Metabolic and functional consequences of cytosolic 5′-nucleotidase-IA overexpression in neonatal rat cardiomyocytes

Adenosine exerts a spectrum of energy-preserving actions on the heart negative chronotropic effects. The pathways leading to adenosine formation have remained controversial. In particular, although cytosolic 5′-nucleotidases can catalyze adenosine formation in cardiomyocytes, their contribution to the actions of adenosine has not been documented previously. We recently cloned two closely related AMP-preferring cytosolic 5′-nucleotidases (cN-IA and -IB); the A form predominates in the heart. In this study, we overexpressed pigeon cN-IA in neonatal rat cardiomyocytes using an adenovirus. cN-IA overexpression increased adenosine formation and release into the medium caused by simulated hypoxia and by isoproterenol in the absence and presence of inhibitors of adenosine metabolism. Adenosine release was not affected by an ecto-5′-nucleotidase inhibitor, α,β-methylene-ADP, but was affected by a nucleoside transporter, dipyridamole. The positive chronotropic effect of isoproterenol (130 ±3 vs. 100 ±4 beats/min) was inhibited (107 ±3 vs. 94 ±3 beats/min) in cells overexpressing cN-IA, and this was reversed by the addition of the adenosine receptor antagonist 8-(p-sulfophenyl)theophilline (120 ± 3 vs. 90 ± 4 beats/min). Our results demonstrate that overexpressed cN-IA can be sufficiently active in cardiomyocytes to generate physiologically effective concentrations of adenosine at its receptors.Fil: Sala-Newby, Graciela B.. University of Bristol; Reino UnidoFil: Freeman, Nicola V. E.. University of Bristol; Reino UnidoFil: Curto, Maria de Los Angeles. University of Bristol; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Newby, Andrew C.. University of Bristol; Reino Unid

Identification of the Acinetobacter baumannii Ribonuclease P Catalytic Subunit: Cleavage of a Target mRNA in the Presence of an External Guide Sequence

The bacterial ribonuclease P or RNase P holoenzyme is usually composed of a catalytic RNA subunit, M1, and a cofactor protein, C5. This enzyme was first identified for its role in maturation of tRNAs by endonucleolytic cleavage of the pre-tRNA. The RNase P endonucleolytic activity is characterized by having structural but not sequence substrate requirements. This property led to development of EGS technology, which consists of utilizing a short antisense oligonucleotide that when forming a duplex with a target RNA induces its cleavage by RNase P. This technology is being explored for designing therapies that interfere with expression of genes, in the case of bacterial infections EGS technology could be applied to target essential, virulence, or antibiotic resistant genes. Acinetobacter baumannii is a problematic pathogen that is commonly resistant to multiple antibiotics, and EGS technology could be utilized to design alternative therapies. To better understand the A. baumannii RNase P we first identified and characterized the catalytic subunit. We identified a gene coding for an RNA species, M1Ab, with the expected features of the RNase P M1 subunit. A recombinant clone coding for M1Ab complemented the M1 thermosensitive mutant Escherichia coli BL21(DE3) T7A49, which upon transformation was able to grow at the non-permissive temperature. M1Ab showed in vitro catalytic activity in combination with the C5 protein cofactor from E. coli as well as with that from A. baumannii, which was identified, cloned and partially purified. M1Ab was also able to cleave a target mRNA in the presence of an EGS with efficiency comparable to that of the E. coli M1, suggesting that EGS technology could be a viable option for designing therapeutic alternatives to treat multiresistant A. baumannii infections

