Pharmacogenomic biomarker information on drug labels of the Spanish Agency of Medicines and Sanitary products: evaluation and comparison with other regulatory agencies.

This work aimed to analyse the pharmacogenetic information in the Spanish Drug Regulatory Agency (AEMPS) Summary of Products Characteristics (SmPC), evaluating the presence of pharmacogenetic biomarkers, as well as the associated recommendations. A total of 55.4% of the 1891 drug labels reviewed included information on pharmacogenetic biomarker(s). Pharmacogenomic information appears most frequently in the "antineoplastic and immunomodulating agents", "nervous system", and "cardiovascular system" Anatomical Therapeutic Chemical groups. A total of 509 different pharmacogenetic biomarkers were found, of which CYP450 enzymes accounted for almost 34% of the total drug-biomarker associations evaluated. A total of 3679 drug-biomarker pairs were identified, 102 of which were at the 1A level (PharmGKB® classification system), and 33.33% of these drug-pharmacogenetic biomarker pairs were assigned to "actionable PGx", 12.75% to "informative PGx", 4.9% to "testing recommended", and 4.9% to "testing required". The rate of coincidence in the assigned PGx level of recommendation between the AEMPS and regulatory agencies included in the PharmGKB® Drug Label Annotations database (i.e., the FDA, EMA, SWISS Medic, PMDA, and HCSC) ranged from 45% to 65%, being 'actionable level' the most frequent. On the other hand, discrepancies between agencies did not exceed 35%. This study highlights the presence of relevant pharmacogenetic information on Spanish drug labels, which would help avoid interactions, toxicity, or lack of treatment efficacy.

Real-world clinical remission of severe asthma with benralizumab in Spanish adults with severe asthma.

OBJECTIVE: Patients with severe eosinophilic asthma experience high risk of exacerbations and reduced quality of life. Benralizumab, a monoclonal antibody binding to IL-5 receptor α subunit, is an approved drug for its treatment. The objective was to describe clinical remission after benralizumab prescription in routine clinical practice. METHODS: Retrospective multicenter study with data from four hospitals in Valencian Community (Spain) with asthma units between 2019 and 2020. Data was gathered at baseline and after 12 months. We considered clinical remission after 1 year if the patient remained without exacerbations and use of systemic corticosteroids and with good clinical control and normal lung function. RESULTS: Data from 139 patients was gathered. At the 12-month follow-up, 44.1% were in clinical remission, since 84.0%, 77.5%, 51.0% and 95.5% of patients did not experience exacerbations, had total asthma control test score of ≥20, prebronchodilator FEV1 of ≥80% and did not use systemic corticosteroids. A significant reduction of long-acting muscarinic antagonists (p = 0.0001), leukotriene receptor antagonists (p = 0.0326), oral corticosteroids (p < 0.0001) and short-acting beta agonists (p = 0.0499) was observed. Baseline factors with greatest individual influence on clinical remission were employment situation, tobacco use, comorbidity number, eosinophil value, number of exacerbations, FEV1, emergency visit number, and ACT, MiniAQLQ and TAI scores. Final analysis of multiple logistic regression indicated that having baseline FEV1 value below 80% increases remission chance 9.7 times a year compared to FEV1 >80%. CONCLUSION: Clinical remission after treatment with benralizumab is achievable in a high percentage of patients with severe asthma eosinophilia not controlled in real life.

Mutagenesis of a Quintuple Mutant Impaired in Environmental Responses Reveals Roles for CHROMATIN REMODELING4 in the Arabidopsis Floral Transition.

