Personalised therapies for all : Targeting alternative chloride channels in Cystic Fibrosis

Cystic Fibrosis (CF) is a life-shortening genetic disorder caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, which encodes a cAMP-regulated chloride (Cl−) and bicarbonate (HCO3−) channel expressed at the apical membrane of epithelial cells. Faulty CFTR causes unbalanced salt and fluid transport, resulting in dehydrated lung secretions, enhanced mucus viscosity, and impaired mucociliary clearance, culminating in progressive obstruction of the airways. Other organs such as the intestine, reproductive tissues, and pancreas are also affected in CF. Despite recent progress in the development of therapies targeting the root cause of the disease, several people with CF, namely the ones with rare or “unrescuable” mutations, still lack effective treatments. An alternative would be to develop “mutation-agnostic” therapies, namely through the modulation of other (non-CFTR) anion channels/transporters. The main goal of this work was to understand if and how these alternative channels can be used as therapeutic targets in CF. TMEM16A is the major contributor to Ca2+-activated Cl– secretion in the airways and has the potential to bypass defective CFTR-dependent Cl– secretion. Here we developed a screening platform that was used to identify novel modulators of TMEM16A trafficking and function (Chapter 1). We have also demonstrated an overlap between Ca2+ and cAMP-induced currents, implying an intimate relationship between TMEM16A and CFTR (Chapter 2). Furthermore, another member of the TMEM16 family, TMEM16F, was also shown to regulate CFTR trafficking and function (Chapter 2). Another interesting alternative target is SLC26A9, a constitutively active Cl– transporter. We showed that CFTR expression, function, and rescue by modulators are dependent on SLC26A9 expression levels (Chapter 3). Finally, we have also identified regulators of SLC26A9 trafficking, that can potentially be used as novel therapeutic targets in CF therapies (Chapter 3). Taken together, our findings support a role for TMEM16A and SLC26A9 as clinically relevant disease modifiers and promising therapeutic targets to circumvent deficient Cl– secretion in CF

In Vitro Reassembly of the Malolactic Fermentation Pathway of Leuconostoc oenos (Oenococcus oeni)

The mechanism of metabolic energy generation by malolactic fermentation was studied with artificial membrane vesicles of Leuconostoc oenos (Oenococcus oeni). (Note that although L. oenos was recently reclassified as O. oeni, the old designation was kept in the present work.) Purified malolactic enzyme was entrapped in artificial membrane vesicles prepared from L. oenos cells able to transport L-malate. We show that the in vitro reconstituted system, including an electrogenic L-malate carrier and the decarboxylating malolactic enzyme, generated a proton motive force that was able to drive intravesicular accumulation of leucine.

Regge trajectories for the (2,0) theories

We investigate the structure of conformal Regge trajectories for the maximally supersymmetric (2, 0) theories in six dimensions. The different conformal multiplets in a single superconformal multiplet must all have similarly-shaped Regge trajectories. We show that these super-descendant trajectories interact in interesting ways, leading to new constraints on their shape. For the four-point function of the stress tensor multiplet supersymmetry also softens the Regge behavior in some channels, and consequently we observe that ‘analyticity in spin’ holds for all spins greater than −3. All the physical operators in this correlator therefore lie on Regge trajectories and we describe an iterative scheme where the Lorentzian inversion formula can be used to bootstrap the four-point function. Some numerical experiments yield promising results, with OPE data approaching the numerical bootstrap results for all theories with rank greater than one

Light Intensity Activity: a possible contribution to delay frailty

Trabalho apresentado em 24th Nordic Congress of Gerontology, 2-4 maio 2018, Oslo, NoruegaN/

Activated Carbon Produced from Tanning Industry Residues Used to Remove Carbamazepine from Wastewater

The 8th International Conference on Energy and Environment Research - ICEER 2021According to UNESCO, emerging pollutants are posing a threat to ecosystems and human health. These compounds can be either synthetic or natural chemicals or microorganisms, that are not usually regulated, and can be found in hospital wastewater, even after conventional treatment processes. Carbamazepine is a mood stabilizing drug and an anticonvulsant. Due to its persistence, carbamazepine is one of the most frequently detected pharmaceuticals in wastewater. Though there are many methods to remove such pollutants, adsorption is one of the most effective treatments. To remove carbamazepine from solution, an activated carbon prepared from leather residues and a commercial activated carbon were used as adsorbents. The adsorption tests show that the leather residue derived activated carbons have higher specific surface area (>1500 m’/g) and higher adsorption capacity (q > 300 mgcnz/g) for carbamazepine when compared to commercial activated carbon (992 m’/g and q < 180 mgcaz/g, respectively).info:eu-repo/semantics/publishedVersio

In vitro digestions to predict the glycemic index of rice

GLUPOR 12 - 12nd International Meeting of the Portuguese Carbohydrate Chemistry GroupPortuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit , and COMPETE 2020 (POCl-01-0145-FEDER-006684) and BioTecNorte operation (NORTE -0 1-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte . The authors would also like to thank the investement projec t n° 017931 , co-funded by Fundo Europeu de Desenvolvimento Regional (FEDER) through Programa Operacional Competitividade e lntemacionalização (CO MPETE 2020) .info:eu-repo/semantics/publishedVersio

Adsorption of protein from several commercial lipase preparations onto a hollow-fiber membrane module

