Methodology and reliability of respiratory muscle assessment

The optimal method for respiratory muscle endurance (RME) assessment remains unclear. This study assessed the test-retest reliability of two RME-test methodologies. Fifteen healthy adults attended the laboratory on four occasions, separated by 5 ± 2 days, and completed each test in a random, “one on two” order. They performed spirometry testing, maximal respiratory pressure assessment and two different RME tests: an inspiratory resistive breathing (IRB) and an isocapnic hyperpnea endurance (IHE) test. Typical error, expressed as coefficient of variation, for IRB maximal inspiratory pressure (MIP) and IHE maximal ventilation were 12.21 (8.85–19.67) % and 10.73 (7.78–17.29) %, respectively. Intraclass correlation coefficients for the same parameters were 0.83 (0.46-0.94) and 0.80 (0.41-0.93), respectively. No correlations were found between RME parameters derived from the IHE and IRB tests (all p > 0.05). Significant positive correlations were found between both IRB and IHE outcomes and spirometry parameters, MIP and maximal expiratory pressure (p < 0.05).Given these results, IRB and IHE appear to be suitable for RME testing in healthy people, although they may reflect different physiological mechanisms (respiratory mechanics and respiratory muscle capacity for IHE test vs. inspiratory muscle capacity for IRB test). Future studies are therefore warranted that compare IRB and IHE tests in clinical settings

Travelling Randomly on the Poincar\'e Half-Plane with a Pythagorean Compass

A random motion on the Poincar\'e half-plane is studied. A particle runs on the geodesic lines changing direction at Poisson-paced times. The hyperbolic distance is analyzed, also in the case where returns to the starting point are admitted. The main results concern the mean hyperbolic distance (and also the conditional mean distance) in all versions of the motion envisaged. Also an analogous motion on orthogonal circles of the sphere is examined and the evolution of the mean distance from the starting point is investigated

FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1-9. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression

Random walks in the space of conformations of toy proteins

Monte Carlo dynamics of the lattice 48 monomers toy protein is interpreted as a random walk in an abstract (discrete) space of conformations. To test the geometry of this space, we examine the return probability $P(T)$, which is the probability to find the polymer in the native state after $T$ Monte Carlo steps, provided that it starts from the native state at the initial moment. Comparing computational data with the theoretical expressions for $P(T)$ for random walks in a variety of different spaces, we show that conformational spaces of polymer loops may have non-trivial dimensions and exhibit negative curvature characteristic of Lobachevskii (hyperbolic) geometry.Comment: 4 pages, 3 figure

β2-adrenergic signalling promotes cell migration by upregulating expression of the metastasis-associated molecule LYPD3

Metastasis is associated with poor prognosis in breast cancer. Although some studies suggest beta-blockers increase survival by delaying metastasis, others have been discordant. This study provides both insights into the anomalous findings and identifies potential biomarkers that may be treatment targets. Cell line models of basal-type and oestrogen receptor-positive breast cancer were profiled for basal levels of adrenoceptor gene/protein expression, and β2-adrenoceptor mediated cell behaviour including migration, invasion, adhesion, and survival in response to adrenoceptor agonist/antagonist treatment. Protein profiling and histology identified biomarkers and drug targets. Baseline levels of adrenoceptor gene expression are higher in basal-type rather than oestrogen receptor-positive cancer cells. Norepinephrine (NE) treatment increased invasive capacity in all cell lines but did not increase proliferation/survival. Protein profiling revealed the upregulation of the pro-metastatic gene Ly6/PLAUR Domain-Containing Protein 3 (LYPD3) in norepinephrine-treated MDA-MB-468 cells. Histology confirmed selective LYPD3 expression in primary and metastatic breast tumour samples. These findings demonstrate that basal-type cancer cells show a more aggressive adrenoceptor-β2-activated phenotype in the resting and stimulated state, which is attenuated by adrenoceptor-β2 inhibition. This study also highlights the first association between ADRβ2 signalling and LYPD3; its knockdown significantly reduced the basal and norepinephrine-induced activity of MCF-7 cells in vitro. The regulation of ADRβ2 signalling by LYPD3 and its metastasis promoting activities, reveal LYPD3 as a promising therapeutic target in the treatment of breast and other cancers

Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC

The time course of different neuromuscular adaptations to short‑term downhill running training and their specific relationships with strength gains

Purpose: Due to its eccentric nature, downhill running (DR) training has been suggested to promote strength gains through neuromuscular adaptations. However, it is unknown whether short-term chronic DR can elicit such adaptations. Methods: Twelve untrained, young, healthy adults (five women, seven men) took part in four weeks’ DR, comprising 10 sessions, with running speed equivalent to 60-65% maximal oxygen uptake (V̇O2max, assessed at weeks 0 and 4). Isometric and isokinetic knee-extensor maximal voluntary torque (MVT), vastus lateralis (VL) muscle morphology/architecture (anatomical cross-sectional area, ACSA; physiological CSA, PCSA; volume; fascicle length, Lf; pennation angle, PA) and neuromuscular activation (VL EMG) were assessed at weeks 0, 2 and 4. Results: MVT increased by 9.7-15.2% after four weeks (p<0.01). VL EMG during isometric MVT increased by 35.6±46.1% after four weeks (p<0.05) and correlated with changes in isometric MVT after two weeks (r=0.86, p=0.001). VL ACSA (+2.9±2.7% and +7.1±3.5%) and volume (+2.5±2.5% and +6.6±3.2%) increased after two and four weeks, respectively (p<0.05). PCSA (+3.8±3.3%), PA (+5.8±3.8%) and Lf (+2.7±2.2%) increased after four weeks (p<0.01). Changes in VL volume (r=0.67, p=0.03) and PCSA (r=0.71, p=0.01) correlated with changes in concentric MVT from two-to-four weeks. V̇O2max (49.4±6.2 vs. 49.7±6.3 mL∙kg-1∙min-1) did not change after four weeks (p=0.73). Conclusion: Just four weeks’ moderate-intensity DR promoted neuromuscular adaptations in young, healthy adults, typically observed after high-intensity eccentric resistance training. Neural adaptations appeared to contribute to most of the strength gains at two and four weeks, while muscle hypertrophy seemed to contribute to MVT changes from two-to-four weeks only