dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe.

The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA-directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.

Magnetoinductive metasurface of capacitively-loaded split rings for local field homogenization in a 7 T MRI birdcage: A simulation study.

The transmit field B1+ in a 7 T birdcage is inherently inhomogeneous due to the effects of wavelengths on tissue. This work investigates the homogenization of this field through metasurfaces that consist of a two-dimensional planar array of capacitively loaded conducting rings. The metasurfaces are placed in the intermediate space between the head and the birdcage on either side of the head. The periodical structure of this type of metasurface supports magnetoinductive waves because of the mutual inductive coupling existing between the elements of the array. The analysis takes advantage of this coupling and exploits the excitation of a standing magnetoinductive wave across the arrays, which creates a strong local field that contributes to locally homogenize the field of the birdcage. The presence of the arrays does not detune the birdcage, so that they can be used with commercial birdcages that operate both to transmit and to receive.

Should we suspect primary aldosteronism in patients with hypokalaemic rhabdomyolysis? A systematic review.

Severe hypokalaemia causing rhabdomyolysis (RML) in primary aldosteronism (PA) is a rare entity, and only a few cases have been reported over the last four decades. This systematic review and case report aims to gather all published data regarding a hypokalaemic RML as presentation of PA in order to contribute to the early diagnosis of this extremely rare presentation. With the use of PubMed Central, EMBASE, and Google Scholar, a thorough internet-based search of the literature was conducted to identify articles and cases with RML secondary to hypokalaemia due to PA between June 1976 and July 2023. The case study concerns a 68-year-old male patient with hypokalaemic RML at presentation of PA. In the systematic review of the literature, 37 cases of RML secondary to hypokalaemia due to PA have been reported to date. In summary, the median age was 47.5 years, the male/female ratio was 17/21, all patients presented symptoms (weakness and/or myalgia), all the patients were hypertensive, and only four patients had complications with acute kidney injury (AKI). Although PA rarely presents with RML, it should be suspected when marked hypokalaemia and hypertension are also present. Early detection and management are essential to reduce the frequency of manifestations such as AKI.

Metasurfaces of capacitively loaded metallic rings for magnetic resonance imaging surface coils.

This work investigates the use of a metasurface made up of a two-dimensional array of capacitively loaded metallic rings to enhance the signal-to-noise ratio of magnetic resonance imaging surface coils and to tailor the magnetic near-field radio frequency pattern of the coils. It is found that the signal-to-noise ratio is increased if the coupling between the capacitively loaded metallic rings in the array is increased. The input resistance and the radiofrequency magnetic field of the metasurface loaded coil are numerically analyzed by means of an efficient algorithm termed the discrete model to determine the signal-to-noise ratio. Standing surface waves or magnetoinductive waves supported by the metasurface introduce resonances in the frequency dependence of the input resistance. The signal-to-noise ratio is found to be optimal at the frequency corresponding to a local minimum existing between these resonances.The discrete model is used in an optimization procedure to fit the structural parameters of a metasurface to enhance the signal-to-noise ratio at the frequency corresponding to this local minimum in the input resistance. It is found that the signal-to-noise ratio can be greatly improved if the mutual coupling between the capacitively loaded metallic rings of the array is made stronger by bringing them closer or by using rings of squared shape instead of circular. These conclusions derived from the numerical results provided by the discrete model are double-checked by means of numerical simulations provided by the commercial electromagnetic solver Simulia CST and by experimental results. Numerical results provided by CST are also shown to demonstrate that the surface impedance of the array of elements can be adjusted to provide a more homogeneous magnetic near-field radio frequency pattern that ultimately leads to a more uniform magnetic resonance image at a desired slice. This is achieved by preventing the reflection of propagating magnetoinductive waves at the edges of the array by matching the elements arranged at the edges of the array with capacitors of suitable value.

