Novel Proteolytic Microvesicles Released from Human Macrophages after Exposure to Tobacco Smoke

Cigarette smoking damages the extracellular matrix in a variety of locations, leading to atherosclerotic plaque instability and emphysematous lung destruction, but the underlying mechanisms remain poorly understood. Here, we sought to determine whether exposure of human macrophages, a key participant in extracellular matrix damage, to tobacco smoke extract (TSE) induces the release of microvesicles (MVs; or microparticles) with proteolytic activity; the major proteases involved; and the cellular mechanisms that might mediate their generation. We found that MVs released from TSE-exposed macrophages carry substantial gelatinolytic and collagenolytic activities that surprisingly can be predominantly attributed to a single transmembrane protease of the matrix metalloproteinase (MMP) superfamily (namely, MMP14). Flow cytometric counts revealed that exposure of human macrophages to TSE for 20 hours more than quadrupled their production of MMP14-positive MVs (control, 1112 ± 231; TSE-induced, 5823 ± 2192 MMP14-positive MVs/μL of conditioned medium; means ± SEM; n = 6; P < 0.01). Our results indicate that the production of these MVs by human macrophages relies on a series of regulated steps that include activation of two mitogen-activated protein kinases (MAPKs, i.e., the Jun N-terminal kinase and p38 MAPK), and then MAPK-dependent induction and maturation of cellular MMP14, a remarkable accumulation of MMP14 into nascent plasma membrane blebs, and finally caspase- and MAPK-dependent apoptosis and apoptotic microvesicle generation. Proteolytically active MVs induced by tobacco smoke may be novel mediators of clinical important matrix destruction in smokers

Evidence that the Nijmegen breakage syndrome protein, an early sensor of double-strand DNA breaks (DSB), is involved in HIV-1 post-integration repair by recruiting the ataxia telangiectasia-mutated kinase in a process similar to, but distinct from, cellular DSB repair

Retroviral transduction involves integrase-dependent linkage of viral and host DNA that leaves an intermediate that requires post-integration repair (PIR). We and others proposed that PIR hijacks the host cell double-strand DNA break (DSB) repair pathways. Nevertheless, the geometry of retroviral DNA integration differs considerably from that of DSB repair and so the precise role of host-cell mechanisms in PIR remains unclear. In the current study, we found that the Nijmegen breakage syndrome 1 protein (NBS1), an early sensor of DSBs, associates with HIV-1 DNA, recruits the ataxia telangiectasia-mutated (ATM) kinase, promotes stable retroviral transduction, mediates efficient integration of viral DNA and blocks integrase-dependent apoptosis that can arise from unrepaired viral-host DNA linkages. Moreover, we demonstrate that the ATM kinase, recruited by NBS1, is itself required for efficient retroviral transduction. Surprisingly, recruitment of the ATR kinase, which in the context of DSB requires both NBS1 and ATM, proceeds independently of these two proteins. A model is proposed emphasizing similarities and differences between PIR and DSB repair. Differences between the pathways may eventually allow strategies to block PIR while still allowing DSB repair

Improving the mental health and mental health support available to adolescents in out-of-home care via Adolescent-Focused Low-Intensity Life Story Work: a realist review

Objectives: Life Story Work (LSW) is used to promote the mental health and well-being of children and adolescents living in out-of-home care. LSW should be offered to all but is conventionally delivered in high-intensity ways. Low-intensity approaches are more accessible but there is significant variation and little guidance for supporting adolescents. We aimed to create guidance for Adolescent-Focused Low-Intensity LSW. // Design: Realist review. // Data sources: MEDLINE, Embase, PsycINFO, Sociology Collection (ProQuest), CINAHL, CDAS, Web of Science (SCIE, SSCI), Social Care Online and grey literature sources. Searches were performed between December 2021 and March 2022. // Eligibility criteria: Documents on children and adolescents in care, LSW and/or low-intensity interventions to improve mental health were included. Documents focusing on parenting style and contact with birth family were excluded. // Analysis: Documents were analysed using a realist logic of analysis. In consultation with Content Expert Groups (comprising professionals and care leavers), we developed an initial programme theory. Data relating to and challenging the initial programme theory were extracted and context-mechanism-outcome-configurations developed, critiqued and refined in an iterative fashion. Interpretations were drawn from context-mechanism-outcome-configurations to enhance the programme theory. // Results: 75 documents contributed to the analysis. Generally, studies were small-scale and lacked in-depth methods and evaluation descriptions. Findings indicated important factors contribute to the development of high-quality Adolescent-Focused Low-Intensity LSW. Adolescent-Focused Low-Intensity LSW should be person-centred, begin in the now, involve co-construction, record everyday positive life events and be supported by trained carer(s). Context-mechanism-outcome-configurations relating to these themes are reported. // Conclusions: Using this knowledge we developed initial practice guidance to support social care to deliver better quality Adolescent-Focused Low-Intensity LSW more consistently. To address gaps in our knowledge about the impact of Adolescent-Focused Low-Intensity LSW, further primary research is needed to strengthen understandings of how this intervention works (or not) in different contexts. // PROSPERO registration number: CRD42021279816

