from ISCIII, co-funded by the European Social Fund, ‘Investing in your future’ (CPII21/00004)

Supernova 2018cuf : a type iip supernova with a slow fall from plateau

We present multiband photometry and spectroscopy of SN 2018cuf, a Type IIP ("P"for plateau) supernova (SN) discovered by the Distance Less Than 40 Mpc Survey within 24 hr of explosion. SN 2018cuf appears to be a typical SN IIP, with an absolute V-band magnitude of -16.73 ± 0.32 at maximum and a decline rate of 0.21 ± 0.05 mag/50 days during the plateau phase. The distance of the object was constrained to be 41.8 ± 5.7 Mpc by using the expanding photosphere method. We used spectroscopic and photometric observations from the first year after the explosion to constrain the progenitor of SN 2018cuf using both hydrodynamic light-curve modeling and late-time spectroscopic modeling. The progenitor of SN 2018cuf was most likely a red supergiant of about 14.5 Me that produced 0.04 ± 0.01 Me 56Ni during the explosion. We also found ∼0.07 Me of circumstellar material (CSM) around the progenitor is needed to fit the early light curves, where the CSM may originate from presupernova outbursts. During the plateau phase, high-velocity features at ∼11,000 km s-1 were detected in both the optical and near-infrared spectra, supporting the possibility that the ejecta were interacting with some CSM. A very shallow slope during the postplateau phase was also observed, and it is likely due to a low degree of nickel mixing or the relatively high nickel mass in the SN.Fil: Dong, Yize. University of California at Davis; Estados UnidosFil: Valenti, S.. University of California at Davis; Estados UnidosFil: Bostroem, K. A.. University of California at Davis; Estados UnidosFil: Sand, D. J.. University of Arizona; Estados UnidosFil: Andrews, Jennifer E.. University of Arizona; Estados UnidosFil: Galbany, Lluís. Universidad de Granada; EspañaFil: Jha, Saurabh W.. State University of New Jersey; Estados UnidosFil: Eweis, Youssef. State University of New Jersey; Estados UnidosFil: Kwok, Lindsey. State University of New Jersey; Estados UnidosFil: Hsiao, Eric. Florida State University; Estados UnidosFil: Davis, Scott. Florida State University; Estados UnidosFil: Brown, Peter J.. Texas A&M University; Estados UnidosFil: Kuncarayakti, H.. University of Turku; FinlandiaFil: Maeda, Keiichi. Kyoto University; JapónFil: Rho, Jeonghee. SETI Institute; Estados UnidosFil: Amaro, R. C.. University of Arizona; Estados UnidosFil: Anderson, J. P.. European Southern Observatory Chile; ChileFil: Arcavi, Iair. Universitat Tel Aviv; IsraelFil: Burke, Jamison. University of California; Estados UnidosFil: Dastidar, Raya. Aryabhatta Research Institute of observational sciences; IndiaFil: Folatelli, Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Haislip, Joshua. University of North Carolina at Chapel Hill; Estados UnidosFil: Hiramatsu, Daichi. University of California; Estados UnidosFil: Hosseinzadeh, Griffin. Harvard-Smithsonian Center for Astrophysics; Estados UnidosFil: Howell, D. Andrew. University of California; Estados UnidosFil: Jencson, J.. University of Arizona; Estados UnidosFil: Kouprianov, Vladimir. University of North Carolina at Chapel Hill; Estados UnidosFil: Lundquist, M.. University of Arizona; Estados UnidosFil: Lyman, J. D.. University of Warwick; Reino UnidoFil: McCully, Curtis. University of California; Estados Unido

Mature iPSC-derived astrocytes of an ALS/FTD patient carrying the TDP43A90V mutation display a mild reactive state and release polyP toxic to motoneurons

Astrocytes play a critical role in the maintenance of a healthy central nervous system and astrocyte dysfunction has been implicated in various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There is compelling evidence that mouse and human ALS and ALS/FTD astrocytes can reduce the number of healthy wild-type motoneurons (MNs) in co-cultures or after treatment with astrocyte conditioned media (ACM), independently of their genotype. A growing number of studies have shown that soluble toxic factor(s) in the ACM cause non-cell autonomous MN death, including our recent identification of inorganic polyphosphate (polyP) that is excessively released from mouse primary astrocytes (SOD1, TARDBP, and C9ORF72) and human induced pluripotent stem cells (iPSC)-derived astrocytes (TARDBP) to kill MNs. However, others have reported that astrocytes carrying mutant TDP43 do not produce detectable MN toxicity. This controversy is likely to arise from the findings that human iPSC-derived astrocytes exhibit a rather immature and/or reactive phenotype in a number of studies. Here, we have succeeded in generating a highly homogenous population of functional quiescent mature astrocytes from control subject iPSCs. Using identical conditions, we also generated mature astrocytes from an ALS/FTD patient carrying the TDP43A90V mutation. These mutant TDP43 patient-derived astrocytes exhibit key pathological hallmarks, including enhanced cytoplasmic TDP-43 and polyP levels. Additionally, mutant TDP43 astrocytes displayed a mild reactive signature and an aberrant function as they were unable to promote synaptogenesis of hippocampal neurons. The polyP-dependent neurotoxic nature of the TDP43A90V mutation was further confirmed as neutralization of polyP in ACM derived from mutant TDP43 astrocytes prevented MN death. Our results establish that human astrocytes carrying the TDP43A90V mutation exhibit a cell-autonomous pathological signature, hence providing an experimental model to decipher the molecular mechanisms underlying the generation of the neurotoxic phenotype

