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Sea louse ectoparasitosis is a major threat to fish aquaculture. Avermectins such as ivermectin and emamectin have been effectively used against sea louse infestation, but the emergence of resistance has limited their use. A better understanding of the molecular targets of avermectins is essential to the development of novel treatment strategies or new, more effective drugs. Avermectins are known to act by inhibiting neurotransmission through allosteric activation of glutamate-gated chloride channels (GluCls). We have investigated the GluCl subunit present in Caligus rogercresseyi , a sea louse affecting aquaculture in the Southern hemisphere. We identify four new subunits, CrGluCl-B to CrGluCl-E, and characterise them functionally. CrGluCl-A (previously reported as CrGluClα), CrGluCl-B and CrGluCl-C all function as glutamate channel receptors with different sensitivities to the agonist, but in contrast to subunit -A and -C, CrGluCl-B is not activated by ivermectin but is rather antagonised by the drug. CrGluCl-D channel appears active in the absence of any stimulation by glutamate or ivermectin and CrGluCl-E does not exhibit any activity. Notably, the expression of CrGluCl-B with either -A or -C subunits gives rise to receptors unresponsive to ivermectin and showing altered response to glutamate, suggesting that coexpression has led to the preferential formation of heteromers to which the presence of CrGluCl-B confers the property of ivermectin-activation refractoriness. Furthermore, there was evidence for heteromer formation with novel properties only when coexpressing pairs E/C and D/B CrGluCl subtypes. Site-directed mutagenesis shows that three transmembrane domain residues contribute to the lack of activation by ivermectin, most crucially Gln 15’ in M2, with mutation Q15’T (the residue present in ivermectin-activated subunits A and C) conferring ivermectin activation to CrGluCl-B. The differential response to avermectin of these Caligus rogercresseyi GluClsubunits, which are highly conserved in the Northern hemisphere sea louse Lepeophtheirus salmonis , could have an influence on the response of these parasites to treatment with macrocyclic lactones. They could serve as molecular markers to assess susceptibility to existing treatments and might be useful molecular targets in the search for novel antiparasitic drugs.

T-cell exhaustion contributes to immunotherapy failure in chronic lymphocytic leukemia (CLL). Here, we analyze T cells from CLL patients’ blood, bone marrow, and lymph nodes, as well as from a CLL mouse model, using single-cell RNA sequencing, mass cytometry, and tissue imaging. T cells in CLL lymph nodes show the most distinct profiles, with accumulation of regulatory T cells and CD8 + T cells in various exhaustion states, including precursor (T PEX ) and terminally exhausted (T EX ) cells. Integration of T-cell receptor sequencing data and use of the predicTCR classifier suggest an enrichment of CLL-reactive T cells in lymph nodes. Interactome studies reveal potential immunotherapy targets, notably galectin-9, a TIM3 ligand. Inhibiting galectin-9 in mice reduces disease progression and TIM3 + T cells. Galectin-9 expression also correlates with worse survival in CLL and other cancers, suggesting its role in immune evasion and potential as a therapeutic target. Multi-omics can be used to characterise tumour and immune cell populations. Here the authors use multi-omics to characterise CLL blood and tissue samples and use prediction models for CLL TCR specificity and implicate interactions between galectin-9 and TIM3 as involved in CLL immune escape and propose galectin-9 as a possible immunotherapy target.

Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders 1 . Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases 2 . This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system 3 , 4 , 5 , 6 . Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2 , underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome 7 , 8 ). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity 9 to the protein networks implicated in neurodegeneration and parkinsonism.

Kir7.1 is an inwardly rectifying K+ channel of the Kir superfamily encoded by the kcnj13 gene. Kir7.1 is present in epithelial tissues where it colocalizes with the Na+/K+-pump probably serving to recycle K+ taken up by the pump. Human mutations affecting Kir7.1 are associated with retinal degeneration diseases. We generated a mouse lacking Kir7.1 by ablation of the Kcnj13 gene. Homozygous mutant null mice die hours after birth and show cleft palate and moderate retardation in lung development. Kir7.1 is expressed in the epithelium covering the palatal processes at the time at which palate sealing takes place and our results suggest it might play an essential role in late palatogenesis. Our work also reveals a second unexpected role in the development and the physiology of the respiratory system, where Kir7.1 is expressed in epithelial cells all along the respiratory tree.

This study aimed to test whether the Behavioral Regulation in Sport Questionnaire and the Behavioral Regulation in Exercise Questionnaire can measure the same constructs in an equivalent manner. Advanced statistical procedures were used to examine if these scales could be interchangeably applied to the sport and the exercise context. In total, 2256 individuals (athletes = 1099; exercisers = 1157) completed translated and validated questionnaires measuring all types of motivation based on Self-Determination Theory. Several measurement models were tested, such as confirmatory factor models, exploratory structural equation models, and bifactor specifications. The exploratory structural equation modelling approach provided the best fit to the data in both groups. Multigroup analysis was performed within samples and between athletes and exercisers. Measurement model invariance was confirmed between samples from the same context; however, it did not achieve equivalence between scales. We hope this examination of context invariance analysis using specific validated scales can further help advance conceptual understanding of the measurement in sport and exercise.

