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Abstract We analyze the effect of obesity on the incidence of hypertension, hyperlipidemia and diabetes in USA using a health production theoretical framework along with a bivariate flexible semi-parametric recursive copula model that account for endogeneity. In this approach, the effects of control variables are flexibly determined using additive predictors that allow for a variety of effects. Our findings suggest that there exist a positive and significant effect of obesity on the prevalence of all chronic diseases examined. In particular, after endogeneity is accounted for, the probability of having hypertension, hyperlipidemia and diabetes for obese individuals are, respectively, 35%, 28% and 11% higher than those under the obesity threshold. These findings suggest that lowering obesity rates could lead to significant reductions in the morbidity and mortality associated with these diseases.

Epilepsy is a neurological disorder characterized by abnormal neuronal excitability, with glutamate playing a key role as the predominant excitatory neurotransmitter involved in seizures. Animal models of epilepsy are crucial in advancing epilepsy research by faithfully replicating the diverse symptoms of this disorder. In particular, the GASH/Sal (genetically audiogenic seizure-prone hamster from Salamanca) model exhibits seizures resembling human generalized tonic-clonic convulsions. A single nucleotide polymorphism (SNP; C9586732T, p.His289Tyr) in the Grik1 gene (which encodes the kainate receptor GluK1) has been previously identified in this strain. The H289Y mutation affects the amino-terminal domain of GluK1, which is related to the subunit assembly and trafficking. We used confocal microscopy in Xenopus oocytes to investigate how the H289Y mutation, compared to the wild type (WT), affects the expression and cell-surface trafficking of GluK1 receptors. Additionally, we employed the two-electrode voltage-clamp technique to examine the functional effects of the H289Y mutation. Our results indicate that this mutation increases the expression and incorporation of GluK1 receptors into an oocyte’s membrane, enhancing kainate-evoked currents, without affecting their functional properties. Although further research is needed to fully understand the molecular mechanisms responsible for this epilepsy, the H289Y mutation in GluK1 may be part of the molecular basis underlying the seizure-prone circuitry in the GASH/Sal model.

A nine year old cross-breed dog was presented with a two week history of ambulatory tetraparesis and proprioceptive ataxia affecting all four limbs. Meningomyelitis of Unknown Origin (MUO) was presumptively diagnosed based on the magnetic resonance imaging (MRI) findings and cerebrospinal fluid (CSF) analysis. The dog received a tapering dose of glucocorticoids and cyclosporine, showing significant improvement and the stabilization of the clinical signs for seven months. After this period, the dog showed an acute clinical deterioration and a follow-up MRI revealed new multiple lesions affecting different spinal nerve roots along the cervicothoracic spinal cord. Following euthanasia, a final diagnose of multiple malignant peripheral nerve sheath tumors (MPNSTs) was made based on the histopathological examination. MPNSTs can affect the cranial nerves, spinal nerves or the associated nerve roots at any location and can lead to secondary spinal cord compression. The aim of the present case report is to describe the clinical presentation and atypical MRI findings of a dog with histologically confirmed multiple MPNSTs. According to the reviewed literature, this is the first reported case of simultaneous MPNSTs in the cervicothoracic spinal cord of a dog.

Cyanobacteria, phototrophic organisms performing oxygenic photosynthesis, must adapt their metabolic processes to important environmental challenges, like those imposed by the succession of days and nights. Not surprisingly, certain regulatory proteins are found exclusively in this phylum. One of these unique proteins, PipX, provides a mechanistic link between signals of carbon/nitrogen and of energy, transduced by the signaling protein PII, and the control of gene expression by the global nitrogen regulator NtcA. PII, required for cell survival unless PipX is inactivated or downregulated, functions by protein–protein interactions with transcriptional regulators, transporters, and enzymes. PipX also functions by protein–protein interactions, and previous studies suggested the existence of additional interacting partners or included it into a relatively robust six-node synteny network with proteins apparently unrelated to the nitrogen regulation system. To investigate additional functions of PipX while providing a proof of concept for the recently developed cyanobacterial linkage network, here we analyzed the physical and regulatory interactions between PipX and an intriguing component of the PipX synteny network, the essential ribosome assembly GTPase EngA. The results provide additional insights into the functions of cyanobacterial EngA and of PipX, showing that PipX interacts with the GD1 domain of EngA in a guanosine diphosphate-dependent manner and interferes with EngA functions in Synechococcus elongatus at a low temperature, an environmentally relevant context. Therefore, this work expands the PipX interaction network and establishes a possible connection between nitrogen regulation and the translation machinery. We discuss a regulatory model integrating previous information on PII–PipX with the results presented in this work.