Integrated sliding-mode algorithms in robot tracking applications

An integrated solution based on sliding mode ideas is proposed for robotic trajectory tracking. The proposal includes three sliding-mode algorithms for speed auto-regulation, path conditioning and redundancy resolution in order to fulfill velocity, workspace and C-space constraints, respectively. The proposed method only requires a few program lines and simplifies the robot user interface since it directly deals with the fulfillment of the constraints to find a feasible solution for the robot trajectory tracking in a short computation time. The proposed approach is evaluated in simulation on the freely accessible 6R robot model PUMA-560, for which the main features of the method are illustrated.This research is partially supported by research project DPI2011-27845-C02-01 of the Spanish Government (Spain), research projects PAID-05-11-2640 and PAID-00-12-SP20120159 of the Universitat Polit'ecnica de Val'encia (Spain), and research projects ANPCyT PICT-2011-0888, CONICET PIP 112-2011-00361, and UNLP 1164 (Argentina).Gracia Calandin, LI.; Garelli, F.; Sala Piqueras, A. (2013). Integrated sliding-mode algorithms in robot tracking applications. Robotics and Computer-Integrated Manufacturing. 29(1):53-62. https://doi.org/10.1016/j.rcim.2012.07.007S536229

Robot coordination using task-priority and sliding-mode techniques

In this work, an approach based on task-priority redundancy resolution and sliding mode ideas is proposed for robot coordination. In particular, equality and inequality constraints representing the coordination of the multi-robot system are considered as mandatory (for instance, rigid-body manipulation constraints to distance between the end-effectors of several robot arms, or other inequality constraints guaranteeing safe operation of a robotic swarm or confining the robot's workspace to avoid collision and joint limits). Besides the mandatory constraints, other constraints with lower priority are considered for the tracking of the workspace reference and to achieve secondary goals. Thus, lower-priority constraints are satisfied only in the null space of the higherpriority ones. The fulfillment of the constraints is achieved using geometric invariance and sliding mode control theory. The validity and effectiveness of the proposed approach is substantiated by 2D and 3D simulation results using two 3R planar robots and two 6R PUMA-762 robots, respectively.This work was supported in part by research under Project DPI2011-27845-C02-01 of the Spanish Government and Projects ANPCyT PICT-2011-0888, CONICET PIP 112-2011-00361 and UNLP 1164 in Argentina.Gracia Calandin, LI.; Sala Piqueras, A.; Garelli, F. (2014). Robot coordination using task-priority and sliding-mode techniques. Robotics and Computer-Integrated Manufacturing. 30(1):74-89. https://doi.org/10.1016/j.rcim.2013.08.003S748930

Sliding mode speed auto-regulation technique for robotic tracking

In advanced industry manufacturing involving robotic operations, the required tasks can be frequently formulated in terms of a path or trajectory tracking. In this paper, an approach based on sliding mode conditioning of a path parametrization is proposed to achieve the greatest tracking speed which is compatible with the robot input constraints (joint speeds). Some distinctive features of the proposal are that: (1) it is completely independent of the robot parameters, and it does not require a priori knowledge of the desired path either, (2) it avoids on-line computations necessary for conventional analytical methodologies, and (3) it can be easily added as a supervisory block to pre-existing path tracking schemes. A sufficient condition (lower bound on desired tracking speed) for the sliding mode regulation to be activated is derived, while a chattering amplitude estimation is obtained in terms of the sampling period and a tunable first-order filter bandwidth. The algorithm is evaluated on the freely accessible 6R robot model PUMA-560, for which a path passing through a wrist singularity is considered to show the effectiveness of the proposal under hard tracking conditions. © 2011 Elsevier B.V. All rights reserved.This research is partially supported by DISICOM project PROM-ETEO 2008/088 of Generalitat Valenciana (Spain), research project DPI2008-06731-C02-01 of the Spanish Government (Spain), Technical University of Valencia (Spain), and the Argentinian Government (UNLP 111127, CONICET PIP 112-200801-0, ANPCyT PICT 2007 00535).Garelli, F.; Gracia Calandin, LI.; Sala, A.; Albertos Pérez, P. (2011). Sliding mode speed auto-regulation technique for robotic tracking. Robotics and Autonomous Systems. 59(7-8):519-529. https://doi.org/10.1016/j.robot.2011.03.007S519529597-

Neuropsychological impairment in post-COVID condition individuals with and without cognitive complaints

