Integrin β3 Crosstalk with VEGFR Accommodating Tyrosine Phosphorylation as a Regulatory Switch

Integrins mediate cell adhesion, migration, and survival by connecting intracellular machinery with the surrounding extracellular matrix. Previous studies demonstrated the importance of the interaction between β3 integrin and VEGF type 2 receptor (VEGFR2) in VEGF-induced angiogenesis. Here we present in vitro evidence of the direct association between the cytoplasmic tails (CTs) of β3 and VEGFR2. Specifically, the membrane-proximal motif around 801YLSI in VEGFR2 mediates its binding to non-phosphorylated β3CT, accommodating an α-helical turn in integrin bound conformation. We also show that Y747 phosphorylation of β3 enhances the above interaction. To demonstrate the importance of β3 phosphorylation in endothelial cell functions, we synthesized β3CT-mimicking Y747 phosphorylated and unphosphorylated membrane permeable peptides. We show that a peptide containing phospho-Y747 but not F747 significantly inhibits VEGF-induced signaling and angiogenesis. Moreover, phospho-Y747 peptide exhibits inhibitory effect only in WT but not in β3 integrin knock-out or β3 integrin knock-in cells expressing β3 with two tyrosines substituted for phenylalanines, demonstrating its specificity. Importantly, these peptides have no effect on fibroblast growth factor receptor signaling. Collectively these data provide novel mechanistic insights into phosphorylation dependent cross-talk between integrin and VEGFR2

Binarity at LOw Metallicity (BLOeM) The multiplicity properties and evolution of BAF-type supergiants

\ua9 The Authors 2025. Given the uncertain evolutionary status of blue supergiant stars, their multiplicity properties hold vital clues to better understand their origin and evolution. As part of The Binarity at LOw Metallicity (BLOeM) campaign in the Small Magellanic Cloud, we present a multi-epoch spectroscopic survey of 128 supergiant stars of spectral type B5–F5, which roughly correspond to initial masses in the 6–30 M range. The observed binary fraction for the B5–9 supergiants is 25 \ub1 6% (10 \ub1 4%) and 5 \ub1 2% (0%) for the A–F stars, which were found using a radial-velocity (RV) variability threshold of 5 km s−1 (10 km s−1) as a criterion for binarity. Accounting for observational biases, we find an intrinsic multiplicity fraction of less than 18% for the B5–9 stars and 8+−97% for the AF stars, for the orbital periods up to 103.5 days and mass ratios (q) in the 0.1 < q < 1 range. The large stellar radii of these supergiant stars prevent short orbital periods, but we demonstrate that this effect alone cannot explain our results. We assessed the spectra and RV time series of the detected binary systems and find that only a small fraction display convincing solutions. We conclude that the multiplicity fractions are compromised by intrinsic stellar variability, such that the true multiplicity fraction may be significantly smaller. Our main conclusions from comparing the multiplicity properties of the B5–9- and AF-type supergiants to that of their less evolved counterparts is that such stars cannot be explained by a direct evolution from the main sequence. Furthermore, by comparing their multiplicity properties to red supergiant stars, we conclude that the AF supergiant stars are neither progenitors nor descendants of red supergiants

