TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling

In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis ‘restrictive soil’ by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38)low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis ‘permissive soil’ with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a ‘seed and soil’ mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.Fil: Bragado, Paloma. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Estrada, Yeriel. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Parikh, Falguni. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Krause, Sarah. University Hospital of Schleswig-Holstein; AlemaniaFil: Capobianco, Carla Sabrina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Farina, Hernán Gabriel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schewe, Denis M.. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Aguirre Ghiso, Julio A.. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unido

Limited Systemic Sclerosis Patients with Pulmonary Arterial Hypertension Show Biomarkers of Inflammation and Vascular Injury

Pulmonary arterial hypertension (PAH) is a common complication for individuals with limited systemic sclerosis (lSSc). The identification and characterization of biomarkers for lSSc-PAH should lead to less invasive screening, a better understanding of pathogenesis, and improved treatment.Forty-nine PBMC samples were obtained from 21 lSSc subjects without PAH (lSSc-noPAH), 15 lSSc subjects with PAH (lSSc-PAH), and 10 healthy controls; three subjects provided PBMCs one year later. Genome-wide gene expression was measured for each sample. The levels of 89 cytokines were measured in serum from a subset of subjects by Multi-Analyte Profiling (MAP) immunoassays. Gene expression clearly distinguished lSSc samples from healthy controls, and separated lSSc-PAH from lSSc-NoPAH patients. Real-time quantitative PCR confirmed increased expression of 9 genes (ICAM1, IFNGR1, IL1B, IL13Ra1, JAK2, AIF1, CCR1, ALAS2, TIMP2) in lSSc-PAH patients. Increased circulating cytokine levels of inflammatory mediators such as TNF-alpha, IL1-beta, ICAM-1, and IL-6, and markers of vascular injury such as VCAM-1, VEGF, and von Willebrand Factor were found in lSSc-PAH subjects.The gene expression and cytokine profiles of lSSc-PAH patients suggest the presence of activated monocytes, and show markers of vascular injury and inflammation. These genes and factors could serve as biomarkers of PAH involvement in lSSc

The XQR-30 Metal Absorber Catalog: 778 Absorption Systems Spanning 2 < z < 6.5

Intervening metal absorption lines in the spectra of z > 6 quasars are fundamental probes of the ionization state and chemical composition of circumgalactic and intergalactic gas near the end of the reionization epoch. Large absorber samples are required to robustly measure typical absorber properties and to refine models of the synthesis, transport, and ionization of metals in the early Universe. The "Ultimate XSHOOTER legacy survey of quasars at z~5.8-6.6" (XQR-30) has obtained high signal-to-noise spectra of 30 luminous quasars, nearly quadrupling the existing sample of 12 high quality z~6 quasar spectra. We use this unprecedented sample to construct a catalog of 778 systems showing absorption in one or more of MgII (360 systems), FeII (184), CII (46), CIV (479), SiIV (127), and NV (13) which span 2 < z < 6.5. This catalog significantly expands on existing samples of z > 5 absorbers, especially for CIV and SiIV which are important probes of the ionizing photon background at high redshift. The sample is 50% (90%) complete for rest-frame equivalent widths W > 0.03AA (0.09AA). We publicly release the absorber catalog along with completeness statistics and a Python script to compute the absorption search path for different ions and redshift ranges. This dataset is a key legacy resource for studies of enriched gas from the era of galaxy assembly to cosmic noon, and paves the way for even higher redshift studies with the James Webb Space Telescope and 30m-class telescopes.Comment: 29 pages and 14 figures including 2 appendices. Accepted for publication in MNRAS. The metal absorber catalogue can be downloaded from https://github.com/XQR-30/Metal-catalogue. Contents unchanged from v1 apart from change to author lis

