Strategies against nonsense: oxadiazoles as translational readthrough-inducing drugs (TRIDs)

This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of truncated proteins. After a brief introduction on nonsense mutations and their pathological effects, the features of various classes of TRIDs will be described discussing differences or similarities in their mechanisms of action. Strategies to correct the PTCs will be presented, particularly focusing on a new class of Ataluren-like oxadiazole derivatives in comparison to aminoglycosides. Additionally, recent results on the efficiency of new candidate TRIDs in restoring the production of the cystic fibrosis transmembrane regulator (CFTR) protein will be presented. Finally, a prospectus on complementary strategies to enhance the effect of TRIDs will be illustrated together with a conclusive paragraph about perspectives, opportunities, and caveats in developing small molecules as TRIDs

EChO Payload electronics architecture and SW design

EChO is a three-modules (VNIR, SWIR, MWIR), highly integrated spectrometer, covering the wavelength range from 0.55 $\mu$m, to 11.0 $\mu$m. The baseline design includes the goal wavelength extension to 0.4 $\mu$m while an optional LWIR module extends the range to the goal wavelength of 16.0 $\mu$m. An Instrument Control Unit (ICU) is foreseen as the main electronic subsystem interfacing the spacecraft and collecting data from all the payload spectrometers modules. ICU is in charge of two main tasks: the overall payload control (Instrument Control Function) and the housekeepings and scientific data digital processing (Data Processing Function), including the lossless compression prior to store the science data to the Solid State Mass Memory of the Spacecraft. These two main tasks are accomplished thanks to the Payload On Board Software (P-OBSW) running on the ICU CPUs.Comment: Experimental Astronomy - EChO Special Issue 201

Breast Reconstruction and the Covid-19 Pandemic: Adapting Practice

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Detection of the Vortex Dynamic Regimes in MgB2 by Third Harmonic AC Susceptibility Measurements

In a type-II superconductor the generation of higher harmonics in the magnetic response to an alternating magnetic field is a consequence of the non-linearity in the I-V relationship. The shape of the current-voltage (I-V) curve is determined by the current dependence of the thermal activation energy U(J) and is thus related to the dynamical regimes governing the vortex motion. In order to investigate the vortex dynamics in MgB2 bulk superconductors we have studied the fundamental (chi1) and third (chi3) harmonics of the ac magnetic susceptibility. Measurements have been performed as a function of the temperature and the dc magnetic field, up to 9 T, for various frequencies and amplitudes of the ac field. We show that the analysis of the behaviour in frequency of chi3(T) and chi3(B) curves can provide clear information about the non-linearity in different regions of the I-V characteristic. By comparing the experimental curves with numerical simulations of the non-linear diffusion equation for the magnetic field we are able to resolve the crossover between a dissipative regime governed by flux creep and one dominated by flux flow phenomena.Comment: to be published in "Horizons in Superconductivity Research" (Nova Science Publishers, Inc., NY, 2003

Altered CD94/NKG2A and perforin expression reduce the cytotoxic activity in malignant pleural effusions

CD94/NKG2A is an inhibitory receptor expressed by NK cells and cytotoxic lymphocytes and, upon activation by HLA-E, downregulates the cytolytic activities of these cells thus representing a tumour immune escape mechanism. This study was aimed at assessing whether cytotoxic lymphocytes (CD8+) and NK cells from malignant pleural effusions have a deregulated expression of CD94/NKG2A. The expression of membrane CD94/NKG2A and perforin was evaluated by flow-cytometry in CD8+ and NK cells from pleural effusions and autologous peripheral blood of cancer (n=19) and congestive heart failure (CHF) (n=11) patients. Intracellular CD94/NKG2A expression was evaluated by flow-cytometry in pleural effusion CD8+ and NK cells from cancer patients (n=10). Cytotoxic activity against cancer cells exerted by pleural and autologous peripheral blood T lymphocytes from cancer patients was assessed by flow-cytometry assay. Pleural CD8+ from cancer patients showed a reduced expression of membrane CD94/NKG2A and perforin when compared to autologous peripheral blood and CHF pleural effusions. Reduced numbers of NK cells were present in pleural effusions from both cancer and CHF patients. Pleural NK from cancer patients showed a reduced expression of membrane CD94/NKG2A and perforin when compared to autologous peripheral blood. Pleural T lymphocytes from cancer patients exhibited a reduced cytotoxic activity against cancer cells when compared to autologous peripheral blood T lymphocytes. The intracellular expression of CD94/NKG2A in CD8+ and NK cells from cancer patients was higher than membrane expression. In conclusion, this study provides compelling evidences of new mechanisms underlying the reduced host defence against cancer within the pleural space

