Virtual screening and molecular dynamics simulation of natural compounds as potential inhibitors of serine/threonine kinase 16 for anticancer drug discovery.

Serine/threonine kinase 16 (STK 16) is involved in many facets of cellular regulation; activation of STK 16 plays a crucial role in the migration of cancer cells. Therefore, it is a novel target for the discovery of anticancer agents. Herein, virtual screening and dynamics simulation were used to screen a large library of natural compounds against STK 16 using Schrodinger suit 2021-2 and GROMACS 2021.6. The results predicted five molecules with high binding affinity against the target, with NPC132329 (Arcyriaflavin C) and NPC160898 having higher binding affinity and molecular mechanics generalized born surface area (MM/GBSA), suggesting that it is better than the standard inhibitor. The molecular dymanics (MD) simulation studies showed that the STK 16-NPC132329 complex has the lowest root mean square deviation, and STK 16-NPC160898 was the most stable compared with the standard drug and selective STK 16 inhibitor. The minimal fluctuation was observed in the STK 16-NPC132329 and STK 16-NPC160898 complexes based on the root mean square fluctuation trajectory with NPC132329 and NPC160898 forming 2 and 3 hydrogen bonds respectively with the amino acid residue of the target's binding site. Overall, NPC132329 and NPC160898 are better STK 16 inhibitors than the standard drug and selective inhibitor, which can be further studied to discover novel anticancer drugs.

What is the relationship between physical fitness level and macro- and micronutrient intake in Spanish older adults?

PURPOSE: The aim of this study was to assess the association between physical fitness (PF) and energy and nutrient intake in Spanish older adults. METHODS: Three hundred and twenty-four participants (59.9% females, aged over 55 years) performed a battery of four validated PF tests and participants were divided into three: low, medium, and high PF. Dietary intake was assessed by two non-consecutive 24 h dietary recalls. Energy and nutrient intake was calculated using the ALIMENTA software. Energy expenditure (EE) was calculated using a validated questionnaire. RESULTS: Median energy intake (EI) was 2135, 1999, and 2111 kcal/day in the low, medium, and high PF in males, respectively. In females, the median EI was 1576, 1564, and 1625 kcal/day in the low, medium, and high PF groups. There were significant and positive associations between participants in the high PF group and intake of phosphorous, selenium, vitamin B6, C, D, E, niacin, and folates (all p < 0.05). However, subjects in the high PF group presented negative associations with thiamine and riboflavin intake (all p < 0.05). A total of 8.3% of participants presented inadequate intake of 11 micronutrients. PF seems to affect total nutrient intake. CONCLUSIONS: Higher protein and fat intake was observed in the high PF group compared to the other PF groups in males, although participants in the high PF group had also higher EE. However, females presented different patterns. In both sexes participants in the high PF group showed a better micronutrient intake profile than the other PF groups. There is a need to develop combined nutritional and fitness programs.

Standard finishing categories for high-throughput sequencing of viral genomes.

Viral genome sequencing has become the cornerstone of almost all aspects of virology. In particular, high-throughput, next-generation viral genome sequencing has become an integral part of molecular epidemiological investigations into outbreaks of viral disease, such as the recent outbreaks of Middle Eastern respiratory syndrome, Ebola virus disease and Zika virus infection. Multiple institutes have acquired the expertise and necessary infrastructure to perform such investigations, as evidenced by the accumulation of thousands of novel viral sequences over progressively shorter time periods. The authors recently proposed a nomenclature comprised of five high-throughput sequencing standard categories to describe the quality of determined viral genome sequences. These five categories (standard draft, high quality, coding complete, complete and finished) cover all levels of viral genome finishing and can be applied to sequences determined by any technology platform or assembly technique.

Le séquençage des génomes viraux est devenu la pierre angulaire de pratiquement toutes les facettes de la virologie. En particulier, le séquençage à haut débit de nouvelle génération est désormais une partie intégrante des enquêtes d'épidémiologie moléculaire relatives aux foyers de maladies virales, par exemple les récentes épidémies du syndrome respiratoire du Moyen-Orient, la maladie due au virus Ebola ou l'infection par le virus Zika. Nombre d'institutions ont acquis les compétences techniques et les infrastructures nécessaires pour réaliser ce type d'enquêtes, comme en témoigne l'accumulation de milliers de séquences virales nouvelles obtenues en un laps de temps de plus en plus court. Les auteurs ont récemment élaboré une nomenclature constituée de cinq catégories de référence décrivant la qualité des séquences d'un génome viral obtenues par séquençage à haut débit. Ces cinq catégories (ébauche de référence, séquence de haute qualité, séquence codante complète, séquence complète et séquence finie) couvrent toutes les étapes de la finition du génome viral et s'appliquent quelle que soit la plateforme technologique ou la technique d'assemblage utilisée pour déterminer la séquence.