Ten commercially available crude preparations of lipase from various microbial sources were adsorbed from aqueous buffers at several initial concentrations onto a bundle of hydrophobic hollow fibers made of poly(propylene) at pH 7.0 and 40 °C. The kinetics of adsorption were evaluated from measurements at various times of the protein content of the supernatant solution (using BSA as equivalent) in a well-mixed reservoir placed in series with the hollow fiber module. Preliminary tracer experiments have indicated that the module and the tank can be simulated as a system consisting of a plug flow reactor in series with a continuous stirred tank reactor. A mechanistic model based on the hydrodynamic assumptions associated with this system coupled with the postulation of two reversible first-order steps for the adsorption of protein was successfully fitted to the experimental data via nonlinear regression analysis. The statistical significance of the model was checked using tests for lack of fit. This work is useful in predicting the time period required to immobilize a (crude) lipase by adsorption onto a hydrophobic hollow fiber module, a configuration which has proved successful in the recent past for the performance of lipase-catalyzed reactions

Modelling the transport of lactic acid, sodium chloride and reducing sugars in carrot slices submerged in brines - Part I. Univariate approach

The transport phenomena pertaining to the independent diffusion of lactic acid and sodium chloride from a brine into carrot slices submerged therein, and of reducing sugars in the opposite direction, were experimentally studied at various temperatures and initial concentrations of salt and acid in the brine. The data sets obtained at each combination of temperature and initial concentration of the brine were independently fit to three analytical models derived from just principles on three alternative mechanisms postulated for the time-variation of the diffusivity. Incremental sum of squares analyses have shown that the diffusion of acid and salt into the carrots is well described by a constant diffusivity, whereas the diffusion of reducing sugars out of the carrots is well described by a diffusivity undergoing a sigmoidal variation with time. This sigmoidal variation may be explained by the assumption that the bursting of the carrot cells is simultaneously proportional to the fraction of intact cells and the fraction of burst cells of the carrot material. The analysis developed is relevant because it allows an approximate prediction of the rates of acid and salt intake, as well as the release rates of reducing sugars, pertaining to bried carrot slices, the basic processes that occur during manufacture of lactic acid carrot pickles

Infección por Mycoplasma pneumoniae: tres casos con complicaciones neurológicas

Summary. Introduction. Mycoplasma pneumoniae infection has been associated with severe central nervous system diseases. The pathogenesis of these disorders is unknown and the treatment uncertain. Case reports. The authors present three cases of central nervous system diseases: acute transverse myelitis, cerebellitis and encephalomyelitis associated with M. pneumoniae infection. Conclusions. M. pneumoniae infection should be considered in all cases of severe acute central nervous system symptomatology. El Mycoplasma pneumoniae es un agente implicado frecuentemente en infecciones respiratorias de niños y adultos [1,2]. Se pueden producir complicaciones extrarrespiratorias básicamente mucocutáneas (eritema multiforme, eritema nudoso, síndrome de StevenJohnson), cardíacas (miocarditis, pericarditis), articulares (artritis), hematológicas (anemia hemolítica, trombocitopenia, coagulación vascular diseminada), pancreatitis, salpingitis y complicaciones neurológicas [13]. La implicación del sistema nervioso central (SNC) se estima en aproximadamente un 0,1% del total de infecciones producidas por M. pneumoniae, y puede afectar al 7% de los pacientes hospitalizados a causa de una infección producida por este agente [2,3]. Las complicaciones neurológicas incluyen: encefalitis, meningoencefalitis, encefalomielitis, polirradiculoneuropatía (como el síndrome de GuillainBarré), cerebelitis, psicosis, mielitis transversa y coma [14]. Presentamos tres casos clínicos con complicaciones neurológicas en el contexto de una infección por M. pneumoniae (mielitis transversa, cerebelitis, encefalomielitis), cuyo diagnóstico se estableció a partir de los análisis clínicos y los exámenes auxiliares de diagnóstico efectuados, principalmente las serologías seriadas. A infecção por Mycoplasma pneumoniae tem sido associada a múltiplas complicações neurológicas. A patogénese destas permanece incerta e o seu tratamento controverso. Casos clínicos. Os autores apresentam três casos de complicação neurológica em contexto de infecção pelo M. pneumoniae: mielite transversa, cerebelite e encefalomielite. Conclusão. A infecção por M. pneumoniae deve ser considerada em todos os casos de sintomatologia severa aguda do sistema nervoso centra

Telomeres in aging and disease: lessons from zebrafish

Age is the highest risk factor for some of the most prevalent human diseases, including cancer. Telomere shortening is thought to play a central role in the aging process in humans. The link between telomeres and aging is highlighted by the fact that genetic diseases causing telomerase deficiency are associated with premature aging and increased risk of cancer. For the last two decades, this link has been mostly investigated using mice that have long telomeres. However, zebrafish has recently emerged as a powerful and complementary model system to study telomere biology. Zebrafish possess human-like short telomeres that progressively decline with age, reaching lengths in old age that are observed when telomerase is mutated. The extensive characterization of its well-conserved molecular and cellular physiology makes this vertebrate an excellent model to unravel the underlying relationship between telomere shortening, tissue regeneration, aging and disease. In this Review, we explore the advantages of using zebrafish in telomere research and discuss the primary discoveries made in this model that have contributed to expanding our knowledge of how telomere attrition contributes to cellular senescence, organ dysfunction and disease.Fundação para a Ciência e Tecnologia grant: (PTDC/BIM-ONC/3402/2014); Howard Hughes Medical Institute