The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined.
To delineate clinical features of childhood PCD ...and their associations with ultrastructural defects and genotype.
A total of 118 participants younger than 19 years old with PCD were evaluated prospectively at six centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping.
Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%). There were no differences in clinical features or respiratory pathogens in subjects with outer dynein arm (ODA) defects (ODA alone; n = 54) and ODA plus inner dynein arm (IDA) defects (ODA + IDA; n = 18) versus subjects with IDA and central apparatus defects with microtubular disorganization (IDA/CA/MTD; n = 40). Median FEV1 was worse in the IDA/CA/MTD group (72% predicted) versus the combined ODA groups (92% predicted; P = 0.003). Median body mass index was lower in the IDA/CA/MTD group (46th percentile) versus the ODA groups (70th percentile; P = 0.003). For all 118 subjects, median number of lobes with bronchiectasis was three and alveolar consolidation was two. However, the 5- to 11-year-old IDA/CA/MTD group had more lobes of bronchiectasis (median, 5; P = 0.0008) and consolidation (median, 3; P = 0.0001) compared with the ODA groups (median, 3 and 2, respectively). Similar findings were observed when limited to participants with biallelic mutations.
Lung disease was heterogeneous across all ultrastructural and genotype groups, but worse in those with IDA/CA/MTD ultrastructural defects, most of whom had biallelic mutations in CCDC39 or CCDC40.
Soil Moisture Active Passive (SMAP) mission of NASA was launched in January 2015. Currently, SMAP has an L-band radiometer and a defunct L-band radar with a rotating 6-m mesh reflector antenna. On ...July 7th, 2015, the SMAP radar malfunctioned and became inoperable. Consequently, the production of high-resolution active-passive soil moisture product got hampered, and only ~2.5 months (April 15th, 2015 to July 7th, 2015) of data remain available. Therefore, during the SMAP post-radar phase, many ways were examined to restart the high-resolution soil moisture product generation of the SMAP mission. One of the feasible approaches was to substitute the SMAP radar with other available SAR data. Sentinel-1A/Sentinel-1B SAR data was found most suitable for combining with the SMAP radiometer data because of its nearly similar orbit configuration that allows overlapping of their swaths with a minimal time difference, a key feature/requirement for the SMAP active-passive algorithm. The Sentinel interferometric wide swath (IW) mode acquisition also provides the co-polarized and cross-polarized observations required for the SMAP active-passive algorithm. However, some differences do exist between the SMAP and Sentinel SAR data. They are mainly: 1) Sentinel has a C-band SAR whereas SMAP operates at L-band; 2) Sentinel has multiple incidence angles within its swath, and SMAP has one single incidence angle; and 3) Sentinel 1A/B Interferometric Wide (IW) swath width is ~250 km as compared to SMAP with 1000 km swath width. On any given day, the narrow swath width of the Sentinel observations significantly reduces the overlap spatial coverage between SMAP and Sentinel as compared to the original SMAP radar and radiometer swath coverage. Hence, the temporal resolution (revisit interval) suffers due to narrow overlapped swath width and degrades from 3 days to 12 days. One advantage of using very high-resolution resolution Sentinel-1A/Sentinel-1B data in the SMAP active-passive algorithm is the potential of obtaining the disaggregated brightness temperature and thus soil moisture at a much finer spatial resolution of 3 km and 1 km at global extent. The assessment of high-resolution product at 3 km and 1 km using the soil moisture calibration and validations sites shows reasonable accuracy of ~0.05 m3/m3. The SMAP-Sentinel1 active-passive high-resolution product is now available to the public (new version released in October 2018) through NSIDC (NASA DAAC). The duration of this product is from April 2015 to current date.
•The article is about the high resolution (1 km and 3 km) soil moisture data from the SMAP mission.•The soil moisture is produced using the SMAP L-band TB and Sentinel 1A/B C-band Sigma0.•The high resolution soil moisture has reasonable accuracy (RMSE) of ~0.05 m3/m3.•The SMAP-Sentinel1 high resolution soil moisture product is ready for geophysical applications.•The temporal frequency of the this product is ~12 days, however, in Europe it is 6 days.