Gangliogliomas are extremely rare tumors of the nervous system composed of neoplastic glial and neuronal cells. The aim of the present paper is to describe the clinical presentation, magnetic resonance imaging (MRI) findings and histopathological and immunophenotypical characteristics of a cerebral cortex ganglioglioma in a 7-year-old Border Collie. The dog presented an acute onset of tonic-clonic epileptic seizures. MRI revealed a well-defined large intra-axial mass located on the left forebrain, mainly affecting the frontal cortex. Following humane euthanasia, the histopathological examination of the mass revealed a diffuse proliferation of neoplastic glial cells mixed with anomalous neuronal bodies. Immunohistochemical analyses confirmed the presence of two different populations of neoplastic cells. Most neoplastic glial cells were immunoreactive to glial fibrillary acidic protein (GFAP) and the other subset of neoplastic cells were positive to neuronal markers such as PGP 9.5, synaptophysin (SYN) and neuron-specific enolase (NSE), suggestive of neuronal cells. These findings confirmed the diagnosis of a cerebrocortical ganglioglioma. To the authors knowledge, this is the first description of a ganglioglioma of the cerebral cortex in a dog.

Many stream ciphers employ linear feedback shift registers (LFSRs) to generate pseudorandom sequences. Many recent LFSRs are defined in GF(2n) to take advantage of the n-bit processors, instead of using the classic binary field. In this way, the bit generation rate increases at the expense of a higher complexity in computations. For this reason, only certain primitive polynomials in GF(2n) are used as feedback polynomials in real ciphers. In this article, we present an efficient implementation of the LFSRs defined in GF(2n). The efficiency is achieved by using equivalent binary LFSRs in combination with binary n-bit grouped operations, n being the processor word’s length. This improvement affects the general considerations about the security of cryptographic systems that uses LFSR. The model also allows the development of a faster method to test the primitiveness of polynomials in GF(2n).

PipX is a unique cyanobacterial protein identified by its ability to bind to PII and NtcA, two key regulators involved in the integration of signals of the nitrogen/carbon and energy status, with a tremendous impact on nitrogen assimilation and gene expression in cyanobacteria. PipX provides a mechanistic link between PII, the most widely distributed signaling protein, and NtcA, a global transcriptional regulator of cyanobacteria. PII, required for cell survival unless PipX is inactivated or down-regulated, functions by protein–protein interactions with transcriptional regulators, transporters, and enzymes. In addition, PipX appears to be involved in a wider signaling network, supported by the following observations: (i) PII–PipX complexes interact with PlmA, an as yet poorly characterized transcriptional regulator also restricted to cyanobacteria; (ii) the pipX gene is functionally connected with pipY, a gene encoding a universally conserved pyridoxal phosphate binding protein (PLPBP) involved in vitamin B6 and amino acid homeostasis, whose loss-of-function mutations cause B6-dependent epilepsy in humans, and (iii) pipX is part of a relatively robust, six-node synteny network that includes pipY and four additional genes that might also be functionally connected with pipX. In this overview, we propose that the study of the protein–protein interaction and synteny networks involving PipX would contribute to understanding the peculiarities and idiosyncrasy of signaling pathways that are conserved in cyanobacteria.