Impacto de las tutorías en la formación integral de estudiantes universitarios / Impacto dos tutoriais na formação integral dos estudantes universitários / Impact of tutorials on the comprehensive training of university students

RESUMEN Los vertiginosos cambios producidos en la sociedad obligan a las instituciones de Educación Superior (IES) a formar ciudadanos con competencias profesionales y personales capaces de enfrentar los permanentes desafíos. En ese contexto, la labor del docente-tutor contribuye significativamente a este propósito y debe fortalecerse. Para ello, se realiza un diagnóstico cuyo objetivo consistió en conocer el estado de implementación de las tutorías y su impacto en la formación de los estudiantes. Se parte del análisis bibliográfico sobre la concepción y la práctica de la tutoría universitaria para, mediante un estudio cuantitativo, determinar el criterio de los educandos como actores principales. La muestra probabilística estuvo conformada por 180 estudiantes, de una población de 1557, de la Facultad de Ciencias de la Educación, Humanas y Tecnologías de la Universidad Nacional de Chimborazo, a quienes se les aplicó una encuesta validada científicamente, que determinó 97 % de fiabilidad y 95 % de confianza, lo que significa un alto porcentaje de correspondencia entre las variables de estudio y las escalas de medición. Estos estudiantes reciben diversas asignaturas, entre ellas algunas relacionadas con la actividad física y el deporte. Los resultados obtenidos se sometieron al análisis inferencial de multivariantes que permitió comprobar la tendencia de los estudiantes con respecto a la actividad tutorial que oferta la institución de Educación Superior.

RESUMO As vertiginosas mudanças na sociedade obrigam as Instituições de Ensino Superior (IES) a formar cidadãos com competências profissionais e pessoais capazes de enfrentar desafios permanentes. Neste contexto, o trabalho do professor-tutor contribui significativamente para este fim e deve ser reforçado. Para o efeito, foi realizado um diagnóstico com o objectivo de conhecer o estado de implementação dos tutoriais e o seu impacto na formação dos estudantes. O ponto de partida foi uma análise bibliográfica da concepção e prática da tutoria universitária a fim de determinar, por meio de um estudo quantitativo, os critérios dos estudantes como principais atores. A amostra probabilística consistiu em 180 estudantes, de uma população de 1557, da Faculdade de Ciências da Educação, Humanidades e Tecnologias da Universidade Nacional de Chimborazo, aos quais foi aplicado um inquérito cientificamente validado, que determinou 97% de fiabilidade e 95% de confiança, o que significa uma elevada percentagem de correspondência entre as variáveis de estudo e as escalas de medição. Estes estudantes recebem várias disciplinas, incluindo algumas relacionadas com atividade física e desporto. Os resultados obtidos foram submetidos a análises inferenciais multivariadas, o que nos permitiu verificar a tendência dos estudantes no que diz respeito à atividade tutorial oferecida pela instituição de ensino superior.

ABSTRACT The vertiginous changes produced in society force Higher Education Institutions (HEI) to train citizens with professional and personal skills capable of facing permanent challenges. In this context, the work of the teacher-tutor contributes significantly to this purpose and should be strengthened. For this, a diagnosis is made which objective was to know the state of implementation of the tutoring and its impact on the training of the students. It is started from the bibliographical analysis on the conception and practice of university tutoring to, through a quantitative study, determines the criteria of the students as main actors. The probabilistic sample consisted of 180 students, from a population of 1557, from the Faculty of Education, Human Sciences and Technology of the National University of Chimborazo, to whom a scientifically validated survey was applied, which determined 97% reliability and 95% confidence, which means a high percentage of correspondence between the study variables and the measurement scales. These students receive various subjects, including some related to physical activity and sports. The results obtained were submitted to the multivariate inferential analysis that allowed verifying the tendency of the students with respect to the tutorial activity offered by the Higher Education institution.

Sequential Colocalization of ERa, PR, and AR Hormone Receptors Using Confocal Microscopy Enables New Insights into Normal Breast and Prostate Tissue and Cancers.