Significance
Immune checkpoint therapy (ICT) has led to durable responses in a subset of cancer patients. Generally, patients who respond to ICT bear tumors with high mutational burden. Radiation is ...used for treatment of many types of cancers and has been shown to induce new mutations in treated tumor cells and to synergistically facilitate ICT. However, these latter actions have largely been explained by radiation-induced tumor cell death and/or effects on the host. Herein, we show that noncurative irradiation induces mutations in tumor cells lacking neoantigens and that these de novo-generated neoantigens function as targets for CD8
+
T cells, resulting in increased immunogenicity of nonimmunogenic tumor cells. This study thus identifies an additional mechanism that explains synergy between immunotherapy and radiation.
Immunotherapies are a promising advance in cancer treatment. However, because only a subset of cancer patients benefits from these treatments it is important to find mechanisms that will broaden the responding patient population. Generally, tumors with high mutational burdens have the potential to express greater numbers of mutant neoantigens. As neoantigens can be targets of protective adaptive immunity, highly mutated tumors are more responsive to immunotherapy. Given that external beam radiation 1) is a standard-of-care cancer therapy, 2) induces expression of mutant proteins and potentially mutant neoantigens in treated cells, and 3) has been shown to synergize clinically with immune checkpoint therapy (ICT), we hypothesized that at least one mechanism of this synergy was the generation of de novo mutant neoantigen targets in irradiated cells. Herein, we use Kras
G12D
x p53
−/−
sarcoma cell lines (KP sarcomas) that we and others have shown to be nearly devoid of mutations, are poorly antigenic, are not controlled by ICT, and do not induce a protective antitumor memory response. However, following one in vitro dose of 4- or 9-Gy irradiation, KP sarcoma cells acquire mutational neoantigens and become sensitive to ICT in vivo in a T cell-dependent manner. We further demonstrate that some of the radiation-induced mutations generate cytotoxic CD8
+
T cell responses, are protective in a vaccine model, and are sufficient to make the parental KP sarcoma line susceptible to ICT. These results provide a proof of concept that induction of new antigenic targets in irradiated tumor cells represents an additional mechanism explaining the clinical findings of the synergy between radiation and immunotherapy.
•First itinerary choice model for all U.S. markets that accounts for price endogeneity.•Highly refined departure time of day preferences estimated.•Segmentation includes direction of travel, ...distance, time zone, day of week.•Results underscore the importance of correcting for price endogeneity.
Network planning models, which forecast the profitability of airline schedules, support many critical decisions, including equipment purchase decisions. Network planning models include an itinerary choice model that is used to allocate air total demand in a city pair to different itineraries. Multinomial logit (MNL) models are commonly used in practice and capture how individuals make trade-offs among different itinerary attributes; however, none that we are aware of account for price endogeneity. This study formulates an itinerary choice model that is consistent with those used by industry and corrects for price endogeneity using a control function that uses several types of instrumental variables. We estimate our model using a database of more than 10million passenger trips provided by the Airlines Reporting Corporation. Results based on Continental U.S. markets for May 2013 departures show that models that fail to account for price endogeneity overestimate customers’ value of time and result in biased price estimates and incorrect pricing recommendations. The size and comprehensiveness of our database allows us to estimate highly refined departure time of day preference curves that account for distance, direction of travel, number of time zones traversed, departure day of week and itinerary type (outbound, inbound or one-way). These time of day preference curves can be used by airlines, researchers, and government organizations in the evaluation of different policies such as congestion pricing.