Binarity at LOw Metallicity (BLOeM) Multiplicity properties of Oe and Be stars

\ua9 The Authors 2025. Context. Rapidly rotating classical OBe stars have been proposed as the products of binary interactions, and the fraction of Be stars with compact companions implies that at least some are. However, to constrain the interaction physics spinning up the OBe stars, a large sample of homogeneously analyzed OBe stars with well-determined binary characteristics and orbital parameters are required. Aims. We investigated the multiplicity properties of a sample of 18 Oe, 62 Be, and two Of?p stars observed within the BLOeM survey in the Small Magellanic Cloud. We analyzed the first nine epochs of spectroscopic observations obtained over approximately three months in 2023. Methods. Radial velocities (RVs) of all stars were measured using cross-correlation based on different sets of absorption and emission lines. Applying commonly used binarity criteria, we classified objects as binaries, binary candidates, and apparently single (RV stable) objects. We further inspected the spectra for double-lined spectroscopic binaries and cross-matched with catalogs of X-ray sources and photometric binaries. Results. We classify 14 OBe stars as binaries, and an additional 11 as binary candidates. The two Of?p stars are apparently single. We find two more objects that are most likely currently interacting binaries. Without those, the observed binary fraction for the remaining OBe sample of 78 stars is fOBeobs = 0.18 \ub1 0.04 (fOBeobs+cand = 0.32\ub10.05 including candidates). This binary fraction is less than half of that measured for OB stars in BLOeM. Combined with the lower fraction of SB2s, this suggests that OBe stars do indeed have fundamentally different present-day binary properties than OB stars. We find no evidence for OBe binaries with massive compact companions, in contrast to expectations from binary population synthesis. Conclusions. Our results support the binary scenario as an important formation channel for OBe stars, as post-interaction binaries may have been disrupted or the stripped companions of OBe stars are harder to detect. Further observations are required to characterize the detected binaries, their orbital parameters, and the nature of their companions

Caspase Inhibition Blocks Cell Death and Enhances Mitophagy but Fails to Promote T-Cell Lymphoma

Caspase-9 is a component of the apoptosome that mediates cell death following release of cytochrome c from mitochondria. Inhibition of Caspase-9 with a dominant negative construct (Casp9DN) blocks apoptosome function, promotes viability and has been implicated in carcinogenesis. Inhibition of the apoptosome in vitro impairs mitochondrial function and promotes mitophagy. To examine whether inhibition of the apoptosome would enhance mitophagy and promote oncogenesis in vivo, transgenic mice were generated that express Casp9DN in the T cell lineage. The effects of Casp9DN on thymocyte viability, mitophagy and thymic tumor formation were examined. In primary thymocytes, Casp9DN delayed dexamethasone (Dex)-induced cell death, altered mitochondrial structure, and decreased oxidant production. Transmission electron microscopy (TEM) revealed that inhibition of the apoptosome resulted in structurally abnormal mitochondria that in some cases were engulfed by double-membrane structures resembling autophagosomes. Consistent with mitochondria being engulfed by autophagosomes (mitophagy), confocal microscopy showed colocalization of LC3-GFP and mitochondria. However, Casp9DN did not significantly accelerate T-cell lymphoma alone, or in combination with Lck-Bax38/1, or with Beclin 1+/− mice, two tumor-prone strains in which altered mitochondrial function has been implicated in promoting tumor development. In addition, heterozygous disruption of Beclin 1 had no effect on T-cell lymphoma formation in Lck-Bax38/1 mice. Further studies showed that Beclin 1 levels had no effect on Casp9DN-induced loss of mitochondrial function. These results demonstrate that neither inhibition of apoptosome function nor Beclin 1 haploinsufficiency accelerate T-cell lymphoma development in mice

Binarity at LOw Metallicity (BLOeM): A spectroscopic VLT monitoring survey of massive stars in the SMC