Multiplex immunohistochemistry (mIHC) use markers staining different cell populations applying widefield optical microscopy. Resolution is low not resolving subcellular co-localization. We sought to colocalize markers at subcellular level with antibodies validated for clinical diagnosis, including the single secondary antibody (combination of anti-rabbit/mouse-antibodies) used for diagnostic IHC with any primary antibody, and confocal microscopy. We explore colocalization in the nucleus (ColNu) of nuclear hormone receptors (ERa, PR, and AR) along with the baseline marker p63 in paired samples of breast and prostate tissues. We established ColNu mIHCF as a reliable technique easily implemented in a hospital setting. In ERa+ breast cancer, we identified different colocalization patterns (nuclear or cytoplasmatic) with PR and AR on the luminal epithelium. A triple-negative breast-cancer case expressed membrane-only ERa. A PR-only case was double positive PR/p63. In normal prostate, we identified an ERa+/p63+/AR-negative distinct population. All prostate cancer cases characteristically expressed ERa on the apical membrane of the AR+ epithelium. We confirmed this using ERa IHC and needle-core biopsies. ColNu mIHCF is feasible and already revealed a new marker for prostate cancer and identified sub-patterns in breast cancer. It could be useful for pathology as well as for functional studies in normal prostate and breast tissues.

The Lorentz force on ions in membrane channels of neurons as a mechanism for transcranial static magnetic stimulation.

Transcranial static magnetic stimulation is a novel noninvasive method of reduction of the cortical excitability in certain neurological diseases that makes use of static magnetic fields generated by permanent magnets. By contrast, ordinary transcranial magnetic stimulation makes use of pulsed magnetic fields generated by strong currents. Whereas the physical principle underlying ordinary transcranial magnetic stimulation is well known, that is, the Faraday´s law, the physical mechanism that explains the interaction between neurons and static magnetic fields in transcranial static magnetic stimulation remains unclear. In the present work, it is discussed the possibility that this mechanism might be the Lorentz force exerted on the ions flowing along the membrane channels of neurons. The overall effect of the static magnetic field would be to introduce an additional friction between the ions and the walls of the membrane channels, thus reducing its conductance. Calculations performed by using a Hodgkin-Huxley model demonstrate that even a slight reduction of the conductance of the membrane channels can lead to the suppression of the action potential, thus inhibiting neuronal activity.

Prothymosin α interacts with SET, ANP32A and ANP32B and other cytoplasmic and mitochondrial proteins in proliferating cells.

Prothymosin α (ProTα) is an acidic protein with a nuclear role related to the chromatin activity through its interaction with histones in mammalian cells. ProTα acts as an anti-apoptotic factor involved in the control of the apoptosome activity in the cytoplasm, however the mechanisms underlying this function are still known. ProTα shares similar biological functions with acidic nuclear-cytoplasmic shuttling proteins included in SET and ANP32 family members. Using affinity chromatography, co-immunoprecipitation and chemical cross-linking, we demonstrate that ProTα interacts with SET, ANP32A and ANP32B proteins. The study by mass spectrometry of the complexes stabilized by chemical cross-linking showed that associations of ProTα consist of six highly acidic ProTα-complexes, which corresponds to differentiated interactions of ProTα either with SET or ANP32 proteins. The presence in the ProTα-complexes of cytoplasmic proteins involved in membrane remodeling and proteins implicated in the mitochondrial permeability, seems to indicate that they could be related to a cytoplasmic-mitochondrial activity. According to the cellular function of the characterized targets of ProTα, and the evolution in the composition of the diverse ProTα-complexes when proliferation activity was reduced or apoptosis induced, leads to hypothesized that ProTα interactions might be related to the proliferation activity and control of the cell survival.

Boerhaave's syndrome: diagnostic gastroscopy.

