High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study

<p>Abstract</p> <p>Background</p> <p>To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses.</p> <p>Methods</p> <p>Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H₂O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured.</p> <p>Results</p> <p>Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed.</p> <p>Conclusions</p> <p>During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.</p

The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution

Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell translocation gene 1 (BTG1), in a large cohort of pediatric ALL cases. BTG1 was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the BTG1 gene, resulting in the expression of truncated BTG1 read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the BTG1 gene body in BCP-ALL cells, but not T-ALL cells. BTG1 deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the ETV6-RUNX1 and BCR-ABL1 positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional BTG1 deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that BTG1 deletions may act as “drivers” of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL

From clump to disc scales in W3 IRS4 A case study of the IRAM NOEMA large programme CORE

Context. High-mass star formation typically takes place in a crowded environment, with a higher likelihood of young forming stars affecting and being affected by their surroundings and neighbours, as well as links between different physical scales affecting the outcome. However, observational studies are often focused on either clump or disc scales exclusively. Aims. We explore the physical and chemical links between clump and disc scales in the high-mass star formation region W3 IRS4, a region that contains a number of different evolutionary phases in the high-mass star formation process, as a case-study for what can be achieved as part of the IRAM NOrthern Extended Millimeter Array (NOEMA) large programme named CORE: “Fragmentation and disc formation in high-mass star formation”. Methods. We present 1.4 mm continuum and molecular line observations with the IRAM NOEMA interferometer and 30 m telescope, which together probe spatial scales from ~0.3−20′′ (600−40 000 AU or 0.003−0.2 pc at 2 kpc, the distance to W3). As part of our analysis, we used XCLASS to constrain the temperature, column density, velocity, and line-width of the molecular emission lines. Results. The W3 IRS4 region includes a cold filament and cold cores, a massive young stellar object (MYSO) embedded in a hot core, and a more evolved ultra-compact (UC)H II region, with some degree of interaction between all components of the region that affects their evolution. A large velocity gradient is seen in the filament, suggesting infall of material towards the hot core at a rate of 10−3−10−4 M⊙ yr−1, while the swept up gas ring in the photodissociation region around the UCH II region may be squeezing the hot core from the other side. There are no clear indications of a disc around the MYSO down to the resolution of the observations (600 AU). A total of 21 molecules are detected, with the abundances and abundance ratios indicating that many molecules were formed in the ice mantles of dust grains at cooler temperatures, below the freeze-out temperature of CO (≲35 K). This contrasts with the current bulk temperature of ~50 K, which was obtained from H2CO. Conclusions. CORE observations allow us to comprehensively link the different structures in the W3 IRS4 region for the first time. Our results argue that the dynamics and environment around the MYSO W3 IRS4 have a significant impact on its evolution. This context would be missing if only high resolution or continuum observations were available

Interpreting and reporting ⁴⁰Ar/³⁹Ar geochronologic data

The ⁴⁰Ar/³⁹Ar dating method is among the most versatile of geochronometers, having the potential to date a broad variety of K-bearing materials spanning from the time of Earth’s formation into the historical realm. Measurements using modern noble-gas mass spectrometers are now producing ⁴⁰Ar/³⁹Ar dates with analytical uncertainties of ∼0.1%, thereby providing precise time constraints for a wide range of geologic and extraterrestrial processes. Analyses of increasingly smaller subsamples have revealed age dispersion in many materials, including some minerals used as neutron fluence monitors. Accordingly, interpretive strategies are evolving to address observed dispersion in dates from a single sample. Moreover, inferring a geologically meaningful “age” from a measured “date” or set of dates is dependent on the geological problem being addressed and the salient assumptions associated with each set of data. We highlight requirements for collateral information that will better constrain the interpretation of ⁴⁰Ar/³⁹Ar data sets, including those associated with single-crystal fusion analyses, incremental heating experiments, and in situ analyses of microsampled domains. To ensure the utility and viability of published results, we emphasize previous recommendations for reporting ⁴⁰Ar/³⁹Ar data and the related essential metadata, with the amendment that data conform to evolving standards of being findable, accessible, interoperable, and reusable (FAIR) by both humans and computers. Our examples provide guidance for the presentation and interpretation of ⁴⁰Ar/³⁹Ar dates to maximize their interdisciplinary usage, reproducibility, and longevity

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta - regulation by selective estrogen receptor modulators and importance in breast cancer

Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ERα and ERβ, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents

The feedback of an HC HII region on its parental molecular core: The case of core A1 in the star-forming region G24.78+0.08

