Identification of Giardia lamblia DHHC Proteins and the Role of Protein S-palmitoylation in the Encystation Process

Protein S-palmitoylation, a hydrophobic post-translational modification, is performed by protein acyltransferases that have a common DHHC Cys-rich domain (DHHC proteins), and provides a regulatory switch for protein membrane association. In this work, we analyzed the presence of DHHC proteins in the protozoa parasite Giardia lamblia and the function of the reversible S-palmitoylation of proteins during parasite differentiation into cyst. Two specific events were observed: encysting cells displayed a larger amount of palmitoylated proteins, and parasites treated with palmitoylation inhibitors produced a reduced number of mature cysts. With bioinformatics tools, we found nine DHHC proteins, potential protein acyltransferases, in the Giardia proteome. These proteins displayed a conserved structure when compared to different organisms and are distributed in different monophyletic clades. Although all Giardia DHHC proteins were found to be present in trophozoites and encysting cells, these proteins showed a different intracellular localization in trophozoites and seemed to be differently involved in the encystation process when they were overexpressed. dhhc transgenic parasites showed a different pattern of cyst wall protein expression and yielded different amounts of mature cysts when they were induced to encyst. Our findings disclosed some important issues regarding the role of DHHC proteins and palmitoylation during Giardia encystation.Fil: Merino, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Zamponi, Nahuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Vranych, Cecilia Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Touz, Maria Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Ropolo, Andrea Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin

f(R) theories

Over the past decade, f(R) theories have been extensively studied as one of the simplest modifications to General Relativity. In this article we review various applications of f(R) theories to cosmology and gravity - such as inflation, dark energy, local gravity constraints, cosmological perturbations, and spherically symmetric solutions in weak and strong gravitational backgrounds. We present a number of ways to distinguish those theories from General Relativity observationally and experimentally. We also discuss the extension to other modified gravity theories such as Brans-Dicke theory and Gauss-Bonnet gravity, and address models that can satisfy both cosmological and local gravity constraints.Comment: 156 pages, 14 figures, Invited review article in Living Reviews in Relativity, Published version, Comments are welcom

Joint UK societies' 2019 consensus statement on renal denervation

Improved and durable control of hypertension is a global priority for healthcare providers and policymakers. There are several lifestyle measures that are proven to result in improved blood pressure (BP) control. Moreover, there is incontrovertible evidence from large scale randomised controlled trials (RCTs) that antihypertensive drugs lower BP safely and effectively in the long-term resulting in substantial reduction in cardiovascular morbidity and mortality. Importantly, however, evidence is accumulating to suggest that patients neither sustain long-term healthy behaviours nor adhere to lifelong drug treatment regimens and thus alternative measures to control hypertension warrant further investigation. Endovascular renal denervation (RDN) appears to hold some promise as a non-pharmacological approach to lowering BP and achieves renal sympathectomy using either radiofrequency energy or ultrasound-based approaches. This treatment modality has been evaluated in clinical trials in humans since 2009 but initial studies were compromised by being non-randomised, without sham control and small in size. Subsequently, clinical trial design and rigour of execution has been greatly improved resulting in recent sham-controlled RCTs that demonstrate short-term reduction in ambulatory BP without any significant safety concerns in both medication-naïve and medication-treated hypertensive patients. Despite this, the joint UK societies still feel that further evaluation of this therapy is warranted and that RDN should not be offered to patients outside of the context of clinical trials. This document reviews the updated evidence since our last consensus statement from 2014 and provides a research agenda for future clinical studies.This article is freely available online via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Profiling of dynamics in protein–lipid–water systems: a time-resolved fluorescence study of a model membrane protein with the label BADAN at specific membrane depths

Profiles of lipid-water bilayer dynamics were determined from picosecond time-resolved fluorescence spectra of membrane-embedded BADAN-labeled M13 coat protein. For this purpose, the protein was labeled at seven key positions. This places the label at well-defined locations from the water phase to the center of the hydrophobic acyl chain region of a phospholipid model membrane, providing us with a nanoscale ruler to map membranes. Analysis of the time-resolved fluorescence spectroscopic data provides the characteristic time constant for the twisting motion of the BADAN label, which is sensitive to the local flexibility of the protein–lipid environment. In addition, we obtain information about the mobility of water molecules at the membrane–water interface. The results provide an unprecedented nanoscale profiling of the dynamics and distribution of water in membrane systems. This information gives clear evidence that the actual barrier of membranes for ions and aqueous solvents is located at the region of carbonyl groups of the acyl chains