Nearly 70% of cystic fibrosis (CF) patients bear the phenylalanine-508 deletion but disease severity differs greatly, and is not explained by the existence of different mutations in compound heterozygous. Studies demonstrated that genes other than CFTR relate to intestinal disease in humans and CF-mouse. Kcnn4 , the gene encoding the calcium-activated potassium channel K Ca 3.1, important for intestinal secretion, is present in a locus linked with occurrence of intestinal CF-disease in mice and humans. We reasoned that it might be a CF-modifier gene and bred a CF-mouse with Kcnn4 silencing, finding that lethality was almost abolished. Silencing of Kcnn4 did not improve intestinal secretory functions, but rather corrected increased circulating TNF-α level and reduced intestinal mast cell increase. Given the importance of mast cells in intestinal disease additional double mutant CF-animals were tested, one lacking mast cells ( C-kit W-sh/W-sh ) and Stat6 −/− to block IgE production. While mast cell depletion had no effect, silencing Stat6 significantly reduced lethality. Our results show that Kcnn4 is an intestinal CF modifier gene partially acting through a STAT6-dependent mechanism.

This study aimed to translate and validate the Learning and Performance Oriented in Physical Education Climate Questionnaire (LAPOPECQ) in a sample of Portuguese students. Additionally, this study examined if the measurement would be equivalent across samples and gender. For nomological validity, current study examined the relationships of motivational climates oriented by teachers and peers and behavioral regulations in the physical education context. Data from 536 Portuguese students (female = 256) aged 10 and 18 years (M = 13.33; SD = .47) were collected. Participants were involved in regular physical education classes two times per week, according to the Portuguese educational system. The four-correlated factor confirmatory and exploratory model provided acceptable fit to the data. In addition, multigroup analysis showed invariance among groups, namely between calibration and validation samples, and female and male students. Last, significant correlations were found between motivational climates and behavioral regulations as theoretically proposed, confirming nomological validity. The translated LAPOPECQ into Portuguese is a valid instrument assessing students’ perception of motivational climates oriented by teachers and peers.

The FCC-ee machines present a huge challenge for the RF systems, which need to be adapted to very diverse beam conditions going from moderate energy and high current for the Z machine to high energy and low beam current for the ttbar. This inverse scaling results naturally from a fixed budget for the synchrotron radiation, which the SRF cavities need to compensate. A global solution was elaborated for the FCC Conceptual Design Report (Abada in Eur Phys J Spec Top 228):261–623, 2019), and is referred here as the baseline. Recently, further studies have led to a new optimized baseline, still based on traditional elliptical cavities. In parallel, a novel concept, named the Slotted Waveguide ELLiptical (SWELL), was proposed with the potential of greatly simplified logistics and reduced costs. Under several aspects, all these changes call for enhanced performance of the RF systems. A vigorous R&D program has therefore continued since the publication of the CDR, with the aim of pushing the performance and demonstrating the feasibility of a more advanced baseline and, more recently, of the SWELL option. The progress and challenges of this ambitious program were presented in the dedicated SRF sessions at FCC week 2022 (FCC week 2022 website, 2022, https://indico.cern.ch/event/1064327/timetable/) and are summarized in this paper.

Conceptualizing an exercise program according to exercisers motives seems to be crucial. Thus, adequate and validated scale assessing motives for physical activity is necessary. This study aimed to translate and validate the Exercise Motives Inventory – 2 (EMI-2), a scale assessing fourteen motives for regular physical activity in Portuguese exercisers. In addition, comparison of motives between groups were made according to gender, age, and fitness activity. For scale validation, data from two independent samples were collected: calibration (n = 820; female = 499) and validation (n = 733; female = 451) participants. For scale reliability and mean difference analysis, data from a new sample was collected (n = 515; female = 342). Results showed that data did not fit the original 51-item model. After reviewing item loadings, two items were eliminated, since they presented factor loadings below acceptable. Hence, the revised model encompassing 49-item had an adequate fit. Convergent and discriminant validity was achieved in the revised model, displaying acceptable construct validity. In addition, invariance criteria were respected between female and male Portuguese exercisers. Regarding mean comparison analysis, differences were found between gender, and across age and fitness activities. Nevertheless, in overall the majority of exercisers indicated “general health” and “physiological” motives as the most valued. The EMI-2 is a reliable scale assessing motives in Portuguese exercisers. This study suggests that exercise programs should be conceptualized considering motives, but also gender, age, and fitness activity.

The aim of the present study was to translate and adapt the Preference for and Tolerance of the Intensity of Exercise Questionnaire to Portuguese (PRETIE-Q-PT), and to analyze its psychometric properties (factorial validity with gender invariance analyses, reliability, temporal stability, and construct validity). The sample was composed of 445 Portuguese participants (55.9% women), with a mean age of 29.6 years (SD = 8.2). To verify the psychometric properties of the scale, structural equation modeling procedures were used. Results showed that an abbreviated 10-item scale presented good fit, reliability, and convergent validity. Latent mean analysis between samples, sex, and time points showed no differences. Construct validity tested with self-reported exercise frequency, vitality, well-being, and habit supported the use of the PRETIE-Q-PT in exercise settings, highlighting the need for exercise professionals to consider these intensity-related trait variables in the promotion of a pleasant exercise experience. As a general conclusion, the PRETIE-Q-PT seems to be a valid scale that can be used to assess intensity-trait characteristics in health club exercisers, and may allow professionals to better adjust exercise prescription to subjective needs aiming to achieve theoretically suggested promotion of pleasurable exercise experiences.