Miracle-dz/UniFAR-FTUs huggingface dataset:
Animal Models of Pulmonary Fibrosis: How Far from Effective Reality?

IDIOPATHIC PULMONARY FIBROSIS (IPF) is a chronic and progressive lung disease, associated with high mortality rates and unresponsive to currently available treatments. Animal models are critical to identify and validate new therapeutic drug targets, a concept that is nicely highlighted by the review by Drs. Bethany Moore and Cory Hogaboam (7) in this issue of AJP-Lung. Dr. Lorraine Ware (9), in an Editorial also in this issue, points out the cautions and necessities of animal models for human diseases, and these are very prevalent in models of pulmonary fibrosis. In the review, the authors point out that the bleomycin model appears the most clinically relevant. While this is true for bleomycin-induced human pulmonary fibrosis, it has not provided relevance for the idiopathic form of disease (1). We (6) recently published a " meta-analysis " on the value of the bleomycin model for the development of useful therapies , which suggests that the clinical relevance of this model is questionable. These models have provided excellent indications of important molecules and cells involved in the fibro-genic process, yet have failed to provide convincing correlative preclinical data for any new effective therapeutic intervention for human disease. This lack of effective correlation may be related to a number of reasons. Although we believe that some drug targets identified through animal studies, such as the transforming growth factor-␤ pathway of ligand activation, receptor binding, and intracellular signaling, are correct ones for human disease, it has recently been pointed out that we know far less about the pathogenesis of human IPF than of experimental fibrosis in mice and rats (3, 4). The other possible explanation of failed drug development in this area may be related to the fact that the assessment of drug efficacy in animals is vastly different from assessment of disease in human patients, and thus there are substantially different therapeutic goals. Basic scientists aim to prevent or completely dissolve scar tissue as a proof of principle , notably in a species that is known to have the ability to regenerate alveolar structure. In contrast, the progressively declining clinical course of patients with IPF, and lack of knowledge regarding the natural history of the disease, would make it a success if even the progression could be halted. Indeed, researchers in pharmaceutical drug development are increasingly aware that " we have relied a bit too much on animal models and fooled ourselves into thinking they …
InSAR measurements of compaction and subsidence in the Ganges‐Brahmaputra Delta, Bangladesh

Many of the world′s largest river deltas are sinking due to sediment loading, compaction, and tectonics but also recently because of groundwater extraction, hydrocarbon extraction, and reduced aggradation. Little is known, however, about the full spatial variability of subsidence rates in complex delta systems. This study reconstructs subsidence rates in the eastern portion of the Ganges‐Brahmaputra Delta (GBD), Bangladesh, covering more than 10,000 km2 at a high spatial resolution of 100 m. The map was produced using Interferometric Synthetic Aperture Radar (InSAR) covering the period 2007 to 2011. Eighteen Advanced Land Observing Satellite Phased‐Array L‐band SAR scenes were used to generate 30 interferograms calibrated with GPS. Interferograms were stacked to yield average subsidence rates over the study period. Small Baseline Subset‐InSAR was then applied to validate the results against an additional GPS record from Dhaka, Bangladesh. Land subsidence of 0 to > 10 mm/yr is seen in Dhaka, with variability likely related to local variations in shallow subsurface sediment properties. Outside of the city, rates vary from 0 to > 18 mm/yr, with the lowest rates appearing primarily in Pleistocene Madhupur Clay and the highest rates in Holocene organic‐rich muds. Results demonstrate that subsidence in this delta is primarily controlled by local stratigraphy, with rates varying by more than an order of magnitude depending on lithology. The ability of L‐band InSAR to differentiate between stratigraphic units in this humid, vegetated subtropical river delta demonstrates the power of interferometry as a tool for studying the subsurface in deltaic environments.
MEASURED REFLECTION STRENGTHS OF UNDERWATER PIPES IRRADIATED BY A PULSED HORIZONTAL DIPOLE IN AIR: COMPARISON WITH CONTINUOUS PLANE‐WAVE SCATTERING THEORY1

