We identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and PLP1 loci. These complex rearrangements were characterized by ...a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only two breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products share a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. We provide evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by >300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. A similar inverted repeat-mediated mechanism may underlie structural variation in many other regions of the human genome. We propose a mechanism that involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
Corticosteroids remain the first‐line treatment for patients with immune thrombocytopenia (ITP). However, 20% to 30% of patients do not respond to treatment at tolerable doses. This ...variation in corticosteroid efficacy is replicated in other autoimmune diseases and may have an adaptive immune basis.
Objective
To test the hypothesis that CD4+ T‐cell responses to corticosteroids are different in patients with clinically defined corticosteroid refractory ITP.
Methods
In this prospective cohort study, CD4+ T cells from patients with ITP were cultured in the presence or absence of dexamethasone (Dex). Intracellular cytokine expression was then quantified by flow cytometry and compared with patients’ clinical response to corticosteroid treatment. A control cohort of patients with autoimmune uveitis was also studied to evaluate whether our findings were limited to ITP or are potentially generalizable across autoimmune diseases.
Results
The ratio of interleukin (IL)‐10 to IL‐17 expression following CD4+ T cell culture with Dex was able to discriminate between ITP patients with a clinically defined complete (n = 33), partial (n = 12) or nonresponse (n = 11) to corticosteroid treatment (P = .002). These findings were replicated in patients with autoimmune uveitis (complete response n = 14, nonresponse n = 22; P = .01).
Conclusions
There is a relative abrogation of IL‐10 and persistence of IL‐17 expression in the CD4+ T cells of patients who clinically fail corticosteroid therapy. This observation has potential to inform both our mechanistic understanding of the action of corticosteroids in the treatment of ITP, and as a biomarker for steroid refractory disease, with potential application across a range of hematological and nonhematological conditions.
ABSTRACT
We present results from our analysis of the Hydra I cluster observed in neutral atomic hydrogen (H i) as part of the Widefield ASKAP L-band Legacy All-sky Blind Survey (WALLABY). These ...WALLABY observations cover a 60-square-degree field of view with uniform sensitivity and a spatial resolution of 30 arcsec. We use these wide-field observations to investigate the effect of galaxy environment on H i gas removal and star formation quenching by comparing the properties of cluster, infall, and field galaxies extending up to ∼5R200 from the cluster centre. We find a sharp decrease in the H i-detected fraction of infalling galaxies at a projected distance of ∼1.5R200 from the cluster centre from $\sim 85{{\ \rm per\ cent}}$ to $\sim 35{{\ \rm per\ cent}}$. We see evidence for the environment removing gas from the outskirts of H i-detected cluster and infall galaxies through the decrease in the H i to r-band optical disc diameter ratio. These galaxies lie on the star-forming main sequence, indicating that gas removal is not yet affecting the inner star-forming discs and is limited to the galaxy outskirts. Although we do not detect galaxies undergoing galaxy-wide quenching, we do observe a reduction in recent star formation in the outer disc of cluster galaxies, which is likely due to the smaller gas reservoirs present beyond the optical radius in these galaxies. Stacking of H i non-detections with H i masses below $M_{\rm {HI}}\lesssim 10^{8.4}\, \rm {M}_{\odot }$ will be required to probe the H i of galaxies undergoing quenching at distances ≳60 Mpc with WALLABY.
For livestock production systems to play a positive role in global food security, the balance between their benefits and disbenefits to society must be appropriately managed. Based on the evidence ...provided by field-scale randomised controlled trials around the world, this debate has traditionally centred on the concept of economic-environmental trade-offs, of which existence is theoretically assured when resource allocation is perfect on the farm. Recent research conducted on commercial farms indicates, however, that the economic-environmental nexus is not nearly as straightforward in the real world, with environmental performances of enterprises often positively correlated with their economic profitability. Using high-resolution primary data from the North Wyke Farm Platform, an intensively instrumented farm-scale ruminant research facility located in southwest United Kingdom, this paper proposes a novel, information-driven approach to carry out comprehensive assessments of economic-environmental trade-offs inherent within pasture-based cattle and sheep production systems. The results of a data-mining exercise suggest that a potentially systematic interaction exists between ‘soil health’, ecological surroundings and livestock grazing, whereby a higher level of soil organic carbon (SOC) stock is associated with a better animal performance and less nutrient losses into watercourses, and a higher stocking density with greater botanical diversity and elevated SOC. We contend that a combination of farming system-wide trials and environmental instrumentation provides an ideal setting for enrolling scientifically sound and biologically informative metrics for agricultural sustainability, through which agricultural producers could obtain guidance to manage soils, water, pasture and livestock in an economically and environmentally acceptable manner. Priority areas for future farm-scale research to ensure long-term sustainability are also discussed.
Abstract
The Southern hemisphere of the 67P/Churyumov–Gerasimenko comet has become visible from Rosetta only since 2015 March. It was illuminated during the perihelion passage and therefore it ...contains the regions that experienced the strongest heating and erosion rates, thus exposing the sub-surface most pristine material. In this work we investigate, thanks to the OSIRIS images, the geomorphology, the spectrophotometry and some transient events of two Southern hemisphere regions: Anhur and part of Bes. Bes is dominated by outcropping consolidated terrain covered with fine particle deposits, while Anhur appears strongly eroded with elongated canyon-like structures, scarp retreats, different kinds of deposits and degraded sequences of strata indicating a pervasive layering. We discovered a new 140 m long and 10 m high scarp formed in the Anhur–Bes boundary during/after the perihelion passage, close to the area where exposed CO2 and H2O ices were previously detected. Several jets have been observed originating from these regions, including the strong perihelion outburst, an active pit and a faint optically thick dust plume. We identify several areas with a relatively bluer slope (i.e. a lower spectral slope value) than their surroundings, indicating a surface composition enriched with some water ice. These spectrally bluer areas are observed especially in talus and gravitational accumulation deposits where freshly exposed material had fallen from nearby scarps and cliffs. The investigated regions become spectrally redder beyond 2 au outbound when the dust mantle became thicker, masking the underlying ice-rich layers.
