Kinetics and Inhibition Studies of the L205R Mutant of cAMP-Dependent Protein Kinase Involved in Cushing’s Syndrome

Overproduction of cortisol by the hypothalamus–pituitary–adrenal hormone system results in the clinical disorder known as Cushing\u27s syndrome. Genomics studies have identified a key mutation (L205R) in the α‐isoform of the catalytic subunit of cAMP‐dependent protein kinase (PKACα) in adrenal adenomas of patients with adrenocorticotropic hormone‐independent Cushing\u27s syndrome. Here, we conducted kinetics and inhibition studies on the L205R‐PKACα mutant. We have found that the L205R mutation affects the kinetics of both Kemptide and ATP as substrates, decreasing the catalytic efficiency (kcat/KM) for each substrate by 12‐fold and 4.5‐fold, respectively. We have also determined the IC50 and Ki for the peptide substrate‐competitive inhibitor PKI(5–24) and the ATP‐competitive inhibitor H89. The L205R mutation had no effect on the potency of H89, but causes a \u3e 250‐fold loss in potency for PKI(5–24). Collectively, these data provide insights for the development of L205R‐PKACα inhibitors as potential therapeutics

Posterior atlanto-axial fixation with polyaxial C1 lateral mass screws and C2 pars screws

Purpose: C1-C2 instability or painful osteoarthritis are recognised indications for posterior atlanto-axial fixation. In the traditional trans-articular C1-C2 screw fixation, up to 20% of patients cannot have safe placement of bilateral screws in the event of a medially located vertebral artery and a straight screw trajectory in the sagittal plane. The more recently developed C1-C2 fixation technique with individual C1 lateral mass screws and converging C2 pars screws can be employed in case of a medially located vertebral artery and has comparable biomechanical strength. This is a prospective observational study to investigate the advantages, the safety, and the drawbacks of posterior atlanto-axial fixation with polyaxial C1 lateral mass screws and C2 pars screws. Methods: Twelve consecutive patients with C1-2 instability (n = 11) and painful osteoarthritis (n = 1) underwent a posterior atlanto-axial fixation with polyaxial C1 lateral mass screws and C2 pars screws. The average follow-up was 16months and all patients reached the 12-month follow-up. Findings: No hardware failure occurred in any of the patients. Correct screw placement and construct stability was found in all 12 patients (100%) at 6 and 12months after surgery. Mean neck pain on a visual analogue scale (VAS) was 2.1 at 6months and 2.0 at 12months. Only transient complications were observed: one patient presented with progressive intestinal herniation through the iliac crest scar; one suffered from severe pain at the posterior iliac crest for 3 months and three patients complained of annoying pain/dysaesthesia in the C2 dermatome for 3-6months after surgery. Conclusion: This study confirms that posterior atlanto-axial fixation with polyaxial C1 lateral mass screws and C2 pars screws is a safe and effective surgical option in the treatment of atlanto-axial instability or painful osteoarthriti

Fungal environment in different rabbit intensive farms

Many environmental factors (for example, temperature, relative humidity, ventilation, NH3 concentration) can influence the health and welfare of rabbits reared in intensive farms. Among these elements, microorganisms and, in particular, fungi play a pivotal role in the spreading of potential pathogenic and zoonotic diseases. Aim of our work was to evaluate the fungal contamination in two different rabbit rearing (A and B). SAS System® (PBI International, Italy) and opened plates, filled with cultural media for fungal growth (environmental and dermatophytes) have been used. The data collected in both the farms showed that, for environmental fungi, Aspergillus, Alternaria and Penicillium were the most spread. On the contrary, for dermatophytes, there was a difference between farm A and B. In fact, in the first one Microsporum canis (a known zoonotic agent) has been recovered in high concentration, while in the second rearing we have isolated Microsporum gypseum a geophilic fungus with a very low pathogenic potential

May the force be with you: why resistance training is essential for subjects with type 2 diabetes mellitus without complications

Physical activity, together with diet and pharmacological therapy, represents one of the three cornerstones in type 2 diabetes mellitus treatment and care. The therapeutic appeal of regular physical activity stems from: (i) its non-pharmacological nature; (ii) its beneficial effects on the metabolic risk factors associated with diabetes complications; (iii) its low costs. Evidence accumulated in the last years suggests that aerobic training\u2014endurance training\u2014constitutes a safe modality of intervention, achievable, and effective in diabetes treatment, whenever it is not limited by comorbidities. Aerobic training exerts insulin-mimetic effects and has been shown to lower mortality risk too. Anaerobic, intense physical activity, such as that of strength or power sports disciplines, is not univocally recognized as safe and simple to realize, however, it is important in stimulating energy and glucose metabolism. According to recent evidence, high-intensity training may be prescribed even in the face of cardiovascular diseases, peripheral vascular disease, or osteoarthritis. Some studies have shown resistance training to be more efficient than aerobic exercise in improving glycemic control. This review explores the most up-to-date indications emerging from literature in support of the beneficial effects of strength stimulation and resistance training in patients with type 2 diabetes without complications