At Delft Geotechnics the technique of ground-penetrating radar is in use for the detection of buried objects such as pipes. In order to give our ‘measurements in the field’ a more quantitative interpretation, a series of experiments has been started under well-defined conditions. A cylindrical vessel contains water, simulating wet soil. A pulsed transmitting antenna (TA) is mounted above the water-surface irradiating horizontal underwater pipes. The reflected pulses are detected by a horizontal receiving dipole (AP, i.e. ‘air-probe’) in the air. The reflecting objects used in the experiments are steel pipes, PVC rods and hollow PVC pipes filled with air or water. The depth of the pipes varies from 0.25 to 2 m. The strength of the reflected pulse depends on the type of pipe, its diameter, its depth, the electromagnetic properties of the water and also on the strength and polarization of the incident E-field. The latter is (mainly) parallel to the axis of the pipe in the present experiments. The experimental results have been compared with calculated results using the theory of a continuous plane wave, incident on an infinitely long cylinder in a homogeneous dielectric medium with the same dielectric constant as water. In a previous paper an experiment was described in which a movable receiving dipole in the water measured the transverse, mutually orthogonal Eo- and Eθ-components of the pulses emitted by the TA. The amplitudes of Eθ versus depth, measured in that paper, are used in the calculations as amplitudes of the incident field. The attenuation of the scattered field is accounted for by assuming exponential damping. The relative amplitudes of the scattered field for different pipes lying at the same depth are reproduced very well by this simple theory. Also the relative values of the scattered amplitudes for a given pipe lying at different depths are described neatly, provided the refraction of the scattered field at the water-air interface is accounted for.
Protein translocation across the endoplasmic reticulum. II. Isolation and characterization of the signal recognition particle receptor

The signal recognition particle (SRP)-mediated elongation arrest of the synthesis of nascent secretory proteins can be released by salt- extracted rough microsomal membranes (Walter, P., and G. Blobel, 1981, J. Cell Biol, 91:557-561). Both the arrest-releasing activity and the signal peptidase activity were solubilized from rough microsomal membranes using the nonionic detergent Nikkol in conjunction with 250 mM KOAc. Chromatography of this extract on SRP-Sepharose separated the arrest-releasing activity from the signal peptidase activity. Further purification of the arrest-releasing activity using sucrose gradient centrifugation allowed the identification of a 72,000-dalton polypeptide as the protein responsible for the activity. Based upon its affinity for SRP, we refer to the 72,000-dalton protein as the SRP receptor. A 60,000-dalton protein fragment (Meyer, D. I., and B. Dobberstein, 1980, J. Cell Biol., 87:503-508) that had been shown previously to reconstitute the translocation activity of protease- digested membranes, was shown here by peptide mapping and immunological criteria to be derived from the SRP receptor. Findings that are in part similar, and in part different from these reported here and in our preceding paper were made independently (Meyer, D. I., E. Krause, and B. Dobberstein, 1982, Nature (Lond.). 297:647-650) and the term "docking protein" was proposed for the SRP receptor. A lower membrane content of both SRP and the SRP receptor than that of membrane bound ribosomes suggests that the SRP-SRP receptor interaction may exist transiently during the formation of a ribosome-membrane junction and during translocation.
Modeling of daily precipitation at multiple locations using a mixture of distributions to characterize the extremes

A stochastic model for the generation of daily time series of rainfall at multiple locations in which the amount of daily rainfall is modeled by a mixture of two different probability distribution functions is presented. A mixture model is implemented with the specific objective of characterizing extremes of daily precipitation. The approach is based on the assumption that the extremes within a time series have a different stochastic behavior compared to the normal regime of precipitation. A multivariate autoregressive model is used to model the local probability of occurrence of rainfall and the amount while keeping the intersite covariance structure using a truncated normal distribution. The amount simulated using the truncated normal distribution is further transformed so that it can be regarded as coming from the actual distribution fitted to the daily precipitation at each station using the probability integral transformation. The seasonal cycles of the amount as well as the temporal and spatial correlations of the daily precipitation are incorporated by fitting the model on the monthly basis. Application was made on 122 stations within the Unstrut catchment with an area of 6343 km2 in central eastern Germany. Results show that the model can fairly well reproduce a number of statistical features of daily precipitation including the extreme value distribution of the annual maximum daily and 3 day total precipitation, both at individual stations and at the catchment scale.
Effects of Different Rock Fragment Contents and Sizes on Solute Transport in Soil Columns