Synechococcus elongatus PCC 7942 is a paradigmatic model organism for nitrogen regulation in cyanobacteria. Expression of genes involved in nitrogen assimilation is positively regulated by the 2-oxoglutarate receptor and global transcriptional regulator NtcA. Maximal activation requires the subsequent binding of the co-activator PipX. PII, a protein found in all three domains of life as an integrator of signals of the nitrogen and carbon balance, binds to PipX to counteract NtcA activity at low 2-oxoglutarate levels. PII-PipX complexes can also bind to the transcriptional regulator PlmA, whose regulon remains unknown. Here we expand the nitrogen regulatory network to PipY, encoded by the bicistronic operon pipXY in S. elongatus. Work with PipY, the cyanobacterial member of the widespread family of COG0325 proteins, confirms the conserved roles in vitamin B6 and amino/keto acid homeostasis and reveals new PLP-related phenotypes, including sensitivity to antibiotics targeting essential PLP-holoenzymes or synthetic lethality with cysK. In addition, the related phenotypes of pipY and pipX mutants are consistent with genetic interactions in the contexts of survival to PLP-targeting antibiotics and transcriptional regulation. We also showed that PipY overexpression increased the length of S. elongatus cells. Taken together, our results support a universal regulatory role for COG0325 proteins, paving the way to a better understanding of these proteins and of their connections with other biological processes.

Cyanobacteria, phototrophic organisms that perform oxygenic photosynthesis, perceive nitrogen status by sensing 2-oxoglutarate levels. PII, a widespread signaling protein, senses and transduces nitrogen and energy status to target proteins, regulating metabolism and gene expression. In cyanobacteria, under conditions of low 2-oxoglutarate, PII forms complexes with the enzyme N-acetyl glutamate kinase, increasing arginine biosynthesis, and with PII-interacting protein X (PipX), making PipX unavailable for binding and co-activation of the nitrogen regulator NtcA. Both the PII-PipX complex structure and in vivo functional data suggested that this complex, as such, could have regulatory functions in addition to PipX sequestration. To investigate this possibility we performed yeast three-hybrid screening of genomic libraries from Synechococcus elongatus PCC7942, searching for proteins interacting simultaneously with PII and PipX. The only prey clone found in the search expressed PlmA, a member of the GntR family of transcriptional regulators proven here by gel filtration to be homodimeric. Interactions analyses further confirmed the simultaneous requirement of PII and PipX, and showed that the PlmA contacts involve PipX elements exposed in the PII-PipX complex, specifically the C-terminal helices and one residue of the tudor-like body. In contrast, PII appears not to interact directly with PlmA, possibly being needed indirectly, to induce an extended conformation of the C-terminal helices of PipX and for modulating the surface polarity at the PII-PipX boundary, two elements that appear crucial for PlmA binding. Attempts to inactive plmA confirmed that this gene is essential in S. elongatus. Western blot assays revealed that S. elongatus PlmA, irrespective of the nitrogen regime, is a relatively abundant transcriptional regulator, suggesting the existence of a large PlmA regulon. In silico studies showed that PlmA is universally and exclusively found in cyanobacteria. Based on interaction data, on the relative amounts of the proteins involved in PII-PipX-PlmA complexes, determined in western assays, and on the restrictions imposed by the symmetries of trimeric PII and dimeric PlmA molecules, a structural and regulatory model for PlmA function is discussed in the context of the cyanobacterial nitrogen interaction network.

El presente artículo plantea las antinomias y aporías que se presentan entre los derechos humanos caracterizados como universales y los dogmas tradicionales de la soberanía y ciudadanía que están ligados a aquella forma de organización política de nuestros días que es el Estado-Nación. El fenómeno de la globalización ha puesto en crisis al Estado-Nación por lo que también se traduce en una crisis de la soberanía y la ciudadanía. Las funciones tradicionales que venía desplegando el Estado están siendo desplazadas y rebasadas por realidades externas (problemas ambientales y terroristas, cesión de facultades de decisión a organismo supranacionales, embates de los especuladores financieros, flujos migratorios, etc.,) e internas (el problema del multiculturalismo) por lo que tenemos un Estado enfrentando severos proceso de transformación o sobre vivencia. En los confines del Estado mexicano y su ordenamiento jurídico, la universalidad de los derechos se queda en retórica. Un constitucionalismo mundial se presenta como la única alternativa viable si se quiere hacer efectiva la protección de los derechos humanos y ser acorde con la superación de la soberanía y ciudadanía