Size-Tailored Design of Highly Monodisperse Lipid Nanocapsules for Drug Delivery

The empirical development of nanocarriers has unfortunately led to high attrition rates in clinical trials. This underpins the importance of the rational design of nanomedicines to achieve efficient disease-driven therapies. Since particle size certainly influences in vivo behaviour, rational disease-driven colloid design can only be achieved by determining the parameters that accurately control their size distribution. To this end, we have thoroughly revisited the parameters that drive the phase-inversion temperature nanoemulsification method to obtain kinetically stable and monodisperse lipid nanocapsules. Notably, we have evidenced that the major parameter driving nanocapsule formation is the oily phase/surfactant ratio and consequently, we have established a linear univariate mathematical model that predicts the particle size distribution for various oily phase-surfactant combinations (R 2 > 0 99). Furthermore, we have observed that the difference between the HLB values of the surfactants and the triglycerides utilized as oily phase correlates with the steepness of the slope of the linear mathematical model. This model will bring the implementation of size-tailored lipid drug carriers determined by pathophysiological features a step closer. Importantly, this model pioneeringly fits all data available in the literature on size distribution of colloids prepared by low-energy methods and that were originally evaluated following other parameters. Moreover, the nanocapsules have been obtained following a single-step process, with the ensuing potential for a future scale-up in an energetically-efficient manner. These findings will eventually enable nanomedicines to be obtained "on-demand" to meet disease-driven criteria in terms of particle size and will also increase their chances of success.Universidad Complutense de MadridBanco SantanderMinisterio de Educación, Cultura y Deporte(España)Depto. de Farmacia Galénica y Tecnología AlimentariaFac. de FarmaciaTRUEpu

The word order of languages predicts native speakers’ working memory

Abstract The relationship between language and thought is controversial. One hypothesis is that language fosters habits of processing information that are retained even in non-linguistic domains. In left-branching (LB) languages, modifiers usually precede the head, and real-time sentence comprehension may more heavily rely on retaining initial information in working memory. Here we presented a battery of working memory and short-term memory tasks to adult native speakers of four LB and four right-branching (RB) languages from Africa, Asia and Europe. In working memory tasks, LB speakers were better than RB speakers at recalling initial stimuli, but worse at recalling final stimuli. Our results show that the practice of parsing sentences in specific directions due to the syntax and word order of our native language not only predicts the way we remember words, but also other non-linguistic stimuli

The word order of languages predicts native speakers' working memory.

The relationship between language and thought is controversial. One hypothesis is that language fosters habits of processing information that are retained even in non-linguistic domains. In left-branching (LB) languages, modifiers usually precede the head, and real-time sentence comprehension may more heavily rely on retaining initial information in working memory. Here we presented a battery of working memory and short-term memory tasks to adult native speakers of four LB and four right-branching (RB) languages from Africa, Asia and Europe. In working memory tasks, LB speakers were better than RB speakers at recalling initial stimuli, but worse at recalling final stimuli. Our results show that the practice of parsing sentences in specific directions due to the syntax and word order of our native language not only predicts the way we remember words, but also other non-linguistic stimuli

The Insula modulates arousal-induced reluctance to try novel tastes through adrenergic transmission in the rat

Reluctance to try novel tastes (neophobia) can be exacerbated in arousing situations, such as when children are under social stress or in rodents, when the new taste is presented in a high arousal context (HA) compared to a low arousal context (LA). The present study aimed at determining whether adrenergic transmission at the Insula regulates the reluctance to try novel tastes induced by arousing contexts. To this end, a combination of systemic and intra-insular manipulations of adrenergic activity was performed before the novel taste (saccharin 0.1%) was presented either in LA or HA contexts in rats. Our results show that systemic adrenergic activity modulates reluctance to try novel tastes. Moreover, intra-insular microinjections of propranolol or norepinephrine were found to modulate the effects of arousing contexts on reluctance to try novel tastes. Finally, intra-insular propranolol blocked epinephrine-induced increased reluctance, while intra-insular norepinephrine blocked oral propranolol-induced decreases in reluctance and increased the reluctance to try novel tastes presented in low arousing contexts. In conclusion, our results suggest that the insula is a critical site for regulating the effects of arousal in the reluctance to try novel tastes via the adrenergic system