A 47-year-old man was attended at the emergency room for severe chest pain after eating sausage with subsequent vomiting and mild upper gastrointestinal bleeding. In the chest radiography we could not see abnormalities. He referred previous episodes of choking without consulting. The urgent gastroscopy detected tertiary contractile activity (nutcracker esophagus) and a foreign body in the lower third of the esophagus. After removing the food bolus, we observed a 4 cm longitudinal tear compatible with esophageal rupture or Boerhaave's syndrome in the right posterior wall of the lower esophagus, proximal to the gastroesophageal junction. Thoracic-abdominal computed tomography (TC) confirmed a perforation of the lower esophagus, with pneumothorax and cervical and chest emphysema. Surgical treatment was indicated: esophageal suture, myotomy and gastric fundoplication. The patient presented good evolution. Boerhaave's syndrome is a rare syndrome, but with high mortality (35%). Mackler triad is very characteristic: vomiting, retrosternal pain and cervical subcutaneous emphysema; but it occurs rarely. Chest radiography is useful, showing abnormalities in up to 90% of patients. The differential diagnosis includes cardiorespiratory disorders: acute myocardial infarction, spontaneous pneumothorax, pericarditis or pneumonia. The role of endoscopy is small, mainly limited to prosthesis placement in high-risk surgical patients. In our case the chest radiograph was initially normal, probably related to bolus impaction and, in presence of upper gastrointestinal bleeding, gastroscopy was performed which allowed us to early diagnosis and treatment.

Lesión de Boerhaave: diagnóstico por gastroscopia / Boerhaave’s syndrome: diagnostic gastroscopy

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Classical Physics and the Bounds of Quantum Correlations.

A unifying principle explaining the numerical bounds of quantum correlations remains elusive, despite the efforts devoted to identifying it. Here, we show that these bounds are indeed not exclusive to quantum theory: for any abstract correlation scenario with compatible measurements, models based on classical waves produce probability distributions indistinguishable from those of quantum theory and, therefore, share the same bounds. We demonstrate this finding by implementing classical microwaves that propagate along meter-size transmission-line circuits and reproduce the probabilities of three emblematic quantum experiments. Our results show that the "quantum" bounds would also occur in a classical universe without quanta. The implications of this observation are discussed.

Comorbilidades y gravedad de la apnea del sueño. Estudio en una cohorte de pacientes portugueses / Co-morbidities and sleep apnoea severity. A study in a cohort of Portuguese patients

Introducción. El síndrome de apnea obstructiva del sueño (SAOS) se asocia frecuentemente a otras enfermedades que actúan como factores de riesgo que influyen en la morbilidad y mortalidad del SAOS. Objetivos. Analizar la presencia de comorbilidades en pacientes con SAOS, seleccionados en una clínica del sueño ambulatoria en el norte de Portugal y clasificados atendiendo a la gravedad del SAOS. Pacientes y métodos. Una cohorte de 319 pacientes con trastornos del sueño fueron evaluados mediante estudios clínicos y registro videopoligráfico durante el sueño. Del total de pacientes (n = 209) con distrés respiratorio durante el sueño, 145 tenían SAOS con gravedad definida según el índice de apnea/hipopnea (IAH); 64 presentaban ronquidos primarios o distrés respiratorio con IAH < 5; y 110 tenían otros trastornos del sueño. Resultados. La presencia de comorbilidades fue del 75% en todos los pacientes con SAOS y del 79,5% en el grupo de pacientes con SAOS grave; 47 pacientes presentaban una única comorbilidad, la más común de las cuales fue la obesidad (56,3%), seguida de hipertensión, diabetes y otros trastornos cardiovasculares. La obesidad estuvo presente en el 84% de los casos más graves de SAOS y en el 100% de casos con múltiples comorbilidades. En comparación con el grupo de pacientes con distrés respiratorio durante el sueño, la comorbilidad aparece normalmente relacionada con el SAOS (p = 0,0196). Conclusión. Las comorbilidades se asocian con frecuencia al SAOS, independientemente de la gravedad de la enfermedad. Entre las comorbilidades presentes, la obesidad resultó ser la más común en los casos más graves de SAOS (AU)