Several pathways conferring environmental flowering responses in Arabidopsis (Arabidopsis thaliana) converge on developmental processes that mediate the floral transition in the shoot apical meristem. Many characterized mutations disrupt these environmental responses, but downstream developmental processes have been more refractory to mutagenesis. Here, we constructed a quintuple mutant impaired in several environmental pathways and showed that it possesses severely reduced flowering responses to changes in photoperiod and ambient temperature. RNA-sequencing (RNA-seq) analysis of the quintuple mutant showed that the expression of genes encoding gibberellin biosynthesis enzymes and transcription factors involved in the age pathway correlates with flowering. Mutagenesis of the quintuple mutant generated two late-flowering mutants, quintuple ems1 (qem1) and qem2 The mutated genes were identified by isogenic mapping and transgenic complementation. The qem1 mutant is an allele of the gibberellin 20-oxidase gene ga20ox2, confirming the importance of gibberellin for flowering in the absence of environmental responses. By contrast, qem2 is impaired in CHROMATIN REMODELING4 (CHR4), which has not been genetically implicated in floral induction. Using co-immunoprecipitation, RNA-seq, and chromatin immunoprecipitation sequencing, we show that CHR4 interacts with transcription factors involved in floral meristem identity and affects the expression of key floral regulators. Therefore, CHR4 mediates the response to endogenous flowering pathways in the inflorescence meristem to promote floral identity.

Neuropsychological effects and cognitive deficits associated with exposure to mercury and arsenic in children and adolescents of the Mojana region, Colombia.

The present study aims to explore the neuropsychological performance and exposure to mercury (Hg) and arsenic (As) in Colombian children and adolescents considering biomarkers in hair and blood. The total sample consisted of 70 participants from the Mojana region, Colombia. A neuropsychological evaluation protocol was used, consisting of 11 internationally recognized tests, with evidence of national validation and use for measurement in neurotoxicology contexts. A 57.1% of the sample presented levels above the reference value according to the USEPA, the WHO, and the ATSDR for total mercury in hair (HgH), blood mercury (HgB), and/or blood arsenic (AsB). The mean values reported for HgH were 1.76 ± 3.1 µg/g (95% CI 1.02-2.50) with ranges between 0.23 and 17.20; for HgB: 4.11 ± 5.93 µg/l (CI 2.69-5.52), ranging between 0.25 and 25.80, and for AsB: 1.96 ± 2.73 (CI 1.31-2.61) ranging between 0.50 and 15.50. In the comparison of groups in relation to the level of exposure, a significant difference was found (p < 0.05) for the subtest The Boston Naming Test (BNT). Correlation analyses found, on the one hand, significant negative relationships in tests integrated within the verbal (CVB) and executive function (EF) components as well as evidence of positive relationships in the manifestation of errors in their performance with the levels of Hg and/or As transformed by biomarker (Log10). In the linear regression analyses it was found that for each increase in the concentration of HgH, HgB, and AsB it is estimated that, both for the models with and without data adjustment, there is a loss of scores in integrated measures within the CVB and EF for the transformed levels of HgH, HgB, and AsB; and an increase in the reported errors in their processing within these functions. According to these results, exposure to mercury and/or arsenic is related with performance in verbal neuropsychological skills and executive functioning.

Improved Methods for Fourier-Based Microwave Imaging.

Fourier-based imaging has been widely adopted for microwave imaging thanks to its efficiency in terms of computational complexity without compromising image resolution. Together with other backpropagation imaging algorithms like delay-and-sum (DAS), they are based on a far-field approach to the electromagnetic expression relating to fields and sources. To improve the accuracy of these techniques, this contribution presents a modified version of the well-known Fourier-based algorithm by taking into account the field radiated by the Tx/Rx antennas of the microwave imaging system. The impact on the imaged targets is discussed, providing a quantitative and qualitative analysis. The performance of the proposed method for subsampled microwave imaging scenarios is compared against other well-known aliasing mitigation methods.

Underwater polypectomy at the appendiceal orifice in a patient on anticoagulation.

A 78-year-old male on warfarin for deep venous thrombosis is referred to us for resection of a sessile polyp in the cecum. A high-definition Fujifilm BL-7000 processor, virtual chromoendoscopy, and EC-760ZP-V/L magnifying endoscope were used. Diathermy source, ERBE VIO 3. Auto cut mode, Effect 5, 80 watts, and Soft coagulation mode, Effect 5, 60 watts. Underwater polypectomy ensued with resection in two fragments. The resection bed was invaginated into the appendiceal orifice, hence no other measures were considered to prevent delayed bleeding. No complications were reported. The histopathological study found a tubulovillous adenoma with lesion-free borders.