Chemical Abundance of z~6 Quasar Broad-Line Regions in the XQR-30 Sample

The elemental abundances in the broad-line regions of high-redshift quasars trace the chemical evolution in the nuclear regions of massive galaxies in the early universe. In this work, we study metallicity-sensitive broad emission-line flux ratios in rest-frame UV spectra of 25 high-redshift (5.8 < z < 7.5) quasars observed with the VLT/X-shooter and Gemini/GNIRS instruments, ranging over $\log(M_{\rm{BH}}/M_{\odot})= 8.4-9.8$ in black hole mass and $\log(L_{\rm{bol}}/\rm{erg\, s}^{-1})= 46.7-47.7$ in bolometric luminosity. We fit individual spectra and composites generated by binning across quasar properties: bolometric luminosity, black hole mass, and blueshift of the \civ\, line, finding no redshift evolution in the emission-line ratios by comparing our high-redshift quasars to lower-redshift (2.0 < z < 5.0) results presented in the literature. Using Cloudy-based locally optimally-emitting cloud photoionisation model relations between metallicity and emission-line flux ratios, we find the observable properties of the broad emission lines to be consistent with emission from gas clouds with metallicity that are at least 2-4 times solar. Our high-redshift measurements also confirm that the blueshift of the CIV emission line is correlated with its equivalent width, which influences line ratios normalised against CIV. When accounting for the CIV blueshift, we find that the rest-frame UV emission-line flux ratios do not correlate appreciably with the black hole mass or bolometric luminosity.Comment: MNRAS accepted, 24 pages, 17 figures, 4 table

The X-shooter/ALMA Sample of Quasars in the Epoch of Reionization. II. Black Hole Masses, Eddington Ratios, and the Formation of the First Quasars

We present measurements of black hole masses and Eddington ratios for a sample of 38 bright (M$_{1450}$ < -24.4 mag) quasars at 5.8 < z < 7.5, derived from VLT/X-shooter near-IR spectroscopy of their broad CIV and MgII emission lines. The black hole masses (on average M$_{BH}$ ~ 4.6 x 10$^9$ M$_{\odot}$) and accretion rates (with Eddington ratios ranging between 0.1 and 1.0) are broadly consistent with that of similarly luminous 0.3 < z < 2.3 quasars, but there is evidence for a mild increase in the median Eddington ratio going towards z > 6. Combined with deep ALMA observations of the [CII] 158 $\mu$m line from the quasar host galaxies and VLT/MUSE investigations of the extended Ly$\alpha$ halos, this study provides fundamental clues to models of the formation and growth of the first massive galaxies and black holes. Compared to local scaling relations, z > 5.7 black holes appear to be over-massive with respect to their host galaxies, and their accretion properties do not change with host galaxy morphology. Under the assumption that the kinematics of the T ~ 10$^4$ K gas, traced by the extended Ly$\alpha$ halos, are dominated by the gravitational potential of the dark matter halo, we report a similar relation between the black hole mass and circular velocity to the one reported for z ~ 0 galaxies. These results paint a picture where the first supermassive black holes reside in massive halos at z > 6 and lead the first stages of galaxy formation by rapidly growing in mass with a duty cycle of order unity. However, this duty cycle needs to drastically drop towards lower redshifts, while the host galaxies continue forming stars at a rate of hundreds of solar masses per year, sustained by the large reservoirs of cool gas surrounding them.Comment: Accepted for publication on AAS journals. 24 pages + appendices, 15 figures, 5 tables (including full list of z>5.7 quasars with MgII based black hole mass estimates). For access to the data and codes used in this work, please contact the author

A SPectroscopic survey of biased halos In the Reionization Era (ASPIRE): Impact of Galaxies on the CGM Metal Enrichment at z > 6 Using the JWST and VLT

