[Modeling T2 high severe asthma using human induced pluripotent stem cells (hiPSC)]. / Modélisation de l'asthme sévère par la technologie des cellules humaines souches pluripotentes induites (hiPSC).

Severe asthma patients with persistent airflow obstruction are characterized by functional obstruction due to mucus plugs containing mucins, fibrin, and eosinophil derived Charcot- Leyden crystals. The molecular mechanisms underlying this endotype are not clearly understood. Developing new models is crucial to respiratory research insofar as critical differences exist between human and rodent airway epithelium. We (and other teams) have shown that it is possible to reconstitute in vitro a complex and functional airway epithelium displaying all the features described in vivo from human-induced pluripotent stem cells (hiPSC). Our aim is to establish a human in vitro model of severe asthma that will recapitulate airway epithelium remodeling and mucus plugs.

Myasthenia gravis concurrent with Parkinson's disease in a Spanish cohort. Causation or correlation?

BACKGROUND: Comorbidity between myasthenia gravis (MG) and other autoimmune diseases is well-documented. However, concurrent MG and Parkinson's disease (PD) have rarely been described. This concurrence has mostly been considered coincidental in cases reported to date. MATERIAL/METHODS: We characterized patients with concurrent MG and PD within a cohort of 631 MG patients by gender, age, MGFA class, quantitative MG score at diagnosis, UPDRS score at diagnosis, and the DaTSCAN uptake pattern, to determine the frequency and the phenotype of individuals with these two concurrent entities. Meta-analysis of cases in the literature was used for comparison with our series. RESULTS: Eighteen cases were identified in which the two diseases were concurrent. The major characteristics of the phenotype are male prevalence, late-onset MG, and frequent initial symptoms of dropped head and oculobulbar involvement. DAT confirmed reduced bilateral uptake in eleven patients and reduced unilateral uptake in the others. CONCLUSIONS: To our knowledge, this is the largest reported series of concurrent MG and PD. This concurrence is more common than expected (2.85%). Either MG or PD may appear first. We found no iatrogenic relationship for the order of appearance. The overlapping of symptoms sometimes leads physicians to overlook the second disease, instead viewing it as a deterioration of the first. This study describes patients with well-documented diagnoses of both MG and PD, thus providing further indications of a shared etiology of these two diseases. Prospective studies including genetic, immunological, and environmental analysis are necessary to identify possible common pathogenic mechanisms.

Mesenchymal stem cell-derived HGF attenuates radiation-induced senescence in salivary glands via compensatory proliferation.

BACKGROUND & AIM: Irradiation of the salivary glands during head and neck cancer treatment induces cellular senescence in response to DNA damage and contributes to radiation-induced hyposalivation by affecting the salivary gland stem/progenitor cell (SGSC) niche. Cellular senescence, such as that induced by radiation, is a state of cell-cycle arrest, accompanied by an altered pro-inflammatory secretome known as the senescence-associated secretory phenotype (SASP) with potential detrimental effects on the surrounding microenvironment. We hypothesized that the pro-regenerative properties of mesenchymal stem cells (MSCs) may attenuate cellular senescence post-irradiation. Therefore, here we evaluated the effects of adipose-derived MSCs (ADSCs) on the radiation-induced response of salivary gland organoids (SGOs). METHODS: Proteomic analyses to identify soluble mediators released by ADSCs co-cultured with SGOS revealed secretion of hepatocyte growth factor (HGF) in ADSCs, suggesting a possible role in the stem cell crosstalk. Next, the effect of recombinant HGF in the culture media of ex vivo grown salivary gland cells was tested in 2D monolayers and 3D organoid models. RESULTS: Treatment with HGF robustly increased salivary gland cell proliferation. Importantly, HGF supplementation post-irradiation enhanced proliferation at lower doses of radiation (0, 3, 7 Gy), but not at higher doses (10, 14 Gy) where most cells stained positive for senescence-associated beta-galactosidase. Furthermore, HGF had no effect on the senescence-associated secretory phenotype (SASP) of irradiated SGOs, suggesting there may be compensatory proliferation by cell-division competent cells instead of a reversal of cellular senescence after irradiation. CONCLUSION: ADSCs may positively influence radiation recovery through HGF secretion and can promote the ex vivo expansion of salivary gland stem/progenitor cells to enhance the effects of co-transplanted SGSC.

Evidence of high compliance and fatigue in mask adherence in two mandates in Barcelona, Spain: a naturalistic observational study.