[Acute pancreatitis due to hepatitis B virus. A case report]. / Pancreatitis aguda por virus de la hepatitis B. Reporte de un caso.

Acute pancreatitis is an inflammatory condition that is related to various etiologies. However, an infrequent one is acute infection by hepatotropic viruses. We present the case of a 33-year-old man who consulted the emergency department for abdominal pain and generalized jaundice. Serological studies reported acute infection by Hepatitis B Virus; The patient was managed with clinical and paraclinical monitoring of liver function tests together with supportive therapy with dextrose. The patient persisted with increasing abdominal pain and cholestasis, so they were considered differential. Magnetic resonance imaging of the upper abdomen showed acute non-biliary pancreatitis that was concluded secondary to the infectious process due to hepatitis B after ruling out other causes. The patient did not require changes in management with improvement in liver function tests, so he was discharged from hospital with favorable evolution in outpatient follow-up. Acute pancreatitis secondary to Hepatitis B Virus is a pathology that should be suspected and studied when the patient's clinical picture does not show improvement; Diagnosis is based on measurement of pancreatic enzyme levels.

Relationships between CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 metabolic phenotypes and genotypes in a Nicaraguan Mestizo population.

Interethnic variability in the drug-metabolizing capacity of CYP450 enzymes may lead to discrepancies in the relationship between genotypes and phenotypes worldwide. The present study was aimed to analyze for the first time whether there is a relationship between clinically relevant CYP450 genetic polymorphisms and their drug oxidation capacity (metabolic phenotype) in a population of healthy Nicaraguan volunteers. Two hundred and twelve participants were genotyped for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and their actual metabolic phenotype (evaluated by the Metabolic Ratio, MR) was analyzed by using the CEIBA cocktail approach. The results showed the wide interindividual variability in all the studied enzymes and a significant difference (p < 0.004) in the activity of CYP1A2 between male and female subjects. The number of CYP2C19 (p < 0.0001) and CYP2D6 (p < 0.0001) active alleles were shown inversely correlated with their corresponding MR, although there were marked genotype-phenotype discrepancies. There was an actual enzyme capacity overlapping (MR) between genotypically Poor (gPMs) and Extensive Metabolizers (gEMs) of 3.14% subjects for CYP2D6 and 0.94% for CYP2C9. Similarly, there was an overlapping for metabolic phenotypes of 11.48% of genotypically ultrarapid metabolizers (gUMs) for CYP2C19 and 2.09% for CYP2D6 and gEMs. Therefore, the current approach for metabolic phenotype prediction based just on genotype does not predict properly for all individuals within this Nicaraguan Mestizo population, thus representing a potential barrier for the clinical implementation of personalized medicine in this region. However, it is necessary to improve the prediction of phenotype from genotype in order to improve the pharmacogenetic implementation in populations with specific ethnic backgrounds.

Unraveling the role of MADS transcription factor complexes in apple tree dormancy.

A group of MADS transcription factors (TFs) are believed to control temperature-mediated bud dormancy. These TFs, called DORMANCY-ASSOCIATED MADS-BOX (DAM), are encoded by genes similar to SHORT VEGETATIVE PHASE (SVP) from Arabidopsis. MADS proteins form transcriptional complexes whose combinatory composition defines their molecular function. However, how MADS multimeric complexes control the dormancy cycle in trees is unclear. Apple MdDAM and other dormancy-related MADS proteins form complexes with MdSVPa, which is essential for the ability of transcriptional complexes to bind to DNA. Sequential DNA-affinity purification sequencing (seq-DAP-seq) was performed to identify the genome-wide binding sites of apple MADS TF complexes. Target genes associated with the binding sites were identified by combining seq-DAP-seq data with transcriptomics datasets obtained using a glucocorticoid receptor fusion system, and RNA-seq data related to apple dormancy. We describe a gene regulatory network (GRN) formed by MdSVPa-containing complexes, which regulate the dormancy cycle in response to environmental cues and hormonal signaling pathways. Additionally, novel molecular evidence regarding the evolutionary functional segregation between DAM and SVP proteins in the Rosaceae is presented. MdSVPa sequentially forms complexes with the MADS TFs that predominate at each dormancy phase, altering its DNA-binding specificity and, therefore, the transcriptional regulation of its target genes.