Introduction. Obstructive sleep apnoea syndrome (OSAS) is frequently associated to other morbid conditions that act as risk factors influencing OSAS morbidity and mortality. Aim. To analyse the presence of co-morbidities in OSAS patients, recruited from a sleep outpatient clinic in Northern Portugal, stratified as a function of OSAS severity. Patients and methods. A cohort of 319 sleep-disordered patients was assessed by clinical and sleep video-polygraphic recording. Patients (n = 209) with sleep respiratory distress had OSAS (n = 145) and severity defined according to Apnoea/ Hypopnea Index (AHI); 64 had primary snoring or respiratory distress with AHI < 5; and 110 had other sleep disorders. A full individual background study was possible in 128 OSAS patients. The association to unique or multiple co-morbidities was assessed by clinical and analytical studies in general group or as a function of OSAS severity. Results. The presence of co-morbidities was of 75% in all OSAS patients and of 79.5% in the severe group of OSAS. Forty seven of patients had only one co-morbidity. The most common was obesity (56.3%) followed by high blood pressure, diabetes and other cardiovascular disorders. Obesity was present in 84% among the most severe OSAS cases and always present in those with multiple co-morbidities. When compared with the group of patients without sleep respiratory distress the co-morbidity condition was more frequently related to OSAS (p = 0.0196). Conclusion. Comorbidities are commonly associated to OSAS independently of disease severity. Among the comorbidities present obesity was the most common in the most severe OSAS cases (AU)

Analysis of the noise correlation in MRI coil arrays loaded with metamaterial magnetoinductive lenses.

A numerical method is shown for calculating the noise correlation coefficient in arrays of magnetic resonance imaging (MRI) coils loaded with capacitively-loaded ring metamaterial lenses, and in the presence of a conducting half-space resembling a sample. This numerical method is validated by comparison with experimental results obtained in two different experimental procedures for double check: noise resistance measurements with a network analyzer and noise correlation measurements in an MRI system. It is found that, for practical array configurations such as overlapping coils or capacitively-decoupled coils, the noise correlation coefficient turns negative for coils loaded with metamaterial lenses. In particular, the analysis is carried out with metamaterial structures known as magnetoinductive lenses, which have been demonstrated in previous works to improve the signal-to-noise ratio of MRI coils. Results are also shown to demonstrate that negative noise correlations have as an effect the improvement of the g-factor in coil arrays for parallel MRI.

Metamaterial magnetoinductive lens performance as a function of field strength.

Metamaterials are artificial composites that exhibit exotic electromagnetic properties, as the ability of metamaterial slabs to behave like lenses with sub-wavelength resolution for the electric or the magnetic field. In previous works, the authors investigated magnetic resonance imaging (MRI) applications of metamaterial slabs that behave like lenses for the radiofrequency magnetic field. In particular, the authors investigated the ability of MRI metamaterial lenses to increase the signal-to-noise ratio (SNR) of surface coils, and to localize the field of view (FOV) of the coils, which is of interest for parallel MRI (pMRI) applications. A metamaterial lens placed between a surface coil and the tissue enhances the sensitivity of the coil. Although the metamaterial lens introduces losses which add to the losses of the tissue, the enhancement of the sensitivity can compensate these additional losses and the SNR of the coil is increased. In a previous work, an optimization procedure was followed to find a metamaterial structure with minimum losses that will maximize the SNR. This structure was termed magnetoinductive (MI) lens by the authors. The properties of surface coils in the presence of MI lenses were investigated in previous works at the proton frequency of 1.5 T systems. The different frequency dependence of the losses in both the MI lenses and the tissue encouraged us to investigate the performance of MI lenses at different frequencies. Thus, in the present work, the SNR and the pMRI ability of MI lenses are investigated as a function of field strength. A numerical analysis is carried out with an algorithm developed by the authors to predict the SNR behavior of a surface coil loaded with a MI lens at the proton frequencies of 0.5 T, 1.5 T and 3 T systems. The results show that, at 0.5 T, there is a gain in the SNR for short distances, but the SNR is highly degraded at deeper distances. However, at 1.5 T and 3T, the MI lenses provide a gain in the SNR up to a certain penetration depth, which is deeper at 3T, and do not degrade the SNR at deeper distances. These numerical results are checked by means of an experiment. Moreover, a second experiment developed with two-channel arrays of surface coils loaded with MI lenses shows that the pMRI ability of the lenses also improves from 1.5 T to 3 T. This improvement was quantified by means of the calculation of the GRAPPA g-factor.

