Complete rupture of the Padul Fault represents one of the largest plausible earthquakes in the Sierra Nevada Range, one of the most seismically active regions of Spain. We performed a regional ...assessment of earthquake-triggered slope instabilities in the western part of the range to determine the most likely types of failures from such an earthquake in the region and suggest where such failures have a higher likelihood of occurring. These results are broadly useful for management of regional life-lines and future development. First, a slope-instability inventory of the Sierra Nevada was produced to identify the most common instability types. Subsequently, the Newmark’s sliding rigid-block methodology, implemented in a geographic information system, was used to obtain the distribution of Newmark displacements in the area considering a M w 6.6 earthquake on the Padul Fault. The Newmark displacements were then compared to the distribution of the inventoried slope instabilities to identify the areas where seismicity could reactivate old slope instabilities or generate new ones, and to identify the involved landslide typology. The most likely seismically induced slope instabilities in the Sierra Nevada are rock falls and rock slides. These types of instabilities could be triggered by Newmark displacements of 2 cm or less.
In this work, a novel all-dielectric metasurface made of arrayed circular slots etched in a silicon layer is proposed and theoretically investigated. The structure is designed to support both ...Mie-type multipolar resonances and symmetry-protected bound states in the continuum (BIC). Specifically, the metasurface consists of interrupted circular slots, following the paradigm of complementary split-ring resonators. This configuration allows both silicon-on-glass and free-standing metasurfaces and the arc length of the split-rings provides an extra tuning parameter. The nature of both BIC and non-BIC resonances supported by the metasurface is investigated by employing the Cartesian multipole decomposition technique. Thanks to the non-radiating nature of the quasi-BIC resonance, extremely high Q-factor responses are calculated, both by fitting the simulated transmittance spectra to an extended Fano model and by an eigenfrequency analysis. Furthermore, the effect of optical losses in silicon on quenching the achievable Q-factor values is discussed. The metasurface features a simple bulk geometry and sub-wavelength dimensions. This novel device, its high Q-factors, and strong energy confinement open new avenues of research on light-matter interactions in view of new applications in non-linear devices, biological sensors, and optical communications.
GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, ...schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABA
receptor-associated protein (GABARAP) to stabilize cell surface GABA
receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.
Five biological drugs are currently marketed for treatment of uncontrolled severe asthma. They all block type 2 inflammatory pathways by targeting IgE (omalizumab), the IL-5 pathway (mepolizumab, ...reslizumab, benralizumab), or the IL-4/IL-13 pathway (dupilumab). Hypereosinophilia has been observed in 4%-25% of patients treated with dupilumab and is transient in most cases, although there have been reports of persistent cases of symptomatic hypereosinophilia consistent with eosinophilic granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, eosinophilic vasculitis, and sudden worsening of asthma symptoms. Cases of EGPA have been reported with all biologics, including anti–IL-5 agents, and with leukotriene receptor antagonists in publications or in the EudraVigilance database. In many cases, EGPA appears during tapering of systemic corticosteroids or after switching from an anti–IL-5 biologic to dupilumab, suggesting that systemic corticosteroids or the anti–IL-5 agent were masking vasculitis. This review investigates plausible mechanisms of dupilumab-induced hypereosinophilia and review cases of symptomatic hypereosinophilia associated with dupilumab. Blockade of the IL-4/IL-13 pathway reduces eosinophil migration and accumulation of blood by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis in bone marrow. When choosing the optimal biologic, it seems necessary to consider the presence of hypereosinophilia (>1500/μL), in which case an anti–IL-5/IL-5R agent its preferable.Furthermore, when switching from an anti–IL-5/5R to an anti–IL-4/13R agent, blood eosinophils and clinical progress should be closely monitored. Nevertheless, dual therapy with anti–IL-5/5R and anti–IL4/IL-13R agents may be needed for optimal control, since both the IL-5 and the IL-4/IL-13 pathways can simultaneously contribute to airway inflammation. This approach can prevent the development of EGPA and other types of symptomatic hypereosinophilia while maintaining control of nasal polyposis. In the near future, it will be possible to use a new generation of biological therapies for the treatment of severe asthma. These act at a higher level of the inflammatory cascade, as is the case of the antialarmins tezepelumab and itepekimab.
New precise results of a measurement of the elastic electron-proton scattering cross section performed at the Mainz Microtron MAMI are presented. About 1400 cross sections were measured with negative ...four-momentum transfers squared up to Q² = 1 (GeV/c)² with statistical errors below 0.2%. The electric and magnetic form factors of the proton were extracted by fits of a large variety of form factor models directly to the cross sections. The form factors show some features at the scale of the pion cloud. The charge and magnetic radii are determined to be <r²E>½ = 0.879(5)stat(4)syst(2)model(4)group fm and <r²M>½ = 0.777(13)stat(9)syst(5)model(2)group fm.