Jesús en la tierra de los hombres

Gesù e la terra degli uomini pertenece al texto que el Papa Juan Pablo II encargó a Mario Luzi para el ejercicio del Via Crucis en el Coliseo romano, en la Pascua de 1999. La obra ha sido publicada posteriormente con el título de La Passione. En 2005, en un intervalo de poco más de un mes, tanto Juan Pablo II como Mario Luzi fallecieron, por lo que la estación adquiere un nuevo y hondo significado. La traducción es de Pedro Luis Ladrón de Guevara, quien también ha traducido y editado Ensayos críticos de Mario Luzi, de próxima aparición en la Colección Cátedra Félix Huarte

Meta-Learning for Color-to-Infrared Cross-Modal Style Transfer

Recent object detection models for infrared (IR) imagery are based upon deep neural networks (DNNs) and require large amounts of labeled training imagery. However, publicly-available datasets that can be used for such training are limited in their size and diversity. To address this problem, we explore cross-modal style transfer (CMST) to leverage large and diverse color imagery datasets so that they can be used to train DNN-based IR image based object detectors. We evaluate six contemporary stylization methods on four publicly-available IR datasets - the first comparison of its kind - and find that CMST is highly effective for DNN-based detectors. Surprisingly, we find that existing data-driven methods are outperformed by a simple grayscale stylization (an average of the color channels). Our analysis reveals that existing data-driven methods are either too simplistic or introduce significant artifacts into the imagery. To overcome these limitations, we propose meta-learning style transfer (MLST), which learns a stylization by composing and tuning well-behaved analytic functions. We find that MLST leads to more complex stylizations without introducing significant image artifacts and achieves the best overall detector performance on our benchmark datasets

The Mw 6.3, 2009 L’Aquila earthquake: source, path and site effects from spectral analysis of strong motion data

The strong motion data of 2009 April 6 L’Aquila (Central Italy) earthquake (Mw = 6.3) and of 12 aftershocks (4.1 ≤ Mw ≤ 5.6) recorded by 56 stations of the Italian strong motion network are spectrally analysed to estimate the source parameters, the seismic attenuation, and the site amplification effects. The obtained source spectra for S wave have stress drop values ranging from 2.4 to 16.8 MPa, being the stress drop of the main shock equal to 9.2 MPa. The spectral curves describing the attenuation with distance show the presence of shoulders and bumps, mainly around 50 and 150 km, as consequence of significant reflected and refracted arrivals from crustal interfaces. The attenuation in the first 50 km is well described by a quality factor equal to Q( f ) = 59 f 0.56 obtained by fixing the geometrical spreading exponent to 1. Finally, the horizontal-to-vertical spectral ratio provides unreliable estimates of local site effects for those stations showing large amplifications over the vertical component of motion

Frequency variation in site response as observed from strong motion data of the L’Aquila (2009) seismic sequence

Previous works based mainly on strong-motion recordings of large Japanese earthquakes showed that site amplification and soil fundamental frequency could vary over long and short time scales. These phenomena were attributed to non-linear soil behaviour: the starting fundamental frequency and amplification were both instantaneously decreasing and then recovering for a time varying from few seconds to several months. The recent April 6, 2009 earthquake (M W 6.3), occurred in the L’Aquila district (central Italy), gave us the possibility to test hypotheses on time variation of amplification function and soil fundamental frequency, thanks to the recordings provided by a pre-existing strong-motion array and by a large number of temporary stations. We investigated the intra- and inter-event soil frequency variations through different spectral analyses, including time-frequency spectral ratios and S-Transform (Stockwell et al. in IEEE Trans Signal Process 44:998–1001, 1996). Finally, analyses on noise recordings were performed, in order to study the soil behaviour in linear conditions. The results provided puzzling evidences. Concerning the long time scale, little variation was observed at the permanent stations of the Aterno Valley array. As for the short time-scale variation, the evidence was often contrasting, with some station showing a time-varying behavior, while others did not change their frequency with respect to the one evaluated from noise measurements. Even when a time-varying fundamental frequency was observed, it was difficult to attribute it to a classical, softening non-linear behaviour. Even for the strongest recorded shocks, with peak ground acceleration reaching 0.7 g, variations in frequency and amplitude seems not relevant from building design standpoint. The only exception seems to be the site named AQV, where the analyses evidence a fundamental frequency of the soil shifting from 3 Hz to about 1.5 Hz during the mainshock