La secuenciación del genoma vírico se ha erigido a día de hoy en la piedra angular de casi todos los aspectos de la virología. La secuenciación de alto rendimiento de próxima generación, en particular, es ahora un componente integral de las investigaciones de epidemiología molecular sobre brotes de enfermedades víricas como los registrados últimamente de síndrome respiratorio de Oriente Medio, enfermedad por el virus del Ebola o infección por el virus Zika. Numerosas instituciones se han dotado de las competencias técnicas y la infraestructura necesaria para llevar a cabo tales investigaciones, como deja patente la acumulación de miles de nuevas secuencias víricas en periodos de tiempo cada vez más cortos. En fechas recientes los autores han propuesto una nomenclatura compuesta de cinco categorías de referencia que sirven para describir la calidad de las secuencias de genoma vírico determinadas por secuenciación de alto rendimiento. Estas cinco categorías (borrador normal, gran calidad, codificación completa, completa y acabada) cubren toda la gradación de acabados en la secuenciación de genoma vírico y pueden ser aplicadas a las secuencias obtenidas por cualquier dispositivo técnico o cualquier técnica de ensamblaje.

A novel begomovirus isolated from sida contains putative cis- and trans-acting replication specificity determinants that have evolved independently in several geographical lineages.

A novel begomovirus isolated from a Sida rhombifolia plant collected in Sinaloa, Mexico, was characterized. The genomic components of sida mosaic Sinaloa virus (SiMSinV) shared highest sequence identity with DNA-A and DNA-B components of chino del tomate virus (CdTV), suggesting a vertical evolutionary relationship between these viruses. However, recombination analysis indicated that a short segment of SiMSinV DNA-A encompassing the plus-strand replication origin and the 5´-proximal 43 codons of the Rep gene was derived from tomato mottle Taino virus (ToMoTV). Accordingly, the putative cis- and trans-acting replication specificity determinants of SiMSinV were identical to those of ToMoTV but differed from those of CdTV. Modeling of the SiMSinV and CdTV Rep proteins revealed significant differences in the region comprising the small ß1/ß5 sheet element, where five putative DNA-binding specificity determinants (SPDs) of Rep (i.e., amino acid residues 5, 8, 10, 69 and 71) were previously identified. Computer-assisted searches of public databases led to identification of 33 begomoviruses from three continents encoding proteins with SPDs identical to those of the Rep encoded by SiMSinV. Sequence analysis of the replication origins demonstrated that all 33 begomoviruses harbor potential Rep-binding sites identical to those of SiMSinV. These data support the hypothesis that the Rep ß1/ß5 sheet region determines specificity of this protein for DNA replication origin sequences.

Random sequential adsorption with correlated defects : A series expansion approach.

The random sequential adsorption (RSA) problem holds crucial theoretical and practical significance, serving as a pivotal framework for understanding and optimizing particle packing in various scientific and technological applications. Here the problem of the one-dimensional RSA of k-mers onto a substrate with correlated defects controlled by uniform and power-law distributions is theoretically investigated: the coverage fraction is obtained as a function of the density of defects and several scaling laws are examined. The results are compared with extensive Monte Carlo simulations and more traditional methods based on master equations. Emphasis is given in elucidating the scaling behavior of the fluctuations of the coverage fraction. The phenomenon of universality breaking and the issues of conventional Gaussian fluctuations and the Lévy type fluctuations from a simple perspective, relying on the central limit theorem, are also addressed.

Genome-scale phylogeny of the alphavirus genus suggests a marine origin.

The genus Alphavirus comprises a diverse group of viruses, including some that cause severe disease. Using full-length sequences of all known alphaviruses, we produced a robust and comprehensive phylogeny of the Alphavirus genus, presenting a more complete evolutionary history of these viruses compared to previous studies based on partial sequences. Our phylogeny suggests the origin of the alphaviruses occurred in the southern oceans and spread equally through the Old and New World. Since lice appear to be involved in aquatic alphavirus transmission, it is possible that we are missing a louse-borne branch of the alphaviruses. Complete genome sequencing of all members of the genus also revealed conserved residues forming the structural basis of the E1 and E2 protein dimers.

Physical properties of a generalized model of multilayer adsorption of dimers.