Context: G24.78+0.08 is a well known high-mass star-forming region, where several molecular cores harboring OB young stellar objects are found inside a clump of size ≈1 pc. This article focuses on the most prominent of these cores, A1, where an intense hypercompact (HC) HII region has been discovered by previous observations. Aims: Our aim is to determine the physical conditions and the kinematics of core A1, and study the interaction of the HII region with the parental molecular core. Methods: We combine ALMA 1.4 mm high-angular resolution (≈0.′′2) observations of continuum and line emission with multi-epoch Very Long Baseline Interferometry data of water 22 GHz and methanol 6.7 GHz masers. These observations allow us to study the gas kinematics on linear scales from 10 to 104 au, and to accurately map the physical conditions of the gas over core A1. Results: The 1.4 mm continuum is dominated by free-free emission from the intense HC HII region (size ≈1000 au) observed to the North of core A1 (region A1N). Analyzing the H30α line, we reveal a fast bipolar flow in the ionized gas, covering a range of LSR velocities (VLSR) of ≈60 km s−1. The amplitude of the VLSR gradient, 22 km s−1 mpc−1, is one of the highest so far observed towards HC HII regions. Water and methanol masers are distributed around the HC HII region in A1N, and the maser three-dimensional (3D) velocities clearly indicate that the ionized gas is expanding at high speed (≥200 km s−1) into the surrounding molecular gas. The temperature distribution (in the range 100–400 K) over core A1, traced with molecular (CH3OCHO, 13CH3CN, 13CH3OH, and CH3CH2CN) transitions with level energy in the range 30 K ≤ Eu/k ≤ 300 K, reflects the distribution of shocks produced by the fast-expansion of the ionized gas of the HII region. The high-energy (550 K ≤ Eu/k ≤ 800 K) transitions of vibrationally excited CH3CN are likely radiatively pumped, and their rotational temperature can significantly differ from the kinetic temperature of the gas. Over core A1, the VLSR maps from both the 1.4 mm molecular lines and the 6.7 GHz methanol masers consistently show a VLSR gradient (amplitude ≈0.3 km s−1 mpc−1) directed approximately S–N. Rather than gravitationally supported rotation of a massive toroid, we interpret this velocity gradient as a relatively slow expansion of core A1

Clustered star formation at early evolutionary stages. Physical and chemical analysis of the young star-forming regions ISOSS J22478+6357 and ISOSS J23053+5953

We aim to characterize the physical and chemical properties of fragmented cores during the earliest evolutionary stages in the very young star-forming regions ISOSS J22478+6357 and ISOSS J23053+5953. NOEMA 1.3 mm data are used in combination with archival mid- and far-infrared observations to construct and fit the SEDs of individual fragmented cores. The radial density profiles are inferred from the 1.3 mm continuum visibility profiles and the radial temperature profiles are estimated from H2CO rotation temperature maps. Molecular column densities are derived with the line fitting tool XCLASS. The physical and chemical properties are combined by applying the physical-chemical model MUSCLE in order to constrain the chemical timescales of a few line-rich cores. The morphology and spatial correlations of the molecular emission are analyzed using the HOG method. The mid-infrared data show that both regions contain a cluster of young stellar objects. Bipolar molecular outflows are observed in the CO 2-1 transition toward the strong mm cores indicating protostellar activity. We find strong molecular emission of SO, SiO, H2CO, and CH3OH in locations which are not associated with the mm cores. These shocked knots can be either associated with the bipolar outflows or, in the case of ISOSS J23053+5953, with a colliding flow that creates a large shocked region between the mm cores. The mean chemical timescale of the cores is lower (20 000 yr) compared to that of the sources of the more evolved CORE sample (60 000 yr). With the HOG method, we find that the spatial emission of species tracing the extended emission and of shock-tracing molecules are well correlated within transitions of these groups

Gene expression profiling of alveolar soft-part sarcoma (ASPS)

<p>Abstract</p> <p>Background</p> <p>Alveolar soft-part sarcoma (ASPS) is an extremely rare, highly vascular soft tissue sarcoma affecting predominantly adolescents and young adults. In an attempt to gain insight into the pathobiology of this enigmatic tumor, we performed the first genome-wide gene expression profiling study.</p> <p>Methods</p> <p>For seven patients with confirmed primary or metastatic ASPS, RNA samples were isolated immediately following surgery, reverse transcribed to cDNA and each sample hybridized to duplicate high-density human U133 plus 2.0 microarrays. Array data was then analyzed relative to arrays hybridized to universal RNA to generate an unbiased transcriptome. Subsequent gene ontology analysis was used to identify transcripts with therapeutic or diagnostic potential. A subset of the most interesting genes was then validated using quantitative RT-PCR and immunohistochemistry.</p> <p>Results</p> <p>Analysis of patient array data versus universal RNA identified elevated expression of transcripts related to angiogenesis (ANGPTL2, HIF-1 alpha, MDK, c-MET, VEGF, TIMP-2), cell proliferation (PRL, IGFBP1, NTSR2, PCSK1), metastasis (ADAM9, ECM1, POSTN) and steroid biosynthesis (CYP17A1 and STS). A number of muscle-restricted transcripts (ITGB1BP3/MIBP, MYF5, MYF6 and TRIM63) were also identified, strengthening the case for a muscle cell progenitor as the origin of disease. Transcript differentials were validated using real-time PCR and subsequent immunohistochemical analysis confirmed protein expression for several of the most interesting changes (MDK, c-MET, VEGF, POSTN, CYP17A1, ITGB1BP3/MIBP and TRIM63).</p> <p>Conclusion</p> <p>Results from this first comprehensive study of ASPS gene expression identifies several targets involved in angiogenesis, metastasis and myogenic differentiation. These efforts represent the first step towards defining the cellular origin, pathogenesis and effective treatment strategies for this atypical malignancy.</p

Substructures in the Keplerian disc around the O-type (proto-)star G17.64+0.16

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