USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi-mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis

Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma

Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF MAPK pathway activation. Here, we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFb Smad signaling which is localised to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BRafV600E or KRASG12D knockin) and TGFb signaling ablation (through Tgfbr1 deletion) in Lgr5+ve stem cells enables rapid cSCC development in the mouse. Mutation of TP53 (which is commonly mutated in sporadic cSCC) coupled with TGFbR1 deletion in Lgr5+ve cells also results in cSCC development. These findings indicate that Lgr5+ve stem cells can act as a cell of origin for cSCC and that RAS-RAF-MAPK pathway hyperactivation or TP53 mutation, coupled with loss of TGFb signaling, are driving events of skin tumorigenesis

Helping Frontline Workers in Texas-A Framework for Resource Development

First responders disproportionately experience occupational stress when compared to the general population, and COVID-19 has exacerbated this stress. The nature of their duties as law enforcement officers, firefighters, and medics exposes them to repeated trauma, increasing their risk of developing a broad array of mental health issues, including post-traumatic stress disorder (PTSD), substance use disorder (SUD), and compassion fatigue. This paper describes the need for resources for frontline workers and provides a framework for creating and implementing resources. A team of interdisciplinary subject matter experts developed two major resources. The first resource was a 24/7 helpline to support first responders and healthcare workers experiencing substance use or mental health concerns. The second resource was the First Responders Educational Campaign, which developed and delivered focused training modules on useful topics covering substance use and mental health concerns as they pertain to this workforce. Utilizing core interprofessional principles, content was sourced from multiple disciplines and contrasting perspectives to provide a comprehensive understanding of mental health and substance use issues. The curriculum was designed so that the content was interdisciplinary, interprofessional, and accessible to audiences across disciplines and professions. After engaging more than 1500 individuals, resources developed here have augmented mental health and substance use support resources available to the target population

Nanoparticles in cigarette smoke; real-time undiluted measurements by a scanning mobility particle sizer

Cigarette smoke is a complex mixture of smoke constituents, often characterised by size-resolved particle distributions. Since descriptions of ultrafine particles <50 nm are absent, our aim was to explore the existence of these nanoparticles in fresh and undiluted cigarette smoke. We measured undiluted smoke particles real-time by a scanning mobility particle sizer with Faraday cup electrometer, integrated in our custom-made smoking machine. Cigarettes were smoked by 2 s puffs, 30 s puff intervals and 50 ml puff volume. We tested six different cigarettes (1–10 mg tar per cigarette) at ten particle size-ranges between 6 and 50 nm, and repeated measurements five times. The formation of nanoparticles in fresh cigarette smoke was observed over the entire range between 6 and 50 nm, and reproduced in all cigarettes. The highest mean yield was 8.8 × 109 (SD = 1.1 × 109) particles per cigarette at the largest particle size range by high-tar cigarettes. Nanoparticle counts appear to increase with particle size, claimed tar values and blocking of filter ventilation holes, and inversely with butt length. Fresh undiluted cigarette smoke contains large amounts of potentially toxic nanoparticles <50 nm. We recommend to further study nanoparticles in the characterisation of cigarette smoke

Struggle in the flood: tree responses to flooding stress in four tropical floodplain systems

This review examines species diversity and structural, physiological and biochemical characteristics associated with survival of annual deep flooding of trees in four contrasting tropical floodplain ecosystems

An update on the arrival direction studies made with data from the Pierre Auger Observatory

The search for anisotropies in the arrival directions of ultra-high-energy cosmic rays plays a key role in the efforts to understand their origin. The observed first-harmonic modulation in right ascension above 8EeV, detected by the Pierre Auger Observatory with a current significance of 6.9σ, suggests an extragalactic origin above this energy. Furthermore, there are indications, at the ∼4σ significance level, of anisotropies at intermediate angular scales, which are obtained when comparing the arrival directions against the distribution of potential sources from astrophysical catalogs, in particular that of nearby starburst galaxies, and around the Centaurus region. In this contribution, we present the status of the different searches for anisotropies at small, intermediate and large angular scales. We use the latest available data set, with 19 years of operation that has yielded 135,000km2yrsr of accumulated exposure, covering the sky at declinations from −90∘ to 45∘. At small and intermediate scales, we report updates of the all-sky blind search for localized excesses, the study around the Centaurus region, and the likelihood analysis with catalogs of candidate sources. We have also studied the regions of the sky from which the Telescope Array Collaboration has reported hints of excesses in their data and we find no significant effects in the same directions with a data set of comparable size. At large angular scales, the dipolar and quadrupolar amplitudes in energy bins are updated. We discuss the prospects of these searches, both in regards to increases in statistics and in relation to the future inclusion of event-by-event mass estimators in these analyses through the upgrade of the Observatory, AugerPrime

The performances of the upgraded surface detector stations of AugerPrime

The surface detector of the Pierre Auger Observatory is an array of 1,600 stations using a water Cherenkov detector (WCD) for particle detection. The array is undergoing a major upgrade known as AugerPrime that involves adding scintillator surface detectors (SSDs) and radio antennas to the existing WCDs. Each WCD is also equipped with a smaller photomultiplier tube added to the original ones. As part of the upgrade, underground muon detectors are being installed in an area with a higher density of surface detector stations. AugerPrime required the development of new electronics to process the signals from all the new detectors and handle a higher sampling rate, a more precise GPS receiver, an extended dynamic range, higher processing capacity, and improved monitoring systems and memory. The deployment of the SSDs on top of each surface detector station is currently completed together with the deployment of the new electronics. This contribution will present the first data from the upgraded stations, emphasizing the performances of the SSDs and the new electronics