The presence of rock fragments in soil can have a great impact on solute transport processes, as well as on soil bulk density, soil structure, and water storage properties. In the laboratory, we studied the effects of different gravimetric rock fragment contents (Rc) and different rock fragment sizes (Rs) on the solute transport processes in soil columns. Using CaCl2 as a tracer, the solute transport processes were accurately described by both the convection–dispersion equation (CDE) and a two‐region model, although the latter model fitted the experimental data slightly better than the CDE. Smooth breakthrough curves were obtained, even for a large Rs or Rc, although the presence of rock fragments impeded solute transport to different degrees depending on the content and size of fragments in the columns. The two models produced the same trends in dispersivity, but the values determined by the two‐region model were smaller than those from the CDE. The Rc and Rs values had a significant effect on the mobile–immobile partition coefficient and the mass transfer coefficient.
Some limits of informed consent

Many accounts of informed consent in medical ethics claim that it is valuable because it supports individual autonomy. Unfortunately there are many distinct conceptions of individual autonomy, and their ethical importance varies. A better reason for taking informed consent seriously is that it provides assurance that patients and others are neither deceived nor coerced. Present debates about the relative importance of generic and specific consent (particularly in the use of human tissues for research and in secondary studies) do not address this issue squarely. Consent is a propositional attitude, so intransitive: complete, wholly specific consent is an illusion. Since the point of consent procedures is to limit deception and coercion, they should be designed to give patients and others control over the amount of information they receive and opportunity to rescind consent already given.
Empirical orthogonal function analysis and modeling of the ionospheric peak height during the years 2002–2011

The ionospheric peak electron density height (hm) is one of the most important ionospheric parameters characterizing high‐frequency radio wave propagation conditions. In this paper, a global hm model based on the empirical orthogonal function (EOF) analysis method is constructed by using Global Navigation Satellite Systems ionospheric radio occultation measurements from COSMIC and CHAMP as well as global ionosonde data during the years 2002–2011. The variability of hm can be well represented by the several EOF base functions Ek and the corresponding coefficients Pk. The rapid convergence of EOF decomposition makes it possible to use only the first four EOFs components, which express 99.133% of total variance in this study, to construct the empirical model. The variations of hm with respect to the magnetic latitude, local time, season, and solar cycle have been studied, and the EOF‐based hm model has been validated through comparisons with the International Reference Ionosphere (IRI) model and other observation. The evaluations indicate that the EOF and IRI model give better hmF2 at middle and high latitudes than those at low latitudes. Since the limited data were used in the EOF model during high solar activity years, its accuracy degrades to some extent. During nighttime of spring, summer, and winter in the auroral zone, the hm derived from the EOF model may range from 90 to 150 km because of the reduction of hm, which is due to particle precipitation, whereas the IRI model does not include this reduction. During the periods of low solar activity, the F2 peak heights (hmF2) from the EOF model are in good agreement with the observed data, while the IRI model tends to overestimate the hmF2 in the middle and high latitudes.
Exploring the relationship between changes in climate and floods using a model‐based analysis

A model‐based approach is implemented to attribute changes in the seasonal extreme river flows to meteorological drivers. A semidistributed model that simulates daily runoff from daily series of meteorological variables was employed together with a multisite, multivariable weather generator. Ensembles of synthetic meteorological variables were synthesized using the weather generator and were used to drive the hydrological model. In order to systematically assess the relative importance of each of the meteorological variables in explaining the detected changes in the flood behavior, the variables were generated by accounting for the year to year variability of the distribution of one of the variables at a time while keeping the distributions of the others temporally stationary. The approach was tested on eight case study catchments from different parts of Germany. The results show the ability of the approach in identifying the meteorological variable that is associated with the detected change in the extreme flow. Changes in precipitation were found to be the major meteorological drivers of the trends detected in the seasonal extreme flows in most of the investigated catchments. Temperature was found to be less important in explaining any of the changes in all catchments.
Challenges of Fungicide Control on Wheat Rusts in Kenya