We characterize the multiphase circumgalactic medium and galaxy properties at z = 6.0-6.5 in four quasar fields from the James Webb Space Telescope A SPectroscopic survey of biased halos In the Reionization Era (ASPIRE) program. We use the Very Large Telescope/X-shooter spectra of quasar J0305-3150 to identify one new metal absorber at z = 6.2713 with multiple transitions (OI, MgI, FeII and CII). They are combined with the published absorbing systems in Davies et al. (2023a) at the same redshift range to form of a sample of nine metal absorbers at z = 6.03 to 6.49. We identify eight galaxies within 1000 km s$^{-1}$ and 350 kpc around the absorbing gas from the ASPIRE spectroscopic data, with their redshifts secured by [OIII]($\lambda\lambda$4959, 5007) doublets and H$\beta$ emission lines. Our spectral energy distribution fitting indicates that the absorbing galaxies have stellar mass ranging from 10$^{7.2}$ to 10$^{8.8}M_{\odot}$ and metallicity between 0.02 and 0.4 solar. Notably, the z = 6.2713 system in the J0305-3150 field resides in a galaxy overdensity region, which contains two (tentatively) merging galaxies within 350 kpc and seven galaxies within 1 Mpc. We measure the relative abundances of $\alpha$ elements to iron ([$\alpha$/Fe]) and find that the CGM gas in the most overdense region exhibits a lower [$\alpha$/Fe] ratio. Our modeling of the galaxy's chemical abundance favors a top-heavy stellar initial mass function, and hints that we may be witnessing the contribution of the first generation Population III stars to the CGM at the end of reionization epoch.Comment: 21 pages, 4 figures in the main text. Accepted for publication in ApJ

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Quality of Neonatal Healthcare in Kilimanjaro Region, Northeast Tanzania: Learning from Mothers' Experiences.

With a decline of infant mortality rates, neonatal mortality rates are striking high in development countries particularly sub Saharan Africa. The toolkit for high quality neonatal services describes the principle of patient satisfaction, which we translate as mother's involvement in neonatal care and so better outcomes. The aim of the study was to assess mothers' experiences, perception and satisfaction of neonatal care in the hospitals of Kilimanjaro region of Tanzania. A cross sectional study using qualitative and quantitative approaches in 112 semi structured interviews from 14 health facilities. Open ended questions for detection of illness, care given to the baby and time spent by the health worker for care and treatment were studied. Probing of the responses was used to extract and describe findings by a mix of in-depth interview skills. Closed ended questions for the quantitative variables were used to quantify findings for statistical use. Narratives from open ended questions were coded by colours in excel sheet and themes were manually counted. 80 mothers were interviewed from 13 peripheral facilities and 32 mothers were interviewed at a zonal referral hospital of Kilimanjaro region. 59 mothers (73.8%) in the peripheral hospitals of the region noted neonatal problems and they assisted for attaining diagnosis after a showing a concern for a request for further investigations. 11 mothers (13.8%) were able to identify the baby's diagnosis directly without any assistance, followed by 7 mothers (8.7%) who were told by a relative, and 3 mothers (3.7%) who were told of the problem by the doctor that their babies needed medical attention. 24 times mothers in the peripheral hospitals reported bad language like "I don't have time to listen to you every day and every time." 77 mothers in the periphery (90.6%) were not satisfied with the amount of time spent by the doctors in seeing their babies. Mothers of the neonates play great roles in identifying the illness of the newborn. Mother's awareness of what might be needed during neonatal support strategies to improve neonatal care in both health facilities and the communities

ICPD to MDGs: Missing links and common grounds

The ICPD agenda of reproductive health was declared as the most comprehensive one, which had actually broadened the spectrum of reproductive health and drove the states to embark upon initiatives to improve reproductive health status of their populations. However, like all other countries, Pakistan also seems to have shifted focus of its policies and programs towards achieving MDGs. As a result, concepts highlighted in the ICPD got dropped eventually. In spite of specific goals on maternal and child mortalities in MDGs and all the investment and policy shift, Pakistan has still one of the highest maternal mortality ratios among developing countries. Lack of synchronized efforts, sector wide approaches, inter-sectoral collaboration, and moreover, the unmet need for family planning, unsafe abortions, low literacy rate and dearth of women empowerment are the main reasons. Being a signatory of both of the international agendas (ICPD and MDGs), Pakistan needed to articulate its policies to keep the balance between the two agendas. There are, however, certainly some common grounds which have been experimented by various countries and we can learn lessons from those best practices. An inter-sectoral cooperation and sector wide approaches would be required to achieve such ambitious goals set out in ICPD-Program of Action while working towards MDGs. There is a need of increasing resource allocation, strengthening primary health care services and emergency obstetric care and motivating the human resource employed in health sector by good governance. These endeavors should lead to formulate evidence based national policies, reproductive health services which are affordable, accessible and culturally acceptable and finally a responsive health system