The NASA Soil Moisture Active Passive (SMAP) mission Level-4 Soil Moisture (L4_SM) product provides global, 3-hourly, 9-km resolution estimates of surface (0-5 cm) and root-zone (0-100 cm) soil ...moisture with a mean latency of ~2.5 days. The underlying L4_SM algorithm assimilates SMAP radiometer brightness temperature (Tb) observations into the NASA Catchment land surface model using a spatially-distributed ensemble Kalman filter. Version 4 of the L4_SM modeling system includes a reduction in the upward recharge of surface soil moisture from below under non-equilibrium conditions, resulting in reduced bias and improved dynamic range of L4_SM surface soil moisture compared to earlier versions. This change and additional technical modifications to the system reduce the mean and standard deviation of the observation-minus-forecast Tb residuals and overall soil moisture analysis increments while maintaining the skill of the L4_SM soil moisture estimates versus independent in situ measurements; the average, bias-adjusted RMSE in Version 4 is 0.039 m(exp 3) m(exp -3) for surface and 0.026 m(exp 3) m(exp -3) for root-zone soil moisture. Moreover, the coverage of assimilated SMAP observations in Version 4 is near-global owing to the use of additional satellite Tb records for algorithm calibration. L4_SM soil moisture uncertainty estimates are biased low (by 0.01-0.02 m(exp 3) m(exp -3)) against actual errors (computed versus in situ measurements). L4_SM runoff estimates, an additional product of the L4_SM algorithm, are biased low (by 35 mm year (exp -1)) against streamflow measurements. Compared to Version 3, bias in Version 4 is reduced by 46% for surface soil moisture uncertainty estimates and by 33% for runoff estimates.
Convalescent Plasma for Covid-19-Induced ARDS Senefeld, Jonathon W; Henderson, Jeffrey P; Joyner, Michael J
The New England journal of medicine,
2024-Jan-25, Letnik:
390, Številka:
4
Journal Article
Several recent studies have identified a relationship between the natural environment and improved health outcomes. However, for practical reasons, most have been observational, cross-sectional ...studies.
A natural experiment, which provides stronger evidence of causality, was used to test whether a major change to the natural environment-the loss of 100 million trees to the emerald ash borer, an invasive forest pest-has influenced mortality related to cardiovascular and lower-respiratory diseases.
Two fixed-effects regression models were used to estimate the relationship between emerald ash borer presence and county-level mortality from 1990 to 2007 in 15 U.S. states, while controlling for a wide range of demographic covariates. Data were collected from 1990 to 2007, and the analyses were conducted in 2011 and 2012.
There was an increase in mortality related to cardiovascular and lower-respiratory-tract illness in counties infested with the emerald ash borer. The magnitude of this effect was greater as infestation progressed and in counties with above-average median household income. Across the 15 states in the study area, the borer was associated with an additional 6113 deaths related to illness of the lower respiratory system, and 15,080 cardiovascular-related deaths.
Results suggest that loss of trees to the emerald ash borer increased mortality related to cardiovascular and lower-respiratory-tract illness. This finding adds to the growing evidence that the natural environment provides major public health benefits.
We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of ...melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.
A reactive transport model was developed to simulate reaction of carbonates within a pore network for the high‐pressure CO2‐acidified conditions relevant to geological carbon sequestration. The pore ...network was based on a synthetic oolithic dolostone. Simulation results produced insights that can inform continuum‐scale models regarding reaction‐induced changes in permeability and porosity. As expected, permeability increased extensively with dissolution caused by high concentrations of carbonic acid, but neither pH nor calcite saturation state alone was a good predictor of the effects, as may sometimes be the case. Complex temporal evolutions of interstitial brine chemistry and network structure led to the counterintuitive finding that a far‐from‐equilibrium solution produced less permeability change than a nearer‐to‐equilibrium solution at the same pH. This was explained by the pH buffering that increased carbonate ion concentration and inhibited further reaction. Simulations of different flow conditions produced a nonunique set of permeability‐porosity relationships. Diffusive‐dominated systems caused dissolution to be localized near the inlet, leading to substantial porosity change but relatively small permeability change. For the same extent of porosity change caused from advective transport, the domain changed uniformly, leading to a large permeability change. Regarding precipitation, permeability changes happen much slower compared to dissolution‐induced changes and small amounts of precipitation, even if located only near the inlet, can lead to large changes in permeability. Exponent values for a power law that relates changes in permeability and porosity ranged from 2 to 10, but a value of 6 held constant when conditions led to uniform changes throughout the domain.
Key Points
Acid dissolves carbonates but neither pH nor saturation alone predicts extent
Dissolution increases porosity but permeability increase depends on flow rate
Permeability decreases due to precipitation but effects are localized
PDF