Bacillus as a source of phytohormones for use in agriculture.

Microbial plant biostimulants (MPBs) are capable of improving the productivity and quality of crops by activating plant physiological and molecular processes, representing an efficient tool in sustainable agriculture. Through phytohormone production, MPBs are capable of regulating plant physiological processes, increasing the productivity and quality of crops, in addition to being an efficient alternative in the industrial production of phytohormones. Bacillus is a bacterial genus with various species on the market being used as biopesticides, due to their ability to produce antimicrobial, nematicidal and insecticidal compounds. The capability of Bacillus species to protect plants against pests and/or pathogens also entails the triggering or increase of plant defense responses. Furthermore, a relevant number of species from the genus Bacillus provoke plant growth promotion by different mechanisms such as increasing the tolerance of their host plants under abiotic stress conditions or improving plant nutrition. In several cases, the plant response is mediated by the bacterial production of phytohormones. In the present work, all studies from recent decades where the production of phytohormones by Bacillus species are reported, highlighting their role in host plants and the mechanisms by which they are capable of increasing plant growth, promoting their development, and improving their response to different stresses. KEY POINTS: • Different Bacillus-species are known as agricultural biopesticides. • Bacillus role as biostimulants is being increasingly addressed. • Bacillus represents a good source of phytohormones of agricultural interest.

A Portable Electromagnetic System Based on mm-Wave Radars and GNSS-RTK Solutions for 3D Scanning of Large Material Piles.

In this paper, a portable three-dimensional (3D) scanning system for the accurate characterization of large raw material (e.g., cereal grain, coal, etc.) stockpiles is presented. The system comprises an array of high resolution millimeter-wave radars and a cm-level accuracy positioning system to accurately characterize large stockpiles by means of a high-resolution 3D map, making it suitable for automation purposes. A control unit manages the data received by the sensors, which are sent to a computer system for processing. As a proof of concept, the entire sensor system is evaluated in a real environment for electromagnetically scan a scaled stockpile of coal, used in the industry for handling raw materials. In addition, a highly efficient processing adaptive algorithm that may reconstruct the scanned structure in real-time has been introduced, enabling continuous dynamic updating of the information. Results are compared with those from a photogrammetry-like technique, revealing an excellent agreement.

The sugar transporter SWEET10 acts downstream of FLOWERING LOCUS T during floral transition of Arabidopsis thaliana.

BACKGROUND: Floral transition initiates reproductive development of plants and occurs in response to environmental and endogenous signals. In Arabidopsis thaliana, this process is accelerated by several environmental cues, including exposure to long days. The photoperiod-dependent promotion of flowering involves the transcriptional induction of FLOWERING LOCUS T (FT) in the phloem of the leaf. FT encodes a mobile protein that is transported from the leaves to the shoot apical meristem, where it forms part of a regulatory complex that induces flowering. Whether FT also has biological functions in leaves of wild-type plants remains unclear. RESULTS: In order to address this issue, we first studied the leaf transcriptomic changes associated with FT overexpression in the companion cells of the phloem. We found that FT induces the transcription of SWEET10, which encodes a bidirectional sucrose transporter, specifically in the leaf veins. Moreover, SWEET10 is transcriptionally activated by long photoperiods, and this activation depends on FT and one of its earliest target genes SUPPRESSOR OF CONSTANS OVEREXPRESSION 1 (SOC1). The ectopic expression of SWEET10 causes early flowering and leads to higher levels of transcription of flowering-time related genes in the shoot apex. CONCLUSIONS: Collectively, our results suggest that the FT-signaling pathway activates the transcription of a sucrose uptake/efflux carrier during floral transition, indicating that it alters the metabolism of flowering plants as well as reprogramming the transcription of floral regulators in the shoot meristem.

