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

SS 433 is a binary system containing a supergiant star that is overflowing its Roche lobe with matter accreting onto a compact object (either a black hole or neutron star)1-3. Two jets of ionized matter with a bulk velocity of approximately 0.26c (where c is the speed of light in vacuum) extend from the binary, perpendicular to the line of sight, and terminate inside W50, a supernova remnant that is being distorted by the jets2,4-8. SS 433 differs from other microquasars (small-scale versions of quasars that are present within our own Galaxy) in that the accretion is believed to be super-Eddington9-11, and the luminosity of the system is about 1040 ergs per second2,9,12,13. The lobes of W50 in which the jets terminate, about 40 parsecs from the central source, are expected to accelerate charged particles, and indeed radio and X-ray emission consistent with electron synchrotron emission in a magnetic field have been observed14-16. At higher energies (greater than 100 gigaelectronvolts), the particle fluxes of γ-rays from X-ray hotspots around SS 433 have been reported as flux upper limits6,17-20. In this energy regime, it has been unclear whether the emission is dominated by electrons that are interacting with photons from the cosmic microwave background through inverse-Compton scattering or by protons that are interacting with the ambient gas. Here we report teraelectronvolt γ-ray observations of the SS 433/W50 system that spatially resolve the lobes. The teraelectronvolt emission is localized to structures in the lobes, far from the centre of the system where the jets are formed. We have measured photon energies of at least 25 teraelectronvolts, and these are certainly not Doppler-boosted, because of the viewing geometry. We conclude that the emission-from radio to teraelectronvolt energies-is consistent with a single population of electrons with energies extending to at least hundreds of teraelectronvolts in a magnetic field of about 16 microgauss.

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.

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.

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.

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.

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.

Protein misfolding diseases: Prospects of pharmacological treatment.

Protein misfolding has been linked to numerous inherited diseases. Loss- and gain-of-function mutations (common features of genetic diseases) may cause the destabilization of proteins, leading to alterations in their properties and/or cellular location, resulting in their incorrect functioning. Misfolded proteins can, however, be rescued via the use of proteostasis regulators and/or pharmacological chaperones, suggesting that treatments with small molecules might be developed for a range of genetic diseases. This work describes the potential of these small molecules in this respect, including for the treatment of congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG).

Comparison of anti-interleukin-5 therapies in patients with severe asthma: global and indirect meta-analyses of randomized placebo-controlled trials.

Inconsistent results have been reported regarding IL-5 blockade treatment in asthma. There were no direct between-treatment comparisons. Only differences between each drug and placebo were studied. We identified all RCTs with anti-IL5 treatments for patients with asthma over the 1990-September 2015 period. RCTs were searched on Medline, Cochrane and Embase. At least 50 patients were enrolled in each study. Outcomes considered were exacerbation rate reduction, FEV1 changes, ACQ-5 improvement, adverse events and serious adverse events. A global meta-analysis was first conducted followed by an indirect comparison of each IL-5-targeting drug: benralizumab, reslizumab and mepolizumab. Further eosinophilic subgroup analysis and sensitivity analysis were also conducted in case of heterogeneity. Ten trials involving 3421 patients were eligible for meta-analysis. IL-5 blockade significantly reduced annual exacerbation rates vs. placebo by 40% [29-50] (P < 0.01, I2 = 0.61). ACQ-5 was significantly improved vs. placebo but below the recognized MCID level (-0.31 [-0.41, -0.21], P < 0.01, I2 = 0.11). FEV1 changes from baseline were improved vs. placebo by 0.09 L [0.05-0.12] (P < 0.01, I2 = 0.28). The subgroup analysis identified a slight additional improvement in mean treatment effects in eosinophilic (> 300 mm3 /L) patients with severe asthma. Similar patterns and rates of adverse events and severe adverse events were reported with the three drugs. The data interpretations were not affected by the sensitivity analysis. IL-5 blockade appears to be a relevant treatment strategy to improve severe asthma management, particularly for eosinophilic patients. No clear superiority appeared between the drugs when appropriate doses were compared.

Roles of context in acquisition of human instrumental learning: Implications for the understanding of the mechanisms underlying context-switch effects.

Four experiments in human instrumental learning explored the associations involving the context that develop after three trials of training on simple discriminations. Experiments 1 and 4 found a deleterious effect of switching the learning context that cannot be explained by the context-outcome binary associations commonly used to explain context-switch effects after short training in human predictive learning and in animal Pavlovian conditioning. Evidence for context-outcome (Experiment 2), context-discriminative stimulus (Experiment 3), and context-instrumental response (Experiment 4) binary associations was found within the same training paradigm, suggesting that contexts became associated with all the elements of the situation, regardless of whether those associations played a role in a specific context-switch effect detected on performance.

Antisense-mediated therapeutic pseudoexon skipping in TMEM165-CDG.