The calcineurin inhibitor Ascomicin interferes with the early stage of the epileptogenic process induced by Latrunculin A microperfusion in rat hippocampus.

Latrunculin A microperfusion in rat hippocampus has shown to be an effective model of acute and chronic seizures for neurochemical studies. The intervention over early synaptic plasticity changes after the epileptogenesis onset represents a big challenge on the design of a suitable therapy to impair the epilepsy development. We previously suggested that receptor location might be essential for controlling neuronal excitability, and that disruption of local cytoskeletal dynamics followed by drastic changes in the synaptic/extrasynaptic ratio of NMDA, AMPA receptors and their subsequent downstream signalling may play an important role in the pathogenesis of seizures. In the present study, we performed a pharmacological intervention in the Latrunculin model by using Ascomicin (ASC) and Phenytoin (PHT). We pointed out the inhibitory action of ASC over the protein phosphatase 2B (PP2B). PP2B pathological mechanism involves changes in actin cytoskeleton and showed to avoid those subsequent changes previously observed in PSD components. On the contrary, PHT didn't seem to modify the F-actin depolymerization process induced, showing a similar redistribution pattern from the PSD towards the extrasynaptic site of several molecular components with more or less dependence on actin for their location, including glutamate receptors. Overall, we propose that the early intervention over changes on the synapse during the epileptogenic process might represent the best approach to avoid the onset of chronic refractory seizures our model. On this regard, the therapeutic potential of ASC, FK506 and derivatives should be further explored as a possible tool in the intervention over epilepsy and other brain diseases.

The influence of phosphorylation of prothymosin α on its nuclear import and antiapoptotic activity.

Phosphorylation of prothymosin α (ProTα) appears not to affect its influence on chromatin remodelling. To determine whether it affects nuclear import or cytosolic antiapoptotic activity, cells were transfected with vectors generating tagged recombinant ProTα (rProTα), either wild-type (rProTα-wt), which is partially phosphorylated posttranslation or the nonphosphorylatable rProTα-T7A. Immunofluorescence microscopy showed the predominant location of native ProTα, rProTα-wt, and rProTα-T7A in the nucleus. The activity of caspases 9 and 3 following apoptosis induction treatment (staurosporine) indicated reduction of apoptosis by rProTα-wt but not by rProTα-T7A. It is concluded that phosphorylation of ProTα is required for its antiapoptotic activity, but it does not affect its nuclear import.

A broadside-split-ring resonator-based coil for MRI at 7 T.

A coil design termed as broadside-coupled loop (BCL) coil and based on the broadside-coupled split ring resonator (BC-SRR) is proposed as an alternative to a conventional loop design at 7T. The BCL coil has an inherent uniform current which assures the rotational symmetry of the radio-frequency field around the coil axis. A comparative analysis of the signal-to-noise ratio provided by BCL coils and conventional coils has been carried out by means of numerical simulations and experiments in a 7T whole body system.

Síndrome de Leriche y trombo mural de aorta torácica / Leriche's syndrome and thoracic aortic mural thrombus

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