VP66.28: Conservative management and ultrasonographic longitudinal follow‐up of borderline ovarian tumour recurrences in pregnant women

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The effect of CT angiography and venous couplers on surgery duration in microvascular breast reconstruction: a single operator’s experience

Background: The use of CT angiography (CTA) or venous couplers (VCs) has led to shorter operative times in free flap breast reconstruction (FFBR). However, there are no reports on the effect of these two interventions relative to each other or combined. Methods: Abdominal based FFBRs performed by a single surgeon before introduction of either intervention were compared to those with VC only, and those after the addition of CTA to VCs (CT-VC). Operative time was defined as from “knife-to-skin” to insertion of the last stitch. Results: One hundred and twenty patients; 40 without intervention (WI), 40 with VC, and 40 with CT-VC. Introduction of VCs did not significantly reduce operative time compared to WI (P=0.73). However, patients in the CT-VC group had significantly shorter operations vs. WI (472 vs. 586 min, P<0.00001) and vs. VC alone (472 vs. 572 min, P=0.0006). Similarly, introduction of each intervention showed a stepwise decrease in ischaemia time (WI vs. VC: 100 vs. 89 min, P=0.0106; VC vs. CT-VC: 89 vs. 80 min, P=0.0307; WI vs. CT-VC: 100 vs. 80 min, P<0.00001). Conclusions: Combination of CTA and VC significantly reduced operative and ischaemic times for FFBR; this was predominantly due to use of CTA. CTA mitigates the surgical learning curve as demonstrated by shorter operating times via providing a vascular anatomy roadmap, thus facilitating flap harvest

Study of coupling loss on bi-columnar BSCCO/Ag tapes by a.c. susceptibility measurements

Coupling losses were studied in composite tapes containing superconducting material in the form of two separate stacks of densely packed filaments embedded in a metallic matrix of Ag or Ag alloy. This kind of sample geometry is quite favorable for studying the coupling currents and in particular the role of superconducting bridges between filaments. By using a.c. susceptibility technique, the electromagnetic losses as function of a.c. magnetic field amplitude and frequency were measured at the temperature T = 77 K for two tapes with different matrix composition. The length of samples was varied by subsequent cutting in order to investigate its influence on the dynamics of magnetic flux penetration. The geometrical factor $\chi_0$ which takes into account the demagnetizing effects was established from a.c. susceptibility data at low amplitudes. Losses vs frequency dependencies have been found to agree nicely with the theoretical model developed for round multifilamentary wires. Applying this model, the effective resistivity of the matrix was determined for each tape, by using only measured quantities. For the tape with pure silver matrix its value was found to be larger than what predicted by the theory for given metal resistivity and filamentary architecture. On the contrary, in the sample with a Ag/Mg alloy matrix, an effective resistivity much lower than expected was determined. We explain these discrepancies by taking into account the properties of the electrical contact of the interface between the superconducting filaments and the normal matrix. In the case of soft matrix of pure Ag, this is of poor quality, while the properties of alloy matrix seem to provoke an extensive creation of intergrowths which can be actually observed in this kind of samples.Comment: 20 pages 11 figure, submitted to Superconductor Science and Technolog

Advanced management protocol of transanal irrigation in order to improve the outcome of pediatric patients with fecal incontinence

Background: Transanal irrigation (TAI) is employed for children with fecal incontinence, but it can present several problems which require a study of their outcomes among different patholo-gies and without a tailored work up. The aim of our study was to evaluate the effectiveness of an advanced protocol in order to tailor TAI, prevent complications, and evaluate outcomes. Methods: We included 70 patients (14 anorectal malformation, 12 Hirschsprung’s disease, 24 neurological impairment, 20 functional incontinence) submitted to a comprehensive protocol with Peristeen®: fecal score, volumetric enema, rectal ultrasound, anorectal 3D manometry, and diary for testing and parameter adjustment. Results: Among the patients, 62.9% needed adaptations to the parameters, mainly volume of irrigated water and number of puffs of balloon. These adaptations were positively correlated with pre-treatment manometric and enema data. In each group, the improvement of score was statistically significant in all cases (p 0.000); the main factor influencing the efficacy was the rate of sphincter anomalies. The ARM group had slower improvement than other groups, whereas functional patients had the best response. Conclusions: Our results showed that TAI should not be standardized for all patients, because each one has different peculiarities; evaluation of patients before TAI with rectal ultrasound, enema, and manometry allowed us to tailor the treatment, highlighting different outcomes among various pathologies, thus improving the efficacy