In Vivo Tumor Targeting and Imaging with Engineered Trivalent Antibody Fragments Containing Collagen-Derived Sequences

There is an urgent need to develop new and effective agents for cancer targeting. In this work, a multivalent antibody is characterized in vivo in living animals. The antibody, termed “trimerbody”, comprises a single-chain antibody (scFv) fragment connected to the N-terminal trimerization subdomain of collagen XVIII NC1 by a flexible linker. As indicated by computer graphic modeling, the trimerbody has a tripod-shaped structure with three highly flexible scFv heads radially outward oriented. Trimerbodies are trimeric in solution and exhibited multivalent binding, which provides them with at least a 100-fold increase in functional affinity than the monovalent scFv. Our results also demonstrate the feasibility of producing functional bispecific trimerbodies, which concurrently bind two different ligands. A trimerbody specific for the carcinoembryonic antigen (CEA), a classic tumor-associated antigen, showed efficient tumor targeting after systemic administration in mice bearing CEA-positive tumors. Importantly, a trimerbody that recognizes an angiogenesis-associated laminin epitope, showed excellent tumor localization in several cancer types, including fibrosarcomas and carcinomas. These results illustrate the potential of this new antibody format for imaging and therapeutic applications, and suggest that some laminin epitopes might be universal targets for cancer targeting

Assessing Historical Fish Community Composition Using Surveys, Historical Collection Data, and Species Distribution Models

Accurate establishment of baseline conditions is critical to successful management and habitat restoration. We demonstrate the ability to robustly estimate historical fish community composition and assess the current status of the urbanized Barton Creek watershed in central Texas, U.S.A. Fish species were surveyed in 2008 and the resulting data compared to three sources of fish occurrence information: (i) historical records from a museum specimen database and literature searches; (ii) a nearly identical survey conducted 15 years earlier; and (iii) a modeled historical community constructed with species distribution models (SDMs). This holistic approach, and especially the application of SDMs, allowed us to discover that the fish community in Barton Creek was more diverse than the historical data and survey methods alone indicated. Sixteen native species with high modeled probability of occurrence within the watershed were not found in the 2008 survey, seven of these were not found in either survey or in any of the historical collection records. Our approach allowed us to more rigorously establish the true baseline for the pre-development fish fauna and then to more accurately assess trends and develop hypotheses regarding factors driving current fish community composition to better inform management decisions and future restoration efforts. Smaller, urbanized freshwater systems, like Barton Creek, typically have a relatively poor historical biodiversity inventory coupled with long histories of alteration, and thus there is a propensity for land managers and researchers to apply inaccurate baseline standards. Our methods provide a way around that limitation by using SDMs derived from larger and richer biodiversity databases of a broader geographic scope. Broadly applied, we propose that this technique has potential to overcome limitations of popular bioassessment metrics (e.g., IBI) to become a versatile and robust management tool for determining status of freshwater biotic communities

Adaptation to Aridity in the Malaria Mosquito Anopheles gambiae: Chromosomal Inversion Polymorphism and Body Size Influence Resistance to Desiccation