We investigate the transport properties of a complex porous structure with branched fractal architectures formed due to the gradual deposition of dimers in a model of multilayer adsorption. We thoroughly study the interplay between the orientational anisotropy parameter p_{0} of deposited dimers and the formation of porous structures, as well as its impact on the conductivity of the system, through extensive numerical simulations. By systematically varying the value of p_{0}, several critical and off-critical scaling relations characterizing the behavior of the system are examined. The results demonstrate that the degree of orientational anisotropy of dimers plays a significant role in determining the structural and physical characteristics of the system. We find that the Einstein relation relating to the size scaling of the electrical conductance holds true only in the limiting case of p_{0}→1. Monitoring the fractal dimension of the interface of the multilayer formation for various p_{0} values, we reveal that in a wide range of p_{0}>0.2 interface shows the characteristic of a self-avoiding random walk, compared to the limiting case of p_{0}→0 where it is characterized by the fractal dimension of the backbone of ordinary percolation cluster at criticality. Our results thus can provide useful information about the fundamental mechanisms underlying the formation and behavior of wide varieties of amorphous and disordered systems that are of paramount importance both in science and technology as well as in environmental studies.

[Limitation of the therapeutic effort]. / Limitación del esfuerzo terapéutico.

The limitation of the therapeutic effort (LTE) consists in not applying extraordinary or disproportionate measures for therapeutic purposes that are proposed for a patient with poor life prognosis and/or poor quality of life. There are two types. The first is to not initiate certain measures or to withdraw them when they are established. A decision of the LTE should be based on some rigorous criteria, so that we make the following proposal. First, it is necessary to know the most relevant details of the case to make a decision: the preferences of the patient, the preferences of the family when pertinent, the prognosis (severity), the quality of life and distribution of the limited resources. After, the decision should be made. In this phase, participatory deliberation should be established to clarify the end of the intervention. Finally, if it is decided to perform an LTE, it should be decided how to do it. Special procedures, disproportionate measures, that are useless and vain should not be initiated for the therapeutic objective designed (withdraw them if they have been established). When it has been decided to treat a condition (interim measures), the treatment should be maintained. This complex phase may need stratification of he measures. Finally, the necessary palliative measures should be established.

Transport properties in multilayer adsorption of dimers.

In this paper, we study the transport properties (percolation and conductivity) of a two-dimensional structure created by depositing dimers on a one-dimensional substrate where multilayer deposition is allowed. Specifically, we are interested in studying how the mentioned properties vary as a function of the height of the multilayer. The critical parameters of the percolation transition are calculated using finite-size scaling analysis, obtaining the scaling laws for the probability of percolation and the conductivity of the system. To calculate the electrical conductivity of the multilayer, we use the Frank-Lobb algorithm.

[Differential characteristics of patients with acute coronary syndrome without ST-segment elevation compared to those with transient ST-segment elevation]. / Características diferenciales de los pacientes con síndrome coronario agudo sin elevación del segmento ST con respecto a los que tienen elevación transitoria del segmento ST.

OBJECTIVE: To evaluate different characteristics of patients with acute coronary syndrome (ACS) without ST-segment elevation compared with transient St-segment elevation. DESIGN: An observational, prospective study. SETTING: A 12-bed coronary care unit. PATIENTS: Consecutive patients of ACS without persistent ST-segment elevation. MAIN VARIABLES OF INTEREST: The population was divided intro 2 groups according to the presence of transient ST-segment elevation. Variables of interest were age, cardiovascular risk factors, troponin I and glucose concentrations on admission, coronary anatomy, left ventricular ejection fraction, inhospital mortality and drugs. RESULTS: Patients identified as ACS with transient ST-segment elevation were significantly younger, smokers and predominantly male. At the same time, they showed a minor peak elevation of troponin I, a higher ejection fraction and, mainly single-vessel coronary disease. CONCLUSIONS: Patients with ACS with transient ST-segment elevation differ in the type of population, myocardial damage and coronary angiographic results with respect to patients with ACS without ST-segment elevation. More research is needed to clarify whether these differences imply a different therapeutic approach.

Circulation of mumps virus genotypes in Spain from 1996 to 2007.

Although the WHO recommends the use of genotyping as a tool for epidemiological surveillance for mumps, limited data on mumps virus (MV) genotype circulation that may be used to trace the patterns of virus spread are available. We describe the first complete series of data from Spain. The small hydrophobic region was sequenced from 237 MV-positive samples from several regions of Spain collected between 1996 and 2007. Six different genotypes were identified: A, C, D (D1), G (G1, G2), H (H1, H2), and J. Genotype H1 was predominant during the epidemic that occurred from 1999 to 2003 but was replaced by genotype G1 as the dominant genotype in the epidemic that occurred from 2005 to 2007. The same genotype G1 strain caused concomitant outbreaks in different parts of the world (the United States, Canada, and the United Kingdom). The remaining genotypes (genotypes A, C, D, and J) appeared in sporadic cases or small limited outbreaks. This pattern of circulation seems to reflect continuous viral circulation at the national level, despite the high rates of vaccine coverage.