CYLD mutation characterizes a subset of HPV-positive head and neck squamous cell carcinomas with distinctive genomics and frequent cylindroma-like histologic features

Mutations in the tumor suppressor CYLD, known to be causative of cylindromas, were recently described in a subset of high-risk (hr) HPV-positive head and neck squamous cell carcinomas (HNSCC). Pathologic and genetic characterization of these CYLD-mutant carcinomas, however, remains limited. Here, we investigated whether CYLD mutations characterize a histopathologically and genomically distinct subset of hrHPV-positive HNSCC. Comprehensive genomic profiling via hybrid capture-based DNA sequencing was performed on 703 consecutive head and neck carcinomas with hrHPV sequences, identifying 148 unique cases (21%) harboring CYLD mutations. Clinical data, pathology reports, and histopathology were reviewed. CYLD mutations included homozygous deletions (n = 61/148; 41%), truncations (n = 52; 35%), missense (n = 26; 18%) and splice-site (n = 9; 6%) mutations, and in-frame deletion (n = 1; 1%). Among hrHPV-positive HNSCC, the CYLD-mutant cohort showed substantially lower tumor mutational burden than CYLD-wildtype cases (n = 555) (median 2.6 vs. 4.4 mut/Mb, p \u3c 0.00001) and less frequent alterations in PIK3CA (11% vs. 34%, p \u3c 0.0001), KMT2D (1% vs. 16%, p \u3c 0.0001), and FBXW7 (3% vs. 11%, p = 0.0018). Male predominance (94% vs. 87%), median age (58 vs. 60 years), and detection of HPV16 (95% vs. 89%) were similar. On available histopathology, 70% of CYLD-mutant HNSCC (98/141 cases) contained hyalinized material, consistent with basement membrane inclusions, within crowded aggregates of tumor cells. Only 7% of CYLD-wildtype cases demonstrated this distinctive pattern (p \u3c 0.0001). Histopathologic patterns of CYLD-mutant HNSCC lacking basement membrane inclusions included nonkeratinizing (n = 22, 16%), predominantly nonkeratinizing (nonkeratinizing SCC with focal maturation; n = 10, 7%), and keratinizing (n = 11, 8%) patterns. The latter two groups showed significantly higher frequency of PTEN alterations compared with other CYLD-mutant cases (38% [8/21] vs. 7% [8/120], p = 0.0004). Within our cohort of hrHPV-positive HNSCCs, CYLD mutations were frequent (21%) and demonstrated distinctive clinical, histopathologic, and genomic features that may inform future study of prognosis and treatment

Improving the mental health and mental health support available to adolescents with social care-experience via low-intensity life story work: A realist review protocol

Introduction: Adolescents are the fastest growing group entering social care and are most at risk of mental ill-health. Life Story Work (LSW) is an existing transdiagnostic intervention thought to improve the well-being and mental health of children and adolescents under the care of a local authority by assisting the processing of trauma. Yet LSW is poorly evidenced, lacks standardisation and focuses on younger children. LSW is also high-intensity, relying on specialist input over several months. Adolescent-focused low-intensity-LSW is a promising alternative. However, there is poor evidence on how LSW, let alone low-intensity-LSW should be delivered to adolescents. We aim to identify why, how, in what contexts, for whom and to what extent low-intensity-LSW interventions can be delivered to adolescents with care-experience. Methods and analysis: Undertaking a realist review, we will: (1) develop an initial programme theory (PrT) of adolescent-focused low-intensity-LSW by consulting with two key expert panels (care-experienced and professional stakeholders), and by searching the literature to identify existing relevant theories; (2) undertake a comprehensive literature search to identify secondary data to develop and refine our emerging PrT. Searches will be run between 12/2021-06/2022 in databases including MEDLINE, PsycINFO, ASSIA and relevant sources of grey literature; (3) select, extract and organise data; (4) synthesise evidence using a realist logic of analysis and undertake further iterative data searching and consultation with our expert panels; (5) write up and share the refined PrT with our expert panels for their final comments. From this process guidance will be developed to help improve the delivery of LSW to support the mental health needs of adolescents with care-experience. Ethics and dissemination: Ethical approval is not required. Dissemination will include input from expert panels. We will develop academic, practice and youth focused outputs targeting adolescents, their carers, social, healthcare, and educational professionals, academics, and policymakers. PROSPERO registration number: CRD42021279816