Unprecedented high catecholamine production causing hair pigmentation after urinary excretion in red deer.

Hormones have not been found in concentrations of orders of magnitude higher than nanograms per milliliter. Here, we report urine concentrations of a catecholamine (norepinephrine) ranging from 0.05 to 0.5 g/l, and concentrations of its metabolite DL-3,4-dihydroxyphenyl glycol (DOPEG) ranging from 1.0 to 44.5 g/l, in wild male red deer Cervus elaphus hispanicus after LC-MS analyses. The dark ventral patch of male red deer, a recently described sexually selected signal, contains high amounts of DOPEG (0.9-266.9 mg/l) stuck in the hairs, while DOPEG is not present in non-darkened hair. The formation of this dark patch is explained by the chemical structure of DOPEG, which is a catecholamine-derived o-diphenol susceptible to be oxidized by air and form allomelanins, nitrogen-free pigments similar to cutaneous melanins; by its high concentration in urine; and by the urine spraying behavior of red deer by which urine is spread through the ventral body area. Accordingly, the size of the dark ventral patch was positively correlated with the concentration of DOPEG in urine, which was in turn correlated with DOPEG absorbed in ventral hair. These findings represent catecholamine concentrations about one million higher than those previously reported for any hormone in an organism. This may have favored the evolution of the dark ventral patch of red deer by transferring information on the fighting capacity to rivals and mates. Physiological limits for hormone production in animals are thus considerably higher than previously thought. These results also unveil a novel mechanism of pigmentation based on the self-application of urine over the fur.

Comment on the Article "A Lightweight and Low-Power UAV-Borne Ground Penetrating Radar Design for Landmine Detection".

This reply aims to correct some incomplete/incorrect information provided in the article "A Lightweight and Low-Power UAV-Borne Ground Penetrating Radar Design for Landmine Detection", when the authors compare their results with some state-of-the-art contributions.

Paving the Way to Eco-Friendly IoT Antennas: Tencel-Based Ultra-Thin Compact Monopole and Its Applications to ZigBee.

An ultrathin, compact ecofriendly antenna suitable for IoT applications around 2.45 GHz is achieved as a result of exploring the use of Tencel fabric for the antenna's design. The botanical ecofriendly Tencel is electromagnetically characterized, in terms of relative dielectric permittivity and loss tangent, in the target IoT frequency band. To explore the suitability of the Tencel, a comparison is conducted with conventionally used RO3003, with similar relative dielectric permittivity, regarding the antenna dimensions and performance. In addition, the antenna robustness under bent conditions is also analyzed by measurement. To assess the relevance of this contribution, the ultrathin ecofriendly Tencel-based antenna is compared with recently published antennas for IoT in the same band and also, with commercial half-wave dipole by performing a range test on a ZigBee-based IoT testbed.

Correction: Elucidation of molecular kinetic schemes from macroscopic traces using system identification.

[This corrects the article DOI: 10.1371/journal.pcbi.1005376.].

Zirconia-Based Ultra-Thin Compact Flexible CPW-Fed Slot Antenna for IoT.

An ultra-thin compact flexible CPW-fed slot monopole antenna suitable for the Internet of Things (IoT) applications was achieved as a result of exploring the use of Zirconia-based ENrG's Thin E-Strate® for the antenna's design. The electromagnetic characterization of the novel material at the frequency range of interest was analyzed. A comparison was made concerning the required dimensions and the simulation results regarding impedance matching and radiation properties, for three different dielectric substrates: Novel flexible ceramic (ENrG's Thin E-Strate), rigid Arlon 25N, and flexible Polypropylene (PP). Two different metallization techniques-electrotextile-based and inkjet printing-were used in the fabrication of prototypes based on ENrG's Thin E-Strate. Return losses measured results for the fabricated prototypes with both procedures was compared, as well as with simulation. The best prototype on the ENrG's Thin E-Strate was compared with one on Arlon 25N, in terms of radiation properties in an anechoic chamber, and conclusions were drawn.