\ua9 The Authors 2024.Surveys in the Milky Way and Large Magellanic Cloud have revealed that the majority of massive stars will interact with companions during their lives. However, knowledge of the binary properties of massive stars at low metallicity, and therefore in conditions approaching those of the Early Universe, remain sparse. We present the Binarity at LOw Metallicity (BLOeM) campaign, an ESO large programme designed to obtain 25 epochs of spectroscopy for 929 massive stars in the Small Magellanic Cloud, allowing us to probe multiplicity in the lowest-metallicity conditions to date (Z = 0.2 Z⊙). BLOeM will provide (i) the binary fraction, (ii) the orbital configurations of systems with periods of P ≲ 3 yr, (iii) dormant black-hole binary candidates (OB+BH), and (iv) a legacy database of physical parameters of massive stars at low metallicity. Main sequence (OB-type) and evolved (OBAF-type) massive stars are observed with the LR02 setup of the GIRAFFE instrument of the Very Large Telescope (3960- 4570 \uc5 resolving power R = 6200; typical signal-to-noise ratio(S/N) ≈70- 100). This paper utilises the first nine epochs obtained over a three-month time period. We describe the survey and data reduction, perform a spectral classification of the stacked spectra, and construct a Hertzsprung-Russell diagram of the sample via spectral-type and photometric calibrations. Our detailed classification reveals that the sample covers spectral types from O4 to F5, spanning the effective temperature and luminosity ranges 6.5 ≲ Teff/kK ≲ 45 and 3.7 < log L/L⊙ < 6.1 and initial masses of 8 ≲ Mini ≲ 80 M⊙. The sample comprises 159 O-type stars, 331 early B-type (B0- 3) dwarfs and giants (luminosity classes V- III), 303 early B-type supergiants (II- I), and 136 late-type BAF supergiants. At least 82 stars are OBe stars: 20 O-type and 62 B-type (13% and 11% of the respective samples). In addition, the sample includes 4 high-mass X-ray binaries, 3 stars resembling luminous blue variables, 2 bloated stripped-star candidates, 2 candidate magnetic stars, and 74 eclipsing binaries

MAPK pathway activation in pilocytic astrocytoma

Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA when compared with other CNS tumors has diagnostic utility. In addition, the frequency of alteration of this key pathway provides an opportunity for molecularly targeted therapy in this tumor. Here, we review the current knowledge on mechanisms of MAPK activation in PA and some of the downstream consequences of this activation, which are now starting to be elucidated both in vitro and in vivo, as well as clinical considerations and possible future directions

The interaction between asthma and anxiety:An interpretative phenomenological analysis of young people’s experiences

Asthma and anxiety are highly co-morbid, and their interaction leads to exacerbations for both conditions. This study explored the interplay between these two conditions from the perspective of children and adolescents. The objective was to identify potential mechanisms of interaction between asthma and anxiety, and to derive improvements for prevention and treatment. Eleven semi-structured interviews of young people (aged 11-15), who met criteria for both asthma and anxiety, were analysed using interpretative phenomenological analysis. Well-established qualitative research recommendations were followed to promote credibility and rigour in the findings. Eight themes emerged, that were organised in three domains: i) asthma affecting anxiety by inhibiting coping activities or developmental tasks and by triggering unhelpful thinking and behaviour; ii) anxiety affecting asthma by impairing self-care and triggering hyperventilation; iii) interactions between asthma and anxiety, including self-perpetuating feedback cycles and symptom confusion. The proposed mechanisms could help tailor cognitive-behavioural interventions to reduce anxiety and asthma complications.<br/

Impact of comorbid conditions on asthmatic adults and children

Comorbid conditions (comorbidities) can complicate the diagnosis and management of asthma. In different age groups, comorbid conditions can present varying challenges, including diagnostic confusion due to mimicking asthma symptoms, exacerbation of asthma symptoms, therapy for comorbid conditions affecting asthma or therapy for asthma affecting these conditions. This review aims to summarise some common comorbid conditions with asthma, such as rhinitis, vocal cord dysfunction, gastro-oesophageal reflux, psychiatric disorders, obesity and obstructive sleep apnoea, and discuss their prevalence, symptoms, diagnosis and treatment, highlighting any differences in how they impact children and adults. Overall, there is a lack of data on the impact of treating comorbid conditions on asthma outcomes and further studies are needed to guide age-appropriate asthma management in the presence of these conditions.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.A.K. reports personal fees from AstraZeneca, Behring, Boehringer Ingelheim, GlaxoSmithKline, Griffols, Teva, Novartis, Novo Nordisk, Paladdin, Pfizer, Purdue, Sanofi and Trudel, outside the submitted work. D.M.G.H. reports personal fees from AstraZeneca, Chiesi and Pfizer and grants and personal fees from Boehringer Ingelheim, GlaxoSmithKline and Novartis, outside the submitted work. S.J.S. reports fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Propeller Health, Regeneron and Sanofi, outside the submitted work all paid to the University of Colorado School of Medicinepublished version, accepted version, submitted versio