OBJECTIVE: We investigated a possible pandemic fatigue effect, comparing adherence to compulsory mask use outdoors in Barcelona during the fourth and sixth waves of the pandemic. STUDY DESIGN: We used naturalistic observation to determine the degree of pedestrians' compliance. METHODS: We assessed mask use outdoors in a sample of pedestrians in Barcelona between 28 December 2021 and 9 February 2022 (during the sixth wave in Spain), and compared it with the fourth wave (which was between 5 April 2021 and 29 April 2021). Masks were compulsory in both periods. RESULTS: The population studied amounted to 45,116 people (21,246 in the fourth wave and 23,870 in the sixth wave). In the sixth wave, only 67.3% wore a mask correctly, 18.6% did so incorrectly and 14.1% did not wear a mask, while the figures for the fourth wave were 78.2%, 16.3% and 5.5%, respectively (P = 0.001). CONCLUSION: Our results suggest that adherence was high in the population studied, but with an evident fatigue effect when the two waves were compared, as the proportion of individuals wearing a mask correctly declined compared to the fourth wave. These results suggest that policymakers need guidance on adopting clear and enforceable guidelines during future mask mandates, assessing advantages and drawbacks in terms of the population's behavior to prevent the fatigue effect.

[Impact of vortioxetine on sexual function compared to other antidepressants]. / Repercusión de vortioxetina sobre la función sexual frente a otros antidepresivos.

OBJECTIVE: To analyze the impact of the antidepressant vortioxetine on sexual function, compared to selective serotonin reuptake inhibitors (SSRIs) and mixed selective serotonin and norepinephrine reuptake inhibitors (IRSN or Dual) in patients with depression. MATERIAL AND METHODS: Analytical, observational, longitudinal and prospective study, which included men and women over 18years of age, with depressive disorder and sexual activity with a partner, separating them into two groups: (i)study, starting treatment with vortioxetine; (2)control, maintaining treatment with SSRIs or Duals. Three visits were made: inclusion, follow-up at 4weeks and final 3months from inclusion. The total follow-up period was 3months. RESULTS: A total of 87 patients were included (mean age 46.85years). At the end of the study, significant differences (SD) were found in the mean value of the sum of the scores of the evaluative domains of the sexual response of the Women's Sexual Function Questionnaire (FSM-2) between the study group and the control (22.42±4.39 and 16.13±7.76, respectively), with a lower risk of sexual dysfunction in women treated with vortioxetine. Also, lower risk of sexual dysfunction in these same women in the domains of desire, lubrication, orgasm, sexual frequency and sexual satisfaction. These differences were not found when assessing male sexual function. CONCLUSIONS: Women treated with vortioxetine presented better sexual function than those treated with SSRIs or Duals and a lower risk of sexual dysfunction.

The impact of prolonging extinction on the ABC "super renewal" of instrumental responses in rats.

Two free operant conditioning experiments with rats examined the impact of conducting a large amount of extinction training on situations that enhance the ABC renewal effect (ABC super renewal). In Experiment 1, ABC renewal was strengthened by conducting acquisition in multiple contexts. All rats were trained to press a lever for food. One group was trained in one context, while the other two groups were trained in three contexts. Then, all rats received extinction in context B. For two groups this phase lasted 4 sessions, whereas it lasted 36 sessions for the other group. In Experiment 2, ABC renewal was strengthened by using a large number of acquisition sessions. Rats were trained to perform an operant response to obtain food in context A. One group received a moderate amount of training, while the rest of the rats received a larger number of acquisition sessions. Responses underwent extinction in context B. Two groups received 4 sessions, while 36 extinction sessions were used for the remaining group. In both experiments, rats were tested in context B (extinction context) and C (renewal context). Greater ABC renewal occurred both when acquisition training was conducted in multiple contexts (Experiment 1) and by increasing the amount of acquisition training (Experiment 2). Nevertheless, we found that conducting a large number of extinction sessions reduced ABC super renewal in Experiment 1 only.

Feasibility of a nasal breathing training during pulmonary rehabilitation. A pilot randomized controlled study.