Assessment of patient competence for making decisions. / Valoración de la competencia de los pacientes para tomar decisiones.

For patients to be able to make decisions autonomously (and to grant informed consent), they must have information, understanding, freedom and willingness, with competence a prerequisite for autonomy. Clinicians are often faced with patients lacking competence to make decisions but detect less than half of such cases and often inadequately assess the patients' competence. This article offers guidelines for assessing the competence of patients for whom there are doubts about their ability to make decisions concerning their health. The procedure is based on 5 steps: 1) recognising the conditions that require a competence assessment; 2) fully evaluating the competence; 3) correlating the degree of competence with the complexity of the decision; 4) improving the patient's competence when possible; and 5) establishing who will make the decision.

Genetic analysis of Israel acute paralysis virus: distinct clusters are circulating in the United States.

Israel acute paralysis virus (IAPV) is associated with colony collapse disorder of honey bees. Nonetheless, its role in the pathogenesis of the disorder and its geographic distribution are unclear. Here, we report phylogenetic analysis of IAPV obtained from bees in the United States, Canada, Australia, and Israel and the establishment of diagnostic real-time PCR assays for IAPV detection. Our data indicate the existence of at least three distinct IAPV lineages, two of them circulating in the United States. Analysis of representatives from each proposed lineage suggested the possibility of recombination events and revealed differences in coding sequences that may have implications for virulence.

Naltrexone effects on male sexual behavior, corticosterone, and testosterone in stressed male rats.

Chronic physical or psychological stress disrupts male reproductive function. Studies in our laboratory have shown that stress by immersion in cold water (ICW) and by electrical foot shocks (EFS) has inhibitory effects on male sexual behavior; these effects do not seem to be mediated by an increase in corticosterone, nor by a decrease in testosterone. On the other hand, it is known that endogenous opioids are released in the brain in response to these same stressors; consequently, they could be participating in the impairment of sexual behavior, as well as in the changes in corticosterone and testosterone caused by stress. The aim of this study was to analyze the effects of the opioid antagonist naltrexone (NTX) on male sexual behavior, corticosterone, and testosterone in both stressed sexually experienced and naive male rats. Sexually experienced adult male rats were assigned to one of the following groups (n=10 each): 1) control group, males without sexual evaluation; 2) control group, rats injected ip with saline, non-stressed; 3) control group, rats injected with NTX (3 mg/kg) non-stressed; 4) rats injected ip with saline, and stressed by EFS; 5) rats injected ip with NTX (1.5 mg/kg) and stressed by EFS; 6) rats injected ip with saline and stressed by ICW; 7) rats injected ip with NTX (1.5 mg/kg) and stressed by ICW; 8) rats injected ip with NTX (3 mg/kg) and stressed by ICW. Naive males were assigned to the same control groups but only stressed by ICW and the NTX dose used was 3 mg/kg. Injections were given 30 min before stress sessions. Stress was applied on 20 consecutive days. Male sexual behavior was assessed 15 min after EFS or 30 min after ICW, on days 1, 4, 8, 12, 15, and 20. Trunk blood was collected at the end of the experiments on day 20 of stress. Corticosterone and testosterone were evaluated by HPLC. Mount, intromission and ejaculation latencies were longer in control saline naive males compared to control saline sexually experienced males on the first day. NTX administration to control naive males caused a decrease in mount, intromission, and ejaculation latencies, as well as an increase in ejaculatory frequency/30 min, compared to control-saline only on day 1. Stressed naive males showed higher mount, intromission and ejaculation latencies, compared to control and stressed sexually experienced males, as well as comparable increase in corticosterone and decrease in testosterone plasma levels. NTX administration before exposure to stress prevented the modifications caused by stress in sexual parameters. Sexual behavior in control sexually-active males injected with saline or NTX was not modified. Saline stressed males showed the previously reported alterations in sexual behavior, as well as an increase in corticosterone and a decrease in testosterone plasma levels. Stressed males injected with NTX before exposure to stress showed no alterations in male sexual behavior. NTX in control non-stressed males did not modify corticosterone plasma levels, but did cause a significant increase in plasma testosterone. The increase in corticosterone and the decrease in testosterone due to stress, were attenuated with the opioid antagonist, both in naive and sexually experienced males. Prevention of ICW stress effects was more effective with higher doses of NTX (3 mg/kg). These data suggest that endogenous opioids could be participating in the effects caused by stress on male sexual behavior, corticosterone, and testosterone.