Deficiencies in glycosyltransferases, glycosidases or nucleotide-sugar transporters involved in protein glycosylation lead to congenital disorders of glycosylation (CDG), a group of genetic diseases mostly showing multisystem phenotype. Despite recent advances in the biochemical and molecular knowledge of these diseases, no effective therapy exists for most. Efforts are now being directed toward therapies based on identifying new targets, which would allow to treat specific patients in a personalized way. This work presents proof-of concept for the antisense RNA rescue of the Golgi-resident protein TMEM165, a gene involved in a new type of CDG with a characteristic skeletal phenotype. Using a functional in vitro splicing assay based on minigenes, it was found that the deep intronic change c.792+182G>A is responsible for the insertion of an aberrant exon, corresponding to an intronic sequence. Antisense morpholino oligonucleotide therapy targeted toward TMEM165 mRNA recovered normal protein levels in the Golgi apparatus of patient-derived fibroblasts. This work expands the application of antisense oligonucleotide-mediated pseudoexon skipping to the treatment of a Golgi-resident protein, and opens up a promising treatment option for this specific TMEM165-CDG.

[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.

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.

Role of comorbid conditions in asthma hospitalizations in the south of France.

BACKGROUND: Reasons for asthma hospitalizations are dynamic and complex. Comorbid conditions are important contributors to most chronic diseases today. We aim to characterize and describe risk factors associated with hospitalizations due to asthma in the Languedoc-Roussillon region (France) in 2009. METHODS: Programme de Médicalisation des Systèmes d'Information (PMSI) data records from 2009 were sorted using selected International Classification of Diseases (ICD10) codes eliciting three groups of asthma hospitalizations according to acute severity. All available data including demographics, comorbid conditions, past hospitalizations either related or unrelated to asthma, seasonality and distance to medical facilities were used to compare the subjects within the three groups. RESULTS: One thousand two hundred and eighty-nine hospitalizations due to asthma exacerbation were found, concerning 1122 patients. We observed significant differences within the groups, using univariate analysis, concerning duration of hospitalizations (mean ± SD, 4.9 ± 5.9 days vs 6.4 ± 6.8 vs 15.8 ± 16.8, P < 0.001), deaths (percentage, 0.03% vs 1.50% vs 9.20%, P < 0.001) and numbers of comorbid conditions (0.80 ± 0.95 vs 0.75 ± 0.97 vs 1.74 ± 1.36, P < 0.001). Recurrent admissions for asthma during the period 2006-2008 were significantly more frequent in the more severe group (1.93 ± 3.91 vs 2.56 ± 4.47 vs 2.81 ± 3.97, P = 0.006). In the multivariate model, age and number of comorbid conditions were independently associated with severe hospitalizations and deaths. CONCLUSIONS: Asthma hospitalizations can be appropriately assessed using PMSI coding databases. In this study, age and the presence of comorbid conditions are the major risk factors for asthma hospitalizations and deaths.

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.

[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.

Mechanisms of contextual control when contexts are informative to solve the task.

An experiment was conducted using a human instrumental learning task with the goal of evaluating the mechanisms underlying the deleterious effect of context-switching on responding to an unambiguous stimulus when contexts are informative to solve the task. Participants were trained in a context-based reversal discrimination in which two discriminative stimuli (X and Y) interchange their meaning across contexts A and B. In context A, discriminative stimulus Z consistently announced that the relationship between a specific instrumental response (RI) and a specific outcome (O1) was in effect. Performance in the presence of stimulus Z was equally deteriorated when the test was conducted outside the training context, regardless of whether the test context was familiar (context B) or new (context C). This result is consistent with the idea that participants code all the information presented in an informative context as context-specific with the context playing a role akin to an occasion setter.

Isolation and characterization of new facultative alkaliphilic Bacillus flexus strains from maize processing waste water (nejayote).

AIMS: This work describes the isolation and characterization of two new alkaliphilic micro-organisms present in nejayote. METHODS AND RESULTS: Samples of fresh industrial nejayote were plated on nejayote medium and incubated for 4 days at 37 °C. Isolates were identified based on morphological and physiological characteristics, as well as 16S rDNA sequence analysis. Two gram-positive strains, NJY2 and NJY4, able to hydrolyse starch, xylan, and gelatin were isolated from nejayote. Comparative sequence analysis of 16S rDNA and phylogenetic studies indicate that the micro-organisms studied were closely related to members of the Bacillus flexus species. The strains were identified as facultative alkaliphilic salt tolerant bacteria. Isolate NJY2 produced cell associated phenolic acid esterases, able to release ferulic acid from nixtamalised corn bran and ethyl and methyl esters. CONCLUSIONS: The isolated strains of B. flexus NJY2 and NJY4 showed important physiological properties to produce high-value molecules from agroindustrial by-products. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report about the isolation of alkaliphilic micro-organisms from nejayote and the first report of phenolic acid esterases synthesised by alkaliphiles. The new alkaliphilic micro-organisms have potential application in the treatment and transformation of tortilla industry residues.

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.