The response of n-channel field-oxide field-effect transistors (FOXFET) exposed to ionizing radiation and annealing is reproduced using a physics-based numerical model that includes the microscopic ...processes leading to hole capture/neutralization and generation of interface traps. The results show that a distribution for the proton emission rate has to be considered in order to reproduce the threshold voltage evolution with dose, and density of interface traps trends at both short and long post-irradiation annealing times if direct release is considered as the mechanism responsible for proton production. This result may suggest a failure of the usual simple drift-diffusion model for proton transport across SiO2 in total dose models, or a limitation of our model based on some processes that were neglected in a first approach, such as hydrogen cracking as a secondary mechanism for proton production.
Objective
Pasireotide LAR (PAS-LAR) was released in Italy in 2017 to treat acromegaly patients resistant to SRLs (Somatostatin Receptors Ligands). The long-term follow-up data of PAS-LAR therapy in ...Italy are limited. This study aimed to evaluate the efficacy and safety of PAS-LAR in acromegaly.
Design
Patients with acromegaly in PAS-LAR treatment were enrolled in three tertiary Italian endocrinological centers and evaluated by a retrospective observational real-life multicentre study.
Methods
Patients have been studied before (baseline) and 1, 6, 12, 24 and > 36 months after PAS-LAR start. Clinical, biochemical, and pituitary magnetic resonance data were collected, along with information on adverse events. Acromegaly disease activity was classified according to the IGF-1 index (normal value < 1.0).
Results
Fifty patients (female 23) were enrolled. PAS-LAR treatment (mean follow-up 24 ± 16 months) significantly decreased IGF-1 levels (IGF-1 index baseline vs last visit: 1.9 ± 0.6 vs 1.2 ± 0.6,
p
< 0.0001). At the last visit, 67% of patients had controlled disease, and 44% showed a decrease in tumor volume. Clinical and biochemical efficacy was observed as early as after 1-month of PAS-LAR treatment (IGF-1 index baseline vs 1-month: 1.9 ± 0.6 vs 1.4 ± 0.7,
p
< 0.0001). Also, 50% of patients referred headache improvement or disappearance. Fifteen patients discontinued PAS-LAR due to failure of treatment and poor glycaemic control. The prevalence of diabetes increased from 33% at the baseline to 54% at the last visit (
p
= 0.0072).
Conclusion
In real-life settings, PAS-LAR significantly decreases symptoms, IGF-1 levels, and the size of adenoma in patients with acromegaly resistant to SRLs. Beneficial effects may occur early after the first injection.
4CMenB is the first broad coverage vaccine for the prevention of invasive meningococcal disease caused by serogroup B strains. To gain a comprehensive picture of the antibody response induced upon ...4CMenB vaccination and to obtain relevant translational information directly from human studies, we have isolated a panel of human monoclonal antibodies from adult vaccinees. Based on the Ig-gene sequence of the variable region, 37 antigen-specific monoclonal antibodies were identified and produced as recombinant Fab fragments, and a subset also produced as full length recombinant IgG1 and functionally characterized. We found that the monoclonal antibodies were cross-reactive against different antigen variants and recognized multiple epitopes on each of the antigens. Interestingly, synergy between antibodies targeting different epitopes enhanced the potency of the bactericidal response. This work represents the first extensive characterization of monoclonal antibodies generated in humans upon 4CMenB immunization and contributes to further unraveling the immunological and functional properties of the vaccine antigens. Moreover, understanding the mechanistic nature of protection induced by vaccination paves the way to more rational vaccine design and implementation.