One of the most prevalent symptoms of post-COVID condition is cognitive impairment, which results in a significant degree of disability and low quality of life. In studies with large sample sizes, attention, memory, and executive function were reported as long-term cognitive symptoms. This study aims to describe cognitive dysfunction in large post-COVID condition individuals, compare objective neuropsychological performance in those post-COVID condition individuals with and without cognitive complaints, and identify short cognitive exams that can differentiate individuals with post-COVID symptoms from controls. To address these aims, the Nautilus project was started in June 2021. During the first year, we collected 428 participants’ data, including 319 post-COVID and 109 healthy controls (18–65 years old) from those who underwent a comprehensive neuropsychological battery for cognitive assessment. Scores on tests assessing global cognition, learning and long-term memory, processing speed, language and executive functions were significantly worse in the post-COVID condition group than in healthy controls. Montreal Cognitive Assessment, digit symbol test, and phonetic verbal fluency were significant in the binomial logistic regression model and could effectively distinguish patients from controls with good overall sensitivity and accuracy. Neuropsychological test results did not differ between those with and without cognitive complaints. Our research suggests that patients with post-COVID conditions experience significant cognitive impairment and that routine tests like the Montreal Cognitive Assessment, digit symbol, and phonetic verbal fluency test might identify cognitive impairment. Thus, the administration of these tests would be helpful for all patients with post-COVID-19 symptoms, regardless of whether cognitive complaints are present or absent.Peer ReviewedNAUTILUS-Project Collaborative GroupPostprint (published version

A supervisory loop approach to fulfill workspace constraints in redundant robots

An approach based on geometric invariance and sliding mode ideas is proposed for redundancy resolution in robotic systems to fulfill configuration and workspace constraints caused by robot mechanical limits, collision avoidance, industrial security, etc. Some interesting features of the proposal are that: (1) it can be interpreted as a limit case of the classical potential field-based approach for collision avoidance which requires using variable structure control concepts, (2) it allows reaching the limit surface of the constraints smoothly, depending on a free design parameter, and (3) it can be easily added as a supervisory block to pre-existing redundancy resolution schemes. The algorithm is evaluated in simulation on a 6R planar robot and on the freely accessible 6R robot model PUMA-560, for which the main features of the method are illustrated.This research is partially supported by DISICOM project PROM-ETEO 2008/088 of Generalitat Valenciana (Spain), research project DPI2011-27845-C02-01 of the Spanish Government (Spain), Technical University of Valencia (Spain), and the Argentinian Government (UNLP 11I127, CONICET PIP 112-200801-0, ANPCyT PICT 2007 00535).Gracia Calandin, LI.; Sala, A.; Garelli, F. (2012). A supervisory loop approach to fulfill workspace constraints in redundant robots. Robotics and Autonomous Systems. 60(1):1-15. https://doi.org/10.1016/j.robot.2011.07.008S11560

Association of lifestyle factors and inflammation with sarcopenic obesity: data from the PREDIMED‐Plus trial

Background: Sarcopenia is a progressive age-related skeletal muscle disorder associated with increased likelihood of adverse outcomes. Muscle wasting is often accompanied by an increase in body fat, leading to ‘sarcopenic obesity’. The aim of the present study was to analyse the association of lifestyle variables such as diet, dietary components, physical activity (PA), body composition, and inflammatory markers, with the risk of sarcopenic obesity. Methods: A cross-sectional analysis based on baseline data from the PREDIMED-Plus study was performed. A total of 1535 participants (48% women) with overweight/obesity (body mass index: 32.5 ± 3.3 kg/m2; age: 65.2 ± 4.9 years old) and metabolic syndrome were categorized according to sex-specific tertiles (T) of the sarcopenic index (SI) as assessed by dual-energy X-ray absorptiometry scanning. Anthropometrical measurements, biochemical markers, dietary intake, and PA information were collected. Linear regression analyses were carried out to evaluate the association between variables. Results: Subjects in the first SI tertile were older, less physically active, showed higher frequency of abdominal obesity and diabetes, and consumed higher saturated fat and less vitamin C than subjects from the other two tertiles (all P < 0.05). Multiple adjusted linear regression models evidenced significant positive associations across tertiles of SI with adherence to the Mediterranean dietary score (P-trend < 0.05), PA (P-trend < 0.0001), and the 30 s chair stand test (P-trend < 0.0001), whereas significant negative associations were found with an inadequate vitamin C consumption (P-trend < 0.05), visceral fat and leucocyte count (all P-trend < 0.0001), and some white cell subtypes (neutrophils and monocytes), neutrophil-tolymphocyte ratio, and platelet count (all P-trend < 0.05). When models were additionally adjusted by potential mediators (inflammatory markers, diabetes, and waist circumference), no relevant changes were observed, only dietary variables lost significance

Determination of essential biomarkers in lung cancer: a real-world data study in Spain.