Stem rust or black rust (caused by Puccinia graminis Pers. f. sp. tritici Erikss. & E. Henn.) is a serious wheat disease causing a decrease of wheat production in many areas of the world (Roelfs, 1978). The effective barberry eradication in the early 20th century and the infrequent occurrence of favourable temperature in Europe has resulted in a decline in importance of stem rust. Until recently, the disease has been under effective control through the wide spread use of resistant varieties (Jin, 2007). The re-emergence of a new virulent race TTKSK (Ug99) in Eastern Africa region (Pretorius et al., 2000), and the subsequent detection of its many variants in Kenya has rendered important commercial varieties susceptible (Jin, 2008). Wide-scale epidemics have been frequent, being recorded in 2004, 2005, 2006, 2007, 2008, 2009 and 2010. Fungicides sprays have become part of the production practice of wheat growers in Kenya, although many are not effective. The fungicides used for the control of wheat leaf diseases have increased costs of production, because of the multiple applications required to protect the crop before it matures. Unlike in other regions e.g. United States, Canada, Australia and South Africa (Table 1), there is currently no fungicide registered for the control of wheat stem rust in Kenya, this is because the effects of fungicide on loss prevention are poorly understood and data is limited (Wanyera et al., 2009). However, fungicides are used extensively by producers in other countries to control stripe and leaf rusts, but only a few are registered for the control of stem rust. Many fungicides have been found to be effective at specific growth stages. Until recently, studies have indicated that up to one-third of applications may be too late for optimal effectiveness. Application timing is critical in managing stem rust. Stem rust activity needs to be closely monitored both in individual fields and across regions. This is because preventive applications consistently provide better results than applications made after disease infection has occurred. Unlike stripe and leaf rust, foliar fungicide applications targeting stem rust must be applied as soon as the disease is detected as opposed to targeting key yield determining leaves. It is important to note that, the severity of any disease is related to inoculum pressure, weather conditions and variety susceptibility (Cook et al., 1999). According to Milne et al. (2007) the fungicide choice and the timing of application are often poor in commercial crops. Sometimes, crops receiving up to three
Hemidesmosome Formation Is Initiated by the (cid:98) 4 Integrin Subunit, Requires Complex Formation of (cid:98) 4 and HD1/Plectin, and Involves a Direct Interaction between (cid:98) 4 and the Bullous Pemphigoid Antigen 180

Hemidesmosomes (HDs) are stable anchoring structures that mediate the link between the intermediate filament cytoskeleton and the cell substratum. We investigated the contribution of various segments of the (cid:98) 4 integrin cytoplasmic domain in the formation of HDs in transient transfection studies using immortalized keratinocytes derived from an epidermolysis bullosa patient deficient in (cid:98) 4 expression. We found that the expression of wild-type (cid:98) 4 restored the ability of the (cid:98) 4-deficient cells to form HDs and that distinct domains in the NH 2 and COOH-terminal regions of the (cid:98) 4 cytoplasmic domain are required for the localization of HD1/plectin and the bullous pemphigoid antigens 180 (BP180) and 230 (BP230) in these HDs. The tyrosine activation motif located in the connecting segment (CS) of the (cid:98) 4 cytoplasmic domain was dispensable for HD formation, although it may be involved in the efficient localization of BP180. Using the yeast two-hybrid system, we could demonstrate a direct interaction between (cid:98) 4 and BP180 which involves sequences within the COOH-terminal part of the CS and the third fibronectin type III (FNIII) repeat. Immunoprecipitation studies using COS-7 cells transfected with cDNAs for (cid:97) 6 and (cid:98) 4 and a mutant BP180 which lacks the collagenous extracellular domain confirmed the interaction of (cid:98) 4 with BP180. Nevertheless, (cid:98) 4 mutants which contained the BP180-binding region, but lacked sequences required for the localization of HD1/plectin, failed to localize BP180 in HDs. Additional yeast two-hybrid assays indicated that the 85 COOH-terminal residues of (cid:98) 4 can interact with the first NH 2 -terminal pair of FNIII repeats and the CS, suggesting that the cytoplasmic domain of (cid:98) 4 is folded back upon itself. Unfolding of the cytoplasmic domain may be part of a mechanism by which the interaction of (cid:98) 4 with other hemidesmosomal components, e.g., BP180, is regulated. the number of colonies on the SC-LT plate compared with on the SC-LTHA plate. a positive control for GAL4-driven activation of the Ade and His reporter genes of PJ69-4A, two combinations of vectors were used enable growth on SC-LTHA plates. One combination was pCL1, full-length GAL4 (which is able to activate the two reporter genes on its own) in a pACT2-like vector (Fields and Song, 1989; Clontech) together with the empty pAS2-1 vector. In the other combination, two vectors, pTD1-1, SV-40 large T antigen in pACT2 (Li and Fields, 1993; Clontech), together
Neotectonics and long‐term seismicity in Europe and the Mediterranean region