Ionocytes of euryhaline teleost fish secrete NaCl, under regulation by serine and threonine kinases, including with-no-lysine kinase (WNK1) and p38 mitogen-activated protein kinase (MAPK). Mummichogs ...(
L.) were acclimated to freshwater (FW), full strength seawater (SW) and hypersaline conditions (2SW). Immunocytochemistry of ionocytes in opercular epithelia of fish acclimated to SW and 2SW revealed that WNK1-anti-pT58 phosphoantibody localized strongly to accessory cells and was present in the cytosol of ionocytes, close to cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane and the sodium potassium 2 chloride cotransporter (NKCC) in the basolateral membrane. In FW acclimated fish, WNK1 localized to a sub-apical zone, did not colocalize with apical membrane-located sodium chloride cotransporter (NCC), and typically was present in one cell of paired ionocytes and in some single ionocytes. Forskolin treatment (10 μM, 30 min) increased WNK1 immunofluorescence in SW ionocytes only, while hypertonicity had little effect, compared to controls. Anti-p38-MAPK antibody localized to the cytosolic compartment. The distribution of WNK1 and p38MAPK is consistent with a proximal position in regulatory cascades, rather than directly affecting transporters. The strong staining of accessory cells by WNK1 phosphoantibody infers an osmoregulatory function for WNK.
Adolescents are particularly vulnerable to inadequate provision of mental health and addictions care, as services have been traditionally conceptualized to serve the needs of children or adults. ...Additionally, rural communities have been largely excluded from research investigating mental healthcare access and exhibit unique barriers that warrant targeted interventions. Finally, perspectives from the target population will be most important when understanding how to optimize adolescent mental health and addictions care. Therefore, the purpose of this study was to identify what adolescents in a rural town perceive as barriers to accessing mental health services. We conducted a cross-sectional survey study with high school students to generate ranked lists of the top perceived individual-level, community-level, and overall barriers. A total of 243 high school students responded to the survey. Perceived barriers were predominantly at the community level. Overall, the top barriers reported were a lack of awareness and education regarding mental health, resources, and the nature of treatment. Students who had previously accessed mental health services identified primary barriers related to mental health professionals, whereas students who had not accessed care reported fear and uncertainty as primary barriers. Modifiable community-level factors related to (1) mental health literacy and (2) mental healthcare professionals were identified by adolescents as the main perceived barriers to accessing mental health and addiction services in a rural town. The findings of this preliminary study should inform intervention strategies and further rigorous research for this traditionally underserved target population.
The kidney is an organ playing an important role in ion regulation in both freshwater (FW) and seawater (SW) fish. The mechanisms of ion regulation in the fish kidney are less well studied than that ...of their gills, especially at the level of transporter proteins. We have found striking differences in the pattern of Na
+
/K
+
/2Cl
-
cotransporter (NKCC) expression between species. In the killifish kidney, NKCC is apically localized in the distal and collecting tubules and basolaterally localized in the proximal tubules. However, in the SW killifish gill, NKCC is basolaterally co-localized with Na
+
/K
+
-ATPase, whereas in FW, NKCC immunoreactivity is primarily apical, although still colocalized within the same mitochondria-rich cell with basolateral Na
+
/K
+
-ATPase. Rainbow trout kidney has NKCC only in the apical membrane of the distal and collecting tubules in both environments, with no signal being detected in the proximal tubule. On the other hand, in the trout gill, NKCC is found basolaterally in both FW and SW environments. An important observation is that, in the gills of rainbow trout, the trailing edge of the filament possesses mostly Na
+
/K
+
-ATPase-positive but NKCC-negative mitochondria-rich cells, whereas in the region between and at the roots of the gill lamellae, most mitochondria-rich cells exhibit both Na
+
/K
+
-ATPase- and NKCC-positive immunoreactivity. These results suggest that the differential localization of transporters between the two species represents differences in function between these two euryhaline fishes with different life histories and strategies.
Claudin (Cldn)-10 tight junction (TJ) proteins are hypothesized to form the paracellular Na+ secretion pathway of hyposmoregulating mummichog (Fundulus heteroclitus) branchial epithelia. ...Organ-specific expression profiles showed that only branchial organs the gill and opercular epithelium (OE) exhibited abundant cldn-10 paralog transcripts, which typically increased following seawater (SW) to hypersaline (2SW) challenge. Post-translational properties, protein abundance, and ionocyte localization of Cldn-10c, were then examined in gill and OE. Western blot analysis revealed two Cldn-10c immunoreactive bands in the mummichog gill and OE at ∼29 kDa and ∼40 kDa. The heavier protein could be eliminated by glycosidase treatment, demonstrating the novel presence of a glycosylated Cldn-10c. Protein abundance of Cldn-10c increased in gill and OE of 2SW-exposed fish. Cldn-10c localized to the sides of gill and OE ionocyte apical crypts and partially colocalized with cystic fibrosis transmembrane conductance regulator and F-actin, consistent with TJ complex localization. Cldn-10c immunofluorescent intensity increased but localization was unaltered by 2SW conditions. In support of our hypothesis, cldn-10/Cldn-10 TJ protein dynamics in gill and OE of mummichogs and TJ localization are functionally consistent with the creation and maintenance of salinity-responsive, cation-selective pores that facilitate Na+ secretion in hyperosmotic environments.