Todos los organismos están expuestos a sufrir el ataque de diversos agentes que pueden alterar la estructura química básica de su material genético, como la luz ultravioleta, metabolitos como las aflatoxinas que producen los hongos, o incluso especies reactivas de oxígeno que se generan como producto de la respiración. Para contrarrestar tal efecto a lo largo de la evolución se han desarrollado y seleccionado diferentes estrategias o mecanismos que le permiten sobreponerse a dichas eventualidades. Dentro de éstas se encuentra la respuesta SOS, durante la cual se incrementa la expresión de un grupo de genes cuya función es la de reparar el daño en el DNA y conferir a la célula más oportunidades de sobreponerse y sobrevivir en condiciones de estrés1.

La reducción del grupo nitro presente en varios medicamentos, pesticidas y materiales de uso diario, produce especies reactivas del oxígeno capaces de interactuar con el ADN. El tinidazol, una droga antimicrobiana de la familia de los 5 nitroimidazoles, fue evaluada por el ensayo cometa. Se estudió la capacidad de la droga para inducir roturas de simple cadena y sitios sensibles al álcali, expresado como el porcentaje de células dañadas y el porcentaje de células en cada nivel de daño. En el ensayo in vitro a concentraciones de 100, 250 y 500 mg/mL se encontró inducción de roturas en los cromosomas de leucocitos de ratón a los 30 min de exposición, esto describió una relación dosis respuesta. La importancia de la reducción del grupo nitro, mediada por la acción de nitrorreductasas microsomales hepáticas, para la actividad mutagénica de los nitroimidazoles, ha sido estudiada. Sin embargo, estos resultados revelaron que el tinidazol no necesitaba ser metabolizado para inducir el daño. A los 30 min de reparación el daño en los leucocitos se mantuvo, a los 60 min solamente el daño producido con la concentración de 500 mg/mL de tinidazol había sido reparado. A concentraciones mayores se disparan diferentes mecanismos de reparación para no comprometer la viabilidad celular. Estos mecanismos pueden ser responsables de estos hallazgos, se reparan las roturas aunque se comprometa la fidelidad de la secuencia del ADN. In vivo se pudo observar que una dosis de 100 mg/kg de peso era capaz de inducir daño en el ADN de los leucocitos de ratón. Este efecto fue observado a las 24 y 48 h después del tratamiento con una dosis 3 veces superior a la dosis terapéutica (2 g/d). El mecanismo propuesto para explicar el efecto clastogénico de los 5 nitroimidazoles está relacionado con la formación de un anión nitro, que se reoxida y genera especies reactivas del oxígenoThe reduction of the mitro group existing in various drugs, pesticides and materials of daily use gives rise to reactive oxygen species capable of interacting with DNA. Tinidazole, an antimicrobial drug of the family of the 5 nitroimidazols was tested using a comet assay. The capacity of this drug to induce single chain breaks and alkali-sensitive sites expressed as the percentages of damaged cells and cells at each level of damage was studied. The in vitro assay at concentrations of 100, 250 and 500 µ/mL showed the induction of breaks in rat leukocyte chromosomes after 30 minutes of exposure. This indicated a dosage-response ratio. The importance of the hepatic microsomal nitroreductase-mediated nitro group reduction for the mutagenic activity of nitroimidazols has been studied. However, these results revealed that tinidazole did not require to be metabolized to induce damage. After 30 minutes of repair, the leukocyte damage persisted, and 60 minutes after only the damage caused by the 500 µ/ml tinidazole concentration had been repaired. At higher concentrations, different repair mechanisms are triggered so as not to put cell viability in jeopardy. These mechanisms may be responsible for these findings; the breaks are repaired even if the fidelity of DNA sequence is endangered. It can be observed in the in vivo/assay that a dose of 100 mg/kg weight can induce damage in mouse leukocyte DNA. This effect was seen 24 and 48 hrs after the treatment with a dose that triplicated the therapeutical dose (2g/day). The suggested mechanism for explaining the clastogenic effect of the five nitrimidazols is related with the formation of a nitro annion which re-oxidizes an generates reactive oxygen species