Chromosomal inversions are thought to confer a selective advantage in alternative habitats by protecting co-adapted alleles from recombination. The frequencies of two inversions (2La and 2Rb) of the afro-tropical malaria mosquito Anopheles gambiae change gradually along geographical clines, increasing in frequency with degree of aridity. Such clines can result from gene flow and local selection acting upon alternative karyotypes along the cline, suggesting that these inversions may be associated with tolerance to xeric conditions. Since water loss represents a major challenge in xeric habitats, it can be supposed that genes inside these inversions are involved in water homeostasis. To test this hypothesis, we compared the desiccation resistance of alternative karyotypes from a colonised 2Rb/2La polymorphic population of A. gambiae from Cameroon. The strain included only the molecular form S, one of the genetic units marking incipient speciation in this taxon. Day-old mosquitoes of both sexes were assayed individually for time to death in a dry environment and the karyotype of each was determined post-mortem using molecular diagnostic assays for each inversion. In agreement with expectations based on their eco-geographical distribution, we found that 2La homokaryotypes survived significantly longer (1.3 hours) than the other karyotypes. However, there was weak support for the effect of 2Rb on desiccation resistance. Larger mosquitoes survived longer than smaller ones. Median survival of females was greater than males, but the effect of sex on desiccation resistance was weakly supported, indicating that differential survival was correlated to differences between sexes in average size. We found weak evidence for a heterotic effect of 2La karyotype on size in females. These results support the notion that genes located inside the 2La inversion are involved in water balance, contributing towards local adaptation of A. gambiae to xeric habitats, beyond the adaptive value conferred by a larger body size

Rationale and methods of the multicenter randomised trial of a heart failure management programme among geriatric patients (HF-Geriatrics)

<p>Abstract</p> <p>Background</p> <p>Disease management programmes (DMPs) have been shown to reduce hospital readmissions and mortality in adults with heart failure (HF), but their effectiveness in elderly patients or in those with major comorbidity is unknown. The Multicenter Randomised Trial of a Heart Failure Management Programme among Geriatric Patients (HF-Geriatrics) assesses the effectiveness of a DMP in elderly patients with HF and major comorbidity.</p> <p>Methods/Design</p> <p>Clinical trial in 700 patients aged ≥ 75 years admitted with a primary diagnosis of HF in the acute care unit of eight geriatric services in Spain. Each patient should meet at least one of the following comorbidty criteria: Charlson index ≥ 3, dependence in ≥ 2 activities of daily living, treatment with ≥ 5 drugs, active treatment for ≥ 3 diseases, recent emergency hospitalization, severe visual or hearing loss, cognitive impairment, Parkinson's disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), anaemia, or constitutional syndrome. Half of the patients will be randomly assigned to a 1-year DMP led by a case manager and the other half to usual care. The DMP consists of an educational programme for patients and caregivers on the management of HF, COPD (knowledge of the disease, smoking cessation, immunizations, use of inhaled medication, recognition of exacerbations), diabetes (knowledge of the disease, symptoms of hyperglycaemia and hypoglycaemia, self-adjustment of insulin, foot care) and depression (knowledge of the disease, diagnosis and treatment). It also includes close monitoring of the symptoms of decompensation and optimisation of treatment compliance. The main outcome variables are quality of life, hospital readmissions, and overall mortality during a 12-month follow-up.</p> <p>Discussion</p> <p>The physiological changes, lower life expectancy, comorbidity and low health literacy associated with aging may influence the effectiveness of DMPs in HF. The HF-Geriatrics study will provide direct evidence on the effect of a DMP in elderly patients with HF and high comorbidty, and will reduce the need to extrapolate the results of clinical trials in adults to elderly patients.</p> <p>Trial registration</p> <p>(ClinicalTrials.gov number, <a href="http://www.clinicaltrials.gov/ct2/show/NCT01076465">NCT01076465</a>).</p

Cryptic species in a well-known habitat: applying taxonomics to the amphipod genus Epimeria (Crustacea, Peracarida)

Taxonomy plays a central role in biological sciences. It provides a communication system for scientists as it aims to enable correct identification of the studied organisms. As a consequence, species descriptions should seek to include as much available information as possible at species level to follow an integrative concept of ‘taxonomics’. Here, we describe the cryptic species Epimeria frankei sp. nov. from the North Sea, and also redescribe its sister species, Epimeria cornigera. The morphological information obtained is substantiated by DNA barcodes and complete nuclear 18S rRNA gene sequences. In addition, we provide, for the first time, full mitochondrial genome data as part of a metazoan species description for a holotype, as well as the neotype. This study represents the first successful implementation of the recently proposed concept of taxonomics, using data from highthroughput technologies for integrative taxonomic studies, allowing the highest level of confidence for both biodiversity and ecological research