Cellular distribution of cystic fibrosis transmembrane conductance regulator (CFTR) immunofluorescence was detected by monoclonal antibody directed to the C terminus of killifish CFTR (kfCFTR) in ...chloride cells of fresh water (FW) adapted fish and animals transferred to sea water (SW) for 24h, 48h and 14+ days. Confocal microscopy allowed localization within mitochondria-rich (MR) cells to be determined as superficial (i.e. in the apical membrane) or deeper within the cytoplasm of the cells. In FW, 90 % of MR cells had diffuse kfCFTR immunofluorescence in the central part of the cytosol, with only 8.1 % having apical kfCFTR, which was 6.6+/-0.54 microm below the microridges of surrounding pavement cells. Curiously, FW but not SW pavement cells also had positive immunofluorescence to kfCFTR. After 24h in SW, a time when kfCFTR expression is elevated, a condensed punctate immunofluorescence appeared among 18.8 % of MR cells, 13.4+/-0.66 microm (mean +/- S.E.M.) below the surface of the cells. By 48h, a majority (76.3 %) of MR cells had punctate kfCFTR distribution and the distance from the surface was less (7.8+/-0.2 microm), a distribution approaching the SW-acclimated condition (i.e. all MR cells showing kfCFTR immunofluorescence, 6.1+/-0.04 microm below the surface). In contrast, NKCC immunofluorescence was condensed and localized in lateral parts of MR cell complexes in FW animals and then redistributed to the whole basal cytoplasm after acclimation to SW. CFTR, the anion channel responsible for Cl(-) secretion in marine teleosts, redistributes in MR cells during SW acclimation by condensation of a diffuse distribution below the apical crypt, followed by translocation and insertion in the apical membrane. NKCC, the cotransporter that translocates Cl(-) across the basolateral membrane, moves from an eccentric cytosolic location in FW to a diffuse basolateral localization in SW chloride cells.
Seawater-acclimated eurythermic mummichogs (Fundulus heteroclitus L.) were acclimated to cold and warm conditions (5 and 20°C, 4weeks). Opercular epithelia (OE) from 20°C-acclimated animals, ...containing numerous mitochondrion-rich chloride cells were mounted in Ussing-style membrane chambers, cooled to 16, 13, 10, 5 and 2.5°C, then subjected to hypotonic shock that normally inhibits Cl− secretion (as short-circuit current, Isc). Cold exposure to 10°C slowed Cl− secretion (Q10=1.62±0.204 95% CI) and OEs responded rapidly and reversibly to hypotonic shock, but below 8.0°C a sharp decrease (Q10=5.63±0.736) occurred and the tissue was unresponsive to hypotonicity. By immunocytochemistry, Focal Adhesion Kinase (FAK) phosphorylated at tyrosine-407 (pY407) colocalized with CFTR in apical membrane and dephosphorylated with hypotonic shock at 20°C but failed to dephosphorylate at 5°C, while opercular epithelia from cold-acclimated fish at 5 and 20°C responded normally to hypotonic shock. Cold-shock of warm-acclimated OEs also stimulated covering over of mitochondrion- rich cell apical crypts, detected by SEM. Cold-acclimation increased C18:1 and decreased C18:0 fatty acids in liver, indicating homeoviscous adaptation. Eurythermic fish acclimate osmoregulatory systems to cold by maintaining membrane fluidity and preserving complex transport regulation pathways.
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