Methylprednisolone for the treatment of children with refractory epilepsy.

Epilepsy is a disease characterized by unprovoked epileptic seizures resulting from a bioelectrical brain dysfunction. Antiepileptic treatment controls 75% of all epileptic patients; the other 25% continue to have epileptic seizures in spite of a combination of multiple antiepileptic drugs. The purpose of this work was to evaluate the use of methylprednisolone in the treatment of children with refractory epilepsy. Fourteen children with refractory epilepsy at the Hospital de Especialidades No. 25 of the Instituto Mexicano del Seguro Social in Monterrey, Northeast Mexico were included. For five consecutively days, each patient received methylprednisolone by intravenous administration at a dosage of 15 mg/kg/day each 8 h, once a month for 3 months. The frequency of epileptic seizures and possible related side effects were evaluated every month during the three months before, during, and after administration of methylprednisolone. The frequency of epileptic seizures was reduced by more than 50% in 12/14 patients during methylprednisolone treatment. The median number of seizures before treatment with methylprednisolone was 8, 8, and 7; during the treatment: 1, 1, and 1; and after treatment: 2, 2, and 3 (p=0.000). We conclude that methylprednisolone reduces the frequency of epileptic seizures in children with refractory epilepsy.

Cluster analysis of the origins of the new influenza A(H1N1) virus.

In March and April 2009, a new strain of influenza A(H1N1) virus has been isolated in Mexico and the United States. Since the initial reports more than 10,000 cases have been reported to the World Health Organization, all around the world. Several hundred isolates have already been sequenced and deposited in public databases. We have studied the genetics of the new strain and identified its closest relatives through a cluster analysis approach. We show that the new virus combines genetic information related to different swine influenza viruses. Segments PB2, PB1, PA, HA, NP and NS are related to swine H1N2 and H3N2 influenza viruses isolated in North America. Segments NA and M are related to swine influenza viruses isolated in Eurasia.

Correction: Two stable variants of Burkholderia pseudomallei strain MSHR5848 express broadly divergent in vitro phenotypes associated with their virulence differences.

[This corrects the article DOI: 10.1371/journal.pone.0171363.].

Antidepressant-like effects of Tagetes lucida Cav. in the forced swimming test.

AIM OF THE STUDY: Tagetes lucida (Asteraceae), has been referred in Mexican traditional medicine for the treatment of different central nervous system (CNS) diseases, mainly depression. Nevertheless, the available scientific information about this species is scarce and there are no reports related to its possible effect on the CNS. In this work, the antidepressant-like effect of extract of Tagetes lucida was evaluated in rats, as well as its potential adverse effects on male sexual behavior (MSB). MATERIALS AND METHODS: Antidepressant activity was studied using forced swimming test (FST), motor activity in the open-field test and on MSB in sexually experienced male. The aqueous extract of Tagetes lucida in doses of 5, 10, 50, 100 and 200mg/(kgday)(-1) were administered orally for 14 consecutive days and evaluated on day 14, 2h after the last dose treatment. Fluoxetine (10mg/(kgday)(-1), p.o.) was used as the control positive. RESULTS: The aqueous extract (10, 50, 100mg/(kgday)(-1)) significantly reduced immobility and increased swimming without affecting climbing behavior in the FST. These same doses were not able to modify neither the motor activity nor the MSB. CONCLUSION: These data indicate that the extract of Tagetes lucida possesses antidepressant-like properties in rats.

[Are we still our patients' keepers?: James Drane's contribution to clinical ethics in the current context]. / ¿Seguimos siendo guardianes de nuestros pacientes?: la contribución de James Drane a la ética clínica actual.

The current article analyzes the figure of the American bioethicist James Drane (1930). Drane not only played a crucial role in the birth of Bioethics in the United States, but was also instrumental in the inception and development of the field in Spain and Latin America. His «sliding scale¼ was the first dynamic tool encouraging a systematic evaluation of a patient's capacity to make healthcare-related decisions. However Drane's major contribution to the field was his application of virtue Ethics to the doctor-patient relationship. His proposal rests on the physician's compromise with the patient in all his/her dimensions. This goal will guide the physician's character and serve as compass, with which to exercise a virtuous practice, since only by exercising these virtues can doctors become truly good.