Hyperventilation syndrome (HVS) is a common source of dyspnea and disability. While pulmonary rehabilitation (PR) including breathing exercises is indicated, randomized controlled trial are warranted to recommend one type of breathing exercise than another. We aimed to compare during PR, the effect of 5 sessions of nasal ventilation exercise (NV+PR) versus voluntary hypoventilation (vHV+PR) on exercise dyspnea (primary outcome) and capacity and health-related quality of life in patients. In this open label randomized controlled trial, 19 HVS patients (age=48.3 ± 15.2 y.o, female/male=18/1, Nijmegen score=33 ± 7.7) were randomized in a NV+PR (n = 9) or vHV+PR (n = 10) group. Modified Medical Research Council (mMRC) dyspnea, 6-minute walking distance (6MWD) with nasal/oral ventilation were assessed before and after 3 months of PR, and questionnaires (Nijmegen, VQ-11). There was a significant effect of PR of but no significant difference between groups in the improvements of dyspnea@max exercise (time effect (T): p < 0.01; group (G): p = 0.63; group*time interaction (G*T): p = 0.49), mMRC dyspnea (T: p < 0.01; G: p = 0.45; G*T: p = 0.62), 6MWD (T: p < 0.05; G: p = 0.36; G*T: p = 0.31), VQ-11 (T: p < 0.001; G: p = 0.16; G*T: p = 0.09) and plasma HCO3- (T: p < 0.05; G: p = 0.93; G*T; p = 0.36), Yet, Nijmegen score (T: p < 0.01; G: p = 0.32; G*T: p < 0.05) improvement was larger in NV+PR group. The exercise oronasal breathing shift during the 6MWT was significantly delayed in all patients (T: p < 0.05; G: p = 0.30; G*T: p = 0.32) and positively correlated with plasma HCO3-(r = 0.42; p < 0.05). Nasal exercise was not superior versus voluntary hypoventilation during PR in HVS patients. Yet, nasal exercise appeared feasible, leading to acquisition of a nasal breathing pattern during walking, improvement of PR outcomes and ventilatory alkalosis. The link between nasal breathing and hyperventilation is discussed in the light of the nasal ventilation rhythm in the limbic system and its role on the limbic emotional and ventilatory functions.

Analysis of Habituation Learning in Mealworm Pupae (Tenebrio molitor).

The decline of response as a consequence of repeated stimulation is known as habituation. The goal of the present experiments was extending the knowledge about habituation of abdominal contractions in the pupa of Tenebrio molitor. Both experiments consisted of two phases. During Phase 1, all groups were exposed to a continuous stimulus (light in Experiment 1 and vibration in Experiment 2). At the beginning of this phase, pupae showed a high number of abdominal contractions. However, during the last minute of Phase 1, the number of abdominal contractions was lower. In the next phase, the pupae were divided in different groups to test for response recovery. We found an increase in the abdominal contractions when subjects were exposed to a different stimulus, be it within the same or in a distinct sensory modality. In addition, we also reported response recovery when the pupae were re-exposed to the original stimuli after a resting period. Results indicate that the increase in responding cannot be explained by either sensory adaptation or fatigue. The findings are consistent with the perspective that suggests that habituation plays a major role in the survival of the species, even in non-feeding developmental stages.

Prostatic artery embolization treatment for patients with benign prostatic hyperplasia who are permanent urinary catheter users ineligible for de-obstructive surgery.

INTRODUCTION: Benign prostatic hyperplasia is considered the most frequent cause of lower urinary tract symptoms. Urinary catheterization is the emergency treatment for patients with urinary retention and surgery is indicated in patients refractory to medical treatment. There is a group of people with important comorbidities that make them ineligible for surgery. Prostatic arterial embolization (PAE) could be presented as a safe and effective alternative to achieve bladder emptying and spontaneous urination, thus avoiding permanent urinary catheterization in patients with significant comorbidities that represent a contraindication for surgery. In this retrospective study, we evaluated the efficacy of PAE in patients with permanent urinary catheterization who are ineligible for surgical treatment. MATERIAL AND METHODS: Retrospective study of 26 patients with permanent urinary catheter who underwent prostatic embolization. Demographic and clinical data (age, use of anticoagulation, prostate volume, length of hospital stay, unilateral or bilateral embolization), Charlson comorbidity index evaluation and Clavien-Dindo classification for procedural complications were reviewed. Successful removal of permanent urinary catheter was analyzed at one month after the procedure. RESULTS: A total of 26 patients were included in the review. The median age was 85 years with a median prostate volume of 90 mL. A Charlson comorbidity score above 7 was obtained in 88.5% of the subjects. Only one patient had one Clavien-Dindo III complication. Of the 26 subjects, 17 (65.4%) had spontaneous micturition and a postvoid residual lower than 100 mL at one month post procedure. Overall, catheter removal was achieved in 19 out of 26 subjects (73.1%). CONCLUSION: PAE is a safe and effective treatment for patients with permanent urinary catheterization who are ineligible for surgical treatment.