Background: The survival of patients with lung cancer has substantially increased in the last decade by about 15%. This increase is, basically, due to targeted therapies available for advanced stages and the emergence of immunotherapy itself. This work aims to study the situation of biomarker testing in Spain. Patients and Methods: The Thoracic Tumours Registry (TTR) is an observational, prospective, registry-based study that included patients diagnosed with lung cancer and other thoracic tumours, from September 2016 to 2020. This TTR study was sponsored by the Spanish Lung Cancer Group (GECP) Foundation, an independent, scientific, multidisciplinary oncology society that coordinates more than 550 experts and 182 hospitals across the Spanish territory. Results: 9,239 patients diagnosed with stage IV non-small cell lung cancer (NSCLC) between 2106 and 2020 were analysed. 7,467 (80.8%) were non-squamous and 1,772 (19.2%) were squamous. Tumour marker testing was performed in 85.0% of patients with non-squamous tumours vs 56.3% in those with squamous tumours (p-value <0.001). The global testing of EGFR, ALK, and ROS1 was 78.9%, 64.7%, 35.6% respectively, in non-squamous histology. PDL1 was determined globally in the same period (46.9%), although if we focus on the last 3 years it exceeds 85%. There has been a significant increase in the last few years of all determinations and there are even close to 10% of molecular determinations that do not yet have targeted drug approval but will have it in the near future. 4,115 cases had a positive result (44.5%) for either EGFR, ALK, KRAS, BRAF, ROS1, or high PDL1. Conclusions: Despite the lack of a national project and standard protocol in Spain that regulates the determination of biomarkers, the situation is similar to other European countries. Given the growing number of different determinations and their high positivity, national strategies are urgently needed to implement next-generation sequencing (NGS) in an integrated and cost-effective way in lung cancer

Determination of essential biomarkers in lung cancer : a real-world data study in Spain with demographic, clinical, epidemiological and pathological characteristics

Background The survival of patients with lung cancer has substantially increased in the last decade by about 15%. This increase is, basically, due to targeted therapies available for advanced stages and the emergence of immunotherapy itself. This work aims to study the situation of biomarker testing in Spain. Patients and methods The Thoracic Tumours Registry (TTR) is an observational, prospective, registry-based study that included patients diagnosed with lung cancer and other thoracic tumours, from September 2016 to 2020. This TTR study was sponsored by the Spanish Lung Cancer Group (GECP) Foundation, an independent, scientific, multidisciplinary oncology society that coordinates more than 550 experts and 182 hospitals across the Spanish territory. Results Nine thousand two hundred thirty-nine patients diagnosed with stage IV non-small cell lung cancer (NSCLC) between 2106 and 2020 were analysed. 7,467 (80.8%) were non-squamous and 1,772 (19.2%) were squamous. Tumour marker testing was performed in 85.0% of patients with non-squamous tumours vs 56.3% in those with squamous tumours (p-value < 0.001). The global testing of EGFR, ALK, and ROS1 was 78.9, 64.7, 35.6% respectively, in non-squamous histology. PDL1 was determined globally in the same period (46.9%), although if we focus on the last 3 years it exceeds 85%. There has been a significant increase in the last few years of all determinations and there are even close to 10% of molecular determinations that do not yet have targeted drug approval but will have it in the near future. 4,115 cases had a positive result (44.5%) for either EGFR, ALK, KRAS, BRAF, ROS1, or high PDL1. Conclusions Despite the lack of a national project and standard protocol in Spain that regulates the determination of biomarkers, the situation is similar to other European countries. Given the growing number of different determinations and their high positivity, national strategies are urgently needed to implement next-generation sequencing (NGS) in an integrated and cost-effective way in lung cancer