PipX provides a functional link between the cyanobacterial global transcriptional regulator NtcA and the signal transduction protein P(II), a protein found in all three domains of life as integrators of signals of the nitrogen and carbon balance. PipX, which is toxic in the absence of P(II), can form alternative complexes with NtcA and P(II) and these interactions are respectively stimulated and inhibited by 2-oxoglutarate, providing a mechanism by which P(II) can modulate expression at the NtcA regulon. Structural information on PipX-NtcA complexes suggests that PipX coactivates NtcA controlled genes by stabilizing the active conformation of NtcA bound to 2-oxoglutarate and by possibly helping recruit RNA polymerase. To get insights into PipX functions, we perform here a mutational analysis of pipX informed by the structures of PipX-P(II) and PipX-NtcA complexes and evaluate the impact of point mutations on toxicity and gene expression. Two amino acid substitutions (Y32A and E4A) were of particular interest, since they increased PipX toxicity and activated NtcA dependent genes in vivo at lower 2-oxoglutarate levels than wild type PipX. While both mutations impaired complex formation with P(II), only Y32A had a negative impact on PipX-NtcA interactions.

Purpose: The aim of the present study was to analyse current surgical treatment preferences for anal fistula (AF) and its subtypes and nationwide results in terms of success and complications. Methods: A retrospective multicentre observational cohort study was conducted. The study period was 1 year (2019), with a follow-up period of at least 1 year. A descriptive analysis of patient characteristics and trends regarding technical options was performed. Univariate and multivariate Cox regression models were used to analyse factors associated with healing and faecal incontinence (FI). Results: Fifty-one hospitals were involved, providing data on 1628 patients with AF. At a median follow-up of 18.3 (9.9–28.3) months, 1231 (75.9%) patients achieved healing, while 390 (24.1%) did not; failure was catalogued as persistence in 279 (17.2.0%) patients and as recurrence in 111 (6.8%). On multivariate analysis, factors associated with healing were fistulotomy (OR 5.5; 95% CI 3.8–7.9; p < 0.001), simple fistula (OR 2.1; 95% CI 1.5–2.8; p < 0.001), single tract (HR 1.9; 95% CI 1.3–2.8; p < 0.001) and number of preparatory surgeries (none vs. 3; HR 1.8; 95% CI 1.2–2.8; p = 0.006). Regarding de novo FI, in the multivariate analysis previous anal surgery (OR 1.5, 95% CI 1.0–2.4, p = 0.037), age (OR 1.02, 95% CI 1.00–1.04, p = 0.002) and being female (OR 1.7, 95% CI 1.1–2.5, p = 0.008) were statistically related. Conclusions: Anal fistulotomy is the most used procedure for AF, especially for simple AF, with a favourable overall balance between healing and continence impairment. Sphincter-sparing or minimally invasive sphincter-sparing techniques resulted in lower rates of healing. In spite of their intended sphincter-sparing design, a certain degree of FI was observed for several of these techniques. [ABSTRACT FROM AUTHOR]

Después de un breve análisis de los principales aspectos del cosmopolitismo en la Ilustración, el artículo estudia la dimensión cosmopolita de los proyectos de paz que se escribieron en ese siglo. Principalmente se estudian las obras de Penn, Saint-Pierre, Rousseau, Gargas, Brun, Bentham, Cloots y Kant. Quizás estos proyectos de paz sean el mejor lugar para estudiar el cosmopolitismo de ese siglo, pues perfilaron sus principales elementos, especialmente la necesidad de instituciones internacionales para alcanzar una paz estable. Además manifiestan que en esta época se puso la paz como un tema central de la agenda filosófica.