Mapping our Universe in 3D with MITEoR

Mapping our universe in 3D by imaging the redshifted 21 cm line from neutral hydrogen has the potential to overtake the cosmic microwave background as our most powerful cosmological probe, because it can map a much larger volume of our Universe, shedding new light on the epoch of reionization, inflation, dark matter, dark energy, and neutrino masses. We report on MITEoR, a pathfinder low-frequency radio interferometer whose goal is to test technologies that greatly reduce the cost of such 3D mapping for a given sensitivity. MITEoR accomplishes this by using massive baseline redundancy both to enable automated precision calibration and to cut the correlator cost scaling from N^2 to NlogN, where N is the number of antennas. The success of MITEoR with its 64 dual-polarization elements bodes well for the more ambitious HERA project, which would incorporate many identical or similar technologies using an order of magnitude more antennas, each with dramatically larger collecting area.Comment: To be published in proceedings of 2013 IEEE International Symposium on Phased Array Systems & Technolog

The Luminosity and Mass Functions of Low-Mass Stars in the Galactic Disk: I. The Calibration Region

We present measurements of the luminosity and mass functions of low-mass stars constructed from a catalog of matched Sloan Digital Sky Survey (SDSS) and 2 Micron All Sky Survey (2MASS) detections. This photometric catalog contains more than 25,000 matched SDSS and 2MASS point sources spanning ~30 square degrees on the sky. We have obtained follow-up spectroscopy, complete to J=16, of more than 500 low mass dwarf candidates within a 1 square degree sub-sample, and thousands of additional dwarf candidates in the remaining 29 square degrees. This spectroscopic sample verifies that the photometric sample is complete, uncontaminated, and unbiased at the 99% level globally, and at the 95% level in each color range. We use this sample to derive the luminosity and mass functions of low-mass stars over nearly a decade in mass (0.7 M_sun > M_* > 0.1 M_sun). We find that the logarithmically binned mass function is best fit with an M_c=0.29 log-normal distribution, with a 90% confidence interval of M_c=0.20--0.50. These 90% confidence intervals correspond to linearly binned mass functions peaking between 0.27 M_sun and 0.12 M_sun, where the best fit MF turns over at 0.17 M_sun. A power law fit to the entire mass range sampled here, however, returns a best fit of alpha=1.1 (where the Salpeter slope is alpha = 2.35). These results agree well with most previous investigations, though differences in the analytic formalisms adopted to describe those mass functions can give the false impression of disagreement. Given the richness of modern-day astronomical datasets, we are entering the regime whereby stronger conclusions can be drawn by comparing the actual datapoints measured in different mass functions, rather than the results of analytic analyses that impose structure on the data a priori. (abridged)Comment: Accepted for publication in the Astronomical Journal. 21 pages, emulateapj format, 12 figures. Figures 1, 4, 11 and 12 degraded for astroph; full resolution version available for download at http://www.cfa.harvard.edu/~kcovey

The Maunakea Spectroscopic Explorer Book 2018

(Abridged) This is the Maunakea Spectroscopic Explorer 2018 book. It is intended as a concise reference guide to all aspects of the scientific and technical design of MSE, for the international astronomy and engineering communities, and related agencies. The current version is a status report of MSE's science goals and their practical implementation, following the System Conceptual Design Review, held in January 2018. MSE is a planned 10-m class, wide-field, optical and near-infrared facility, designed to enable transformative science, while filling a critical missing gap in the emerging international network of large-scale astronomical facilities. MSE is completely dedicated to multi-object spectroscopy of samples of between thousands and millions of astrophysical objects. It will lead the world in this arena, due to its unique design capabilities: it will boast a large (11.25 m) aperture and wide (1.52 sq. degree) field of view; it will have the capabilities to observe at a wide range of spectral resolutions, from R2500 to R40,000, with massive multiplexing (4332 spectra per exposure, with all spectral resolutions available at all times), and an on-target observing efficiency of more than 80%. MSE will unveil the composition and dynamics of the faint Universe and is designed to excel at precision studies of faint astrophysical phenomena. It will also provide critical follow-up for multi-wavelength imaging surveys, such as those of the Large Synoptic Survey Telescope, Gaia, Euclid, the Wide Field Infrared Survey Telescope, the Square Kilometre Array, and the Next Generation Very Large Array.Comment: 5 chapters, 160 pages, 107 figure