We present a neotectonic model of ongoing lithosphere deformation and a corresponding estimate of long‐term shallow seismicity across the Africa‐Eurasia plate boundary, including the eastern Atlantic, Mediterranean region, and continental Europe. GPS and stress data are absent or inadequate for the part of the study area covered by water. Thus, we opt for a dynamic model based on the stress equilibrium equation; this approach allows us to estimate the long‐term behavior of the lithosphere (given certain assumptions about its structure and physics) for both land and sea areas. We first update the existing plate model by adding five quasirigid plates (the Ionian Sea, Adria, Northern Greece, Central Greece, and Marmara) to constrain the deformation pattern of the study area. We use the most recent data sets to estimate the lithospheric structure. The models are evaluated in comparison with updated data sets of geodetic velocities and the most compressive horizontal principal stress azimuths. We find that the side and basal strengths drive the present‐day motion of the Adria and Aegean Sea plates, whereas lithostatic pressure plays a key role in driving Anatolia. These findings provide new insights into the neotectonics of the greater Mediterranean region. Finally, the preferred model is used to estimate long‐term shallow seismicity, which we retrospectively test against historical seismicity. As an alternative to reliance on incomplete geologic data or historical seismic catalogs, these neotectonic models help to forecast long‐term seismicity, although requiring additional tuning before seismicity rates are used for seismic hazard purposes.
Results of PMIP2 coupled simulations of the Mid-Holocene and Last Glacial Maximum – Part 2: feedbacks with emphasis on the location of the ITCZ and mid- and high latitudes heat budget

A set of coupled ocean-atmosphere(-vegetation) simulations using state of the art climate models is now available for the Last Glacial Maximum (LGM) and the Mid-Holocene (MH) through the second phase of the Paleoclimate Modeling Intercomparison Project (PMIP2). Here we quantify the latitudinal shift of the location of the Intertropical Convergence Zone (ITCZ) in the tropical regions during boreal summer and the change in precipitation in the northern part of the ITCZ. For both periods the shift is more pronounced over the continents and East Asia. The maritime continent is the region where the largest spread is found between models. We also clearly establish that the larger the increase in the meridional temperature gradient in the tropical Atlantic during summer at the MH, the larger the change in precipitation over West Africa. The vegetation feedback is however not as large as found in previous studies, probably due to model differences in the control simulation. Finally, we show that the feedback from snow and sea-ice at mid and high latitudes contributes for half of the cooling in the Northern Hemisphere for the LGM, with the remaining being achieved by the reduced CO2 and water vapour in the atmosphere. For the MH the snow and albedo feedbacks strengthen the spring cooling and enhance the boreal summer warming, whereas water vapour reinforces the late summer warming. These feedbacks are modest in the Southern Hemisphere. For the LGM most of the surface cooling is due to CO2 and water vapour.