Conducting extinction in multiple contexts attenuates relapse of operant behavior in humans.

In one experiment with human participants, we investigated the effects of using multiple contexts during extinction on the renewal of operant responses. Undergraduate students played a videogame in which they learned to shoot at enemies in Context A. Then, all participants experienced an extinction training. For half of the participants, extinction trials were conducted in a single context, whereas the other half received extinction in three different contexts. Finally, all participants were tested in Context A. We observed that conducting extinction in multiple contexts attenuated ABA renewal. The present results suggest that conducting extinction in multiple contexts can be used as a behavioral technique to reduce operant renewal.

The state of transfer of stimulus control after extinction in human instrumental conditioning: A key factor in therapy strategies based in nonhuman animal research.

Previous research has shown that instrumental training can encourage the formation of binary associations between the representations of the elements present at the time of learning, that is, between the discriminative stimulus and the instrumental response (the S-R association), between the stimulus and outcome (the S-O association), and between the response and outcome (the R-O association). Studies with rats have used transfer procedures to explore the effects of discriminative extinction (i.e., extinction that is carried out in the presence of the discriminative stimuli) on these three binary associations. Thus, a reduction in the response rate of the extinguished response (R) can be detected in situations involving a different discriminative stimulus that was associated with the same outcome, and to unextinguished responses controlled by the discriminative stimulus (S) and associated with the outcome (O). These transfer effects suggest that R-O and S-O associations remain active after extinction in nonhuman animals. We carried out an experiment to explore these postextinction transfer effects in humans using a within-subject design. Contrary to nonhuman reports, the S-O association was affected by discriminative extinction, suggesting differences in the associative structure of instrumental conditioning in human and nonhuman animals that should be considered by those therapeutic strategies based in nonhuman animal research aimed to reduce unhealthy instrumental behaviours in human beings. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Constraints on Lorentz Invariance Violation from HAWC Observations of Gamma Rays above 100 TeV.

Because of the high energies and long distances to the sources, astrophysical observations provide a unique opportunity to test possible signatures of Lorentz invariance violation (LIV). Superluminal LIV enables the decay of photons at high energy. The high altitude water Cherenkov (HAWC) observatory is among the most sensitive gamma-ray instruments currently operating above 10 TeV. HAWC finds evidence of 100 TeV photon emission from at least four astrophysical sources. These observations exclude, for the strongest of the limits set, the LIV energy scale to 2.2×10^{31} eV, over 1800 times the Planck energy and an improvement of 1 to 2 orders of magnitude over previous limits.

On the Relationship between Mechanical Properties and Crystallisation of Chemically Post-Processed Additive Manufactured Polylactic Acid Pieces.

Nowadays, improvement of the surface finish of parts manufactured by fused deposition modelling is a well-studied topic. Chemical post-treatments have proven to be the best technique in terms of time consumption and smoothness improvement. However, these treatments modify the structure of the material and, consequently, its mechanical properties. This relationship was studied in this work. In this case, on the basis of a previous study on crystallisation, polylactic acid pieces were subjected to different post-treatments to evaluate their effects on the sample's mechanical properties, i.e., tensile strength and hardness. Models were obtained according to their percentage of crystallisation, which was related to the different treatments, as well as immersion time. Dramatic changes were obtained within a wide range of material behaviour with some treatments. Specifically, changes were obtained in the maximum stress (from 55 to 20 MPa), in elongation (from 3% to 260%), and in the hardness scale (Shore D to A).

Preimaginal conditioning affects oviposition choices in the silkworm moth (Bombyx mori).

Nowadays we can find a number of experiments that have showed the importance of learning in several situations related with survival of many animal species. For instance, knowledge acquired in the early stages of life could be crucial on the choice of egg-laying site. In this study we explored the influence of Pavlovian conditioning of silkworm larvae on their oviposition behaviour as adult female moths. For this, the larvae learning have to survive the metamorphosis and be shown in oviposition choice. In acquisition phase, a larvae group experienced an odour (conditioned stimulus) paired with mulberry leaves (unconditioned stimulus), another one experienced the odour and the mulberry leaves in an unpaired way and the last one experienced the odour alone during this phase. The results show that when these larvae became moths, only the first group preferred to lay their eggs near the odour when it was present during the test, so that associations learned during the larval stage seem to influence oviposition behaviour during adulthood.

Proteostasis regulators as potential rescuers of PMM2 activity.

Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-glycosylation disorder. To date there is no treatment. Following the identification of a number of destabilizing pathogenic variants, our group suggested PMM2-CDG to be a conformational disease. The aim of the present study was to evaluate the possible use of proteostasis network regulators to increase the stability, and subsequently the enzymatic activity, of misfolded PMM2 mutant proteins. Patient-derived fibroblasts transduced with their own PMM2 folding or oligomerization variants were treated with different concentrations of the proteostasis regulators celastrol or MG132. Celastrol treatment led to a significant increase in mutant PMM2 protein concentration and activity, while MG132 had a small effect on protein concentration only. The increase in enzymatic activity with celastrol correlated with an increase in the transcriptional and proteome levels of the heat shock proteins Hsp90 and Hsp70. The use of specific Hsp70 or Hsp90 inhibitors showed the positive effect of celastrol on PMM2 stability and activity to occur through Hsp90-driven modulation of the proteostasis network. The synergistic effect of celastrol and a previously described pharmacological chaperone was also examined, and a mutation-dependent synergistic effect on PMM2 activity was noted. These results provide proof-of-concept regarding the potential treatment of PMM2-CDG by proteostasis regulators, either alone or in combination with pharmacological chaperones.

Multiple Galactic Sources with Emission Above 56 TeV Detected by HAWC.

We present the first catalog of gamma-ray sources emitting above 56 and 100 TeV with data from the High Altitude Water Cherenkov Observatory, a wide field-of-view observatory capable of detecting gamma rays up to a few hundred TeV. Nine sources are observed above 56 TeV, all of which are likely galactic in origin. Three sources continue emitting past 100 TeV, making this the highest-energy gamma-ray source catalog to date. We report the integral flux of each of these objects. We also report spectra for three highest-energy sources and discuss the possibility that they are PeVatrons.

The reoccurrence of voluntary behavior in humans is reduced by retrieval cues from extinction.

Changes in the temporal as well as the physical context produces the reappearance of extinguished behaviors. Furthermore, combining both kinds of contextual stimuli often causes greater levels of recovery. The current experiment explored the impact of extinction reminders on spontaneous recovery, renewal, and a combination of both effects using an instrumental learning task with humans. All participants learned to shoot at enemies in a videogame. Then, throughout extinction, the instrumental response was eliminated. We found a return of the extinguished behavior by introducing a retention interval of 48 h, by changing the physical background and by testing participants in a spatiotemporal context different from the extinction context. However, we also found that the presentation of a stimulus directly associated with extinction attenuates all three forms of operant reoccurrence. These results are consistent with the perspective that emphasizes that context plays a key role in response-recovery phenomena. Moreover, our findings may be promissory for therapeutic strategies involving relapse treatment.

Publisher Correction: Very-high-energy particle acceleration powered by the jets of the microquasar SS 433.

In this Letter, owing to a production error, the penultimate version of the PDF was published. The HTML version was always correct. The PDF has been corrected online.

The Reinstatement Effect in Human Predictive Learning: Contextual Modulation and the Impact of Extinction Reminders.

One of the most relevant phenomena both from a theoretical and clinical perspective is extinction. In particular, several researchers are interested in the response recovery effects from extinction. Reinstatement is an effect that has been proposed as a laboratory model to study relapse from extinction-based therapeutic treatments. We designed two experiments with humans to evaluate the reinstatement effect in a predictive learning task. In both experiments, participants learned a specific relationship between two cues (X and Y) and two outcomes (O1 and O2) during the first phase. Throughout extinction, both cues were presented without outcomes. After an exposure to the original outcomes, reinstatement of the first-learned information was observed during testing in both experiments. However, we found that the reinstatement effect was contextual modulated (Experiment 1; ηp2 = .78, 90% CI [.48, .86], p < .0001). Furthermore, in Experiment 2 we showed a reduction of reinstatement when an extinction reminder was used ηp2 = .45, 90% CI [.07, .65], p = .012. Theoretical implications are discussed, and some potential uses are mentioned.

The role of learning in the oviposition behavior of the silkworm moth (Bombyx mori).

One of the most relevant behaviors in the life of some insects is oviposition, because reproductive fitness largely depends on the choice of egg-laying site. We report one experiment that explored the influence of Pavlovian conditioning on oviposition choices of the silkworm. Our results show that moths that jointly experienced an odor (conditioned stimulus) and mulberry leaves (the preferred oviposition place for the moths) preferred to lay their eggs near the odor when it was present, whereas moths in which the odor and the mulberry leaves never appeared together showed no preference. This result provides evidence of the important role that a psychological process such as Pavlovian conditioning has for the survival of this species.