Determination of antidepressants in human urine extracted by magnetic multiwalled carbon nanotube poly(styrene-co-divinylbenzene) composites and separation by capillary electrophoresis.

Poly(styrene-co-divinylbenzene)-coated magnetic multiwalled carbon nanotube composite synthesized by in-situ high temperature combination and precipitation polymerization of styrene-co-divinylbenzene has been employed as a magnetic sorbent for the solid phase extraction of antidepressants in human urine samples. Fluoxetine, venlafaxine, citalopram and sertraline were, afterwards, separated and determined by capillary electrophoresis with diode array detection. The presence of magnetic multiwalled carbon nanotubes in native poly(styrene-co-divinylbenzene) not only simplified sample treatment but also enhanced the adsorption efficiencies, obtaining extraction recoveries higher than 89.5% for all analytes. Moreover, this composite can be re-used at least ten times without loss of efficiency and limits of detection ranging from 0.014 to 0.041 µg/mL were calculated. Additionally, precision values ranging from 0.08 to 7.50% and from 0.21 to 3.05% were obtained for the responses and for the migration times of the analytes, respectively.

Elucidation of molecular kinetic schemes from macroscopic traces using system identification.

Overall cellular responses to biologically-relevant stimuli are mediated by networks of simpler lower-level processes. Although information about some of these processes can now be obtained by visualizing and recording events at the molecular level, this is still possible only in especially favorable cases. Therefore the development of methods to extract the dynamics and relationships between the different lower-level (microscopic) processes from the overall (macroscopic) response remains a crucial challenge in the understanding of many aspects of physiology. Here we have devised a hybrid computational-analytical method to accomplish this task, the SYStems-based MOLecular kinetic scheme Extractor (SYSMOLE). SYSMOLE utilizes system-identification input-output analysis to obtain a transfer function between the stimulus and the overall cellular response in the Laplace-transformed domain. It then derives a Markov-chain state molecular kinetic scheme uniquely associated with the transfer function by means of a classification procedure and an analytical step that imposes general biological constraints. We first tested SYSMOLE with synthetic data and evaluated its performance in terms of its rate of convergence to the correct molecular kinetic scheme and its robustness to noise. We then examined its performance on real experimental traces by analyzing macroscopic calcium-current traces elicited by membrane depolarization. SYSMOLE derived the correct, previously known molecular kinetic scheme describing the activation and inactivation of the underlying calcium channels and correctly identified the accepted mechanism of action of nifedipine, a calcium-channel blocker clinically used in patients with cardiovascular disease. Finally, we applied SYSMOLE to study the pharmacology of a new class of glutamate antipsychotic drugs and their crosstalk mechanism through a heteromeric complex of G protein-coupled receptors. Our results indicate that our methodology can be successfully applied to accurately derive molecular kinetic schemes from experimental macroscopic traces, and we anticipate that it may be useful in the study of a wide variety of biological systems.

The genetic basis of flowering responses to seasonal cues.

Plants respond to the changing seasons to initiate developmental programmes precisely at particular times of year. Flowering is the best characterized of these seasonal responses, and in temperate climates it often occurs in spring. Genetic approaches in Arabidopsis thaliana have shown how the underlying responses to changes in day length (photoperiod) or winter temperature (vernalization) are conferred and how these converge to create a robust seasonal response. Recent advances in plant genome analysis have demonstrated the diversity in these regulatory systems in many plant species, including several crops and perennials, such as poplar trees. Here, we report progress in defining the diverse genetic mechanisms that enable plants to recognize winter, spring and autumn to initiate flower development.