Abstract Evaluation of specific antibody (Ab) response to polysaccharide antigens is essential for diagnosis of primary immunodeficiencies. We assessed the specific Ab responses to the ...pneumococcal-polysaccharide (PPV) and to Salmonella typhi-polysaccharide (TyphimVi) vaccines in a prospective study (EMPATHY) in patients with common variable immunodeficiency (CVID-Group, n = 22), hypogammaglobulinemia (HYPOG-Group; n = 27) and healthy controls (HC-Group; n = 16). Specific Ab concentrations in response to PPV and to TyphimVi vaccines were measured by ELISA (The Binding Site, UK), defining 3-fold increase as normal response (Ratio:3 ×). The RatioTyphimVi:3 × was significantly greater in HC than in CVID-Group ( p < 0.0001), but not than HYPOG-Group ( p = 0.138). However, the RatioPPV:3 × showed no significant differences among the three groups. By ROC analysis, TyphimVi better differentiated HC from CVID (AUC:0.893, IC95%: 0.791–0.996, p < 0.0001) than PPV. Our results suggest that the use of specific Ab response to TyphimVi could represent a complementary assay for the diagnosis of anti -polysaccharide Ab production deficiency in patients with CVID.
In this study, 20 women with staphylococcal mastitis were randomly divided in two groups. Those in the probiotic group daily ingested 10 log₁₀ CFU of Lactobacillus salivarius CECT5713 and the same ...quantity of Lactobacillus gasseri CECT5714 for 4 weeks, while those in the control one only ingested the excipient. Both lactobacillus strains were originally isolated from breast milk. On day 0, the mean staphylococcal counts in the probiotic and control groups were similar (4.74 and 4.81 log₁₀ CFU/ml, respectively), but lactobacilli could not be detected. On day 30, the mean staphylococcal count in the probiotic group (2.96 log₁₀ CFU/ml) was lower than that of the control group (4.79 log₁₀ CFU/ml). L. salivarius CECT5713 and L. gasseri CECT5714 were isolated from the milk samples of 6 of the 10 women of the probiotic group. At day 14, no clinical signs of mastitis were observed in the women assigned to the probiotic group, but mastitis persisted throughout the study period in the control group women. In conclusion, L. salivarius CECT5713 and L. gasseri CECT5714 appear to be an efficient alternative for the treatment of lactational infectious mastitis during lactation.
Summary
Background
Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline ...phosphatase ALP and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long‐term effectiveness of second‐line treatments remains uncertain.
Aims
To evaluate the long‐term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation).
Methods
We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non‐responsive PBC patients (Paris‐II criteria) from Spain and Portugal who received OCA ± fibrates.
Results
Of 255 patients, median follow‐up was 35.1 months (IQR: 20.2–53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE‐PBC and 5‐year UK‐PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension.
Conclusion
Triple therapy was superior in achieving therapeutic goals in UDCA‐nonresponsive PBC. Decompensation was linked to pre‐existing portal hypertension.
Longitudinal, real‐world study on 255 UDCA‐nonresponsive PBC patients (Per Paris II criteria); median follow‐up of 35.1 months (IQR: 20–53). All patients received obeticholic acid (OCA), with 25% receiving later add‐on fibrate treatment (triple therapy). In multivariate analysis, triple therapy outperformed dual therapy across all surrogate biochemical endpoints of outcomes.
Extensive scanning tunneling microscopy and spectroscopy experiments complemented by first-principles and parametrized tight binding calculations provide a clear answer to the existence, origin, and ...robustness of van Hove singularities (vHs) in twisted graphene layers. Our results are conclusive: vHs due to interlayer coupling are ubiquitously present in a broad range (from 1° to 10°) of rotation angles in our graphene on 6H-SiC(000-1) samples. From the variation of the energy separation of the vHs with the rotation angle we are able to recover the Fermi velocity of a graphene monolayer as well as the strength of the interlayer interaction. The robustness of the vHs is assessed both by experiments, which show that they survive in the presence of a third graphene layer, and by calculations, which test the role of the periodic modulation and absolute value of the interlayer distance. Finally, we clarify the role of the layer topographic corrugation and of electronic effects in the apparent moiré contrast measured on the STM images.
The degradation and detoxification towards the duckweed Lemna minor of 4-nitrophenol (4NP) was studied by means of bench-scale constructed wetlands (CWs), TiO2-photocatalysis and Fenton + photoFenton ...reactions. The main goal of this work was to compare the three treatment techniques to evaluate their possible combination for the efficient, low cost treatment of 4NP effluents. In CWs, adsorption on the substrate of 4NP was found to achieve 34–45%. Low concentrations (up to 100 ppm) of 4NP were successfully treated by CWs in 8–12 h. The microbial degradation of 4NP started after a lag phase which was longer with higher initial concentrations of the pollutant. The greatest degradation rate was found to occur at initial concentrations of 4NP between 60 and 90 ppm. Solar TiO2-photocatalysis was faster than the CWs. The greatest removals in terms of mass of 4NP removed after 6 h of irradiation were found to occur at 4NP concentrations of about 200 ppm. Fenton reaction provided complete 4NP degradation up to 500 ppm in only 30 min but TOC was removed by only about 40%. The resulting toxicities were below 20% for initial 4NP concentrations below 300 ppm. It was the Fenton + photoFenton combination (180 min in total) that provided TOC reductions up to 80% and negative L. minor growth inhibition for almost all the 4NP concentrations tested. The combination of solar TiO2-photocatalysis (6 h) with CWs (16 h) was able to completely treat and detoxify 4NP effluents with concentrations as high as 200 ppm of the organic.
► We studied the treatment 4NP by CWs and advanced oxidation technologies. ► In CWs biodegradation and adsorption were the main removal pathways. ► The 4NP removal order was: CWs < TiO2-photocatalysis < Fenton–photoFenton. ► The combination of CWs with photocatalysis is proposed as a convenient treatment.
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