In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum ...histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria.
Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log(10) plasma PfHRP2 and risk of death. Mortality increased 20% per log(10) increase in PfHRP2 above 174 ng/mL (adjusted odds ratio AOR 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings.
Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neonatologists can use echocardiography for real-time assessment of the hemodynamic state of neonates to support clinical decision-making. There is a large body of evidence showing the shortcomings ...of conventional echocardiographic indices in neonates. Newer imaging modalities have evolved. Tissue Doppler imaging is a new technique that can provide measurements of myocardial movement and timing of myocardial events and may overcome some of the shortcomings of conventional techniques. The high time resolution and its ability to assess left and right cardiac function make tissue Doppler a favorable technique for assessing heart function in neonates. The aim of this review is to provide an up-to-date overview of tissue Doppler techniques for the assessment of cardiac function in the neonatal context, with focus on measurements from the atrioventricular (AV) plane. We discuss basic concepts, protocol for assessment, feasibility, and limitations, and we report reference values and give examples of its use in neonates.
Aims. Hydrocarbons are ubiquitous in the interstellar medium, but their formation is still not well understood, depending on the physical environment in which they are found. Messier 8 (M8) is host ...to one of the brightest H II regions and photodissociation regions (PDRs) in our galaxy. With the observed C2H and c-C3H2 data toward M8, we aim at obtaining their densities and abundances and to shed some light on their formation mechanism. Methods. Using the Atacama Pathfinder Experiment (APEX) 12 m, and the Institut de Radioastronomie Millimétrique (IRAM) 30 m telescopes, we performed a line survey toward Herschel 36 (Her 36), which is the main ionizing stellar system in M8, and an imaging survey within 1.3 × 1.3 pc around Her 36 of various transitions of C2H and c-C3H2. We used both local thermodynamic equilibrium (LTE) and non-LTE methods to determine the physical conditions of the emitting gas along with the column densities and abundances of the observed species, which we compared with (updated) gas-phase photochemical PDR models. In order to examine the role of polycyclic aromatic hydrocarbons (PAHs) in the formation of small hydrocarbons and to investigate their association with the H II region, the PDR and the molecular cloud, we compared archival Galactic Legacy Infrared Mid-Plane Survey Extraordinaire (GLIMPSE) 8 μm and the Spectral and Photometric Imaging Receiver (SPIRE) 250 μm continuum images with the C2H emission maps. Results. We observed a total of three rotational transitions of C2H with their hyperfine structure components and four rotational transitions of c-C3H2 with ortho and para symmetries toward the H II region and the PDR of M8. Fragmentation of PAHs seems less likely to contribute to the formation of small hydrocarbons as the 8 μm emission does not follow the distribution of C2H emission, which is more associated with the molecular cloud toward the north west of Her 36. From the quantitative analysis, we obtained abundances of ~10−8 and 10−9 for C2H and c-C3H2 respectively, and volume densities of the hydrocarbon emitting gas in the range n(H2) ~5 × 104–5 × 106 cm−3. Conclusions. The observed column densities of C2H and c-C3H2 are reproduced reasonably well by our PDR models. This supports the idea that in high-UV flux PDRs, gas-phase chemistry is sufficient to explain hydrocarbon abundances.
A sustained outbreak of leptospirosis occurred in northeast Thailand between 1999 and 2003, the basis for which was unknown.
A prospective study was conducted between 2000 and 2005 to identify ...patients with leptospirosis presenting to Udon Thani Hospital in northeast Thailand, and to isolate the causative organisms from blood. A multilocus sequence typing scheme was developed to genotype these pathogenic Leptospira. Additional typing was performed for Leptospira isolated from human cases in other Thai provinces over the same period, and from rodents captured in the northeast during 2004. Sequence types (STs) were compared with those of Leptospira drawn from a reference collection. Twelve STs were identified among 101 isolates from patients in Udon Thani. One of these (ST34) accounted for 77 (76%) of isolates. ST34 was Leptospira interrogans, serovar Autumnalis. 86% of human Leptospira isolates from Udon Thani corresponded to ST34 in 2000/2001, but this figure fell to 56% by 2005 as the outbreak waned (p = 0.01). ST34 represented 17/24 (71%) of human isolates from other Thai provinces, and 7/8 (88%) rodent isolates. By contrast, 59 STs were found among 76 reference strains, indicating a much more diverse population genetic structure; ST34 was not identified in this collection.
Development of an MLST scheme for Leptospira interrogans revealed that a single ecologically successful pathogenic clone of L. interrogans predominated in the rodent population, and was associated with a sustained outbreak of human leptospirosis in Thailand.
Mechanotransduction is the interpretation of physical cues by cells through mechanosensation mechanisms that elegantly translate mechanical stimuli into biochemical signaling pathways. While ...mechanical stress and their resulting cellular responses occur in normal physiologic contexts, there are a variety of cancer-associated physical cues present in the tumor microenvironment that are pathological in breast cancer. Mechanistic in vitro data and in vivo evidence currently support three mechanical stressors as mechanical modifiers in breast cancer that will be the focus of this review: stiffness, interstitial fluid pressure, and solid stress. Increases in stiffness, interstitial fluid pressure, and solid stress are thought to promote malignant phenotypes in normal breast epithelial cells, as well as exacerbate malignant phenotypes in breast cancer cells.
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