This introduction to quantum chromodynamics presents the basic concepts and calculations in a clear and didactic style accessible to those new to the field. Readers will find useful methods for ...obtaining numerical results, including pure gauge theory and quenched spectroscopy.
A priori prediction of the flow properties of polydisperse rodlike macromolecules is a prerequisite for the understanding of many industrial and biological processes. Using mixtures of two naturally ...monodisperse viruses, we create a benchmark bidisperse suspension of rodlike colloids to test the effect of length bidispersity on the shear flow behavior. We find that the zero-shear viscosity is a nonlinear function of the fraction of long rods because of the strong length dependence of the rotational dynamics, which determine this quantity. With increasing concentration and fraction of long rods, the shear thinning gets more pronounced, following the predictions of our recently proposed theory which we extended for bidisperse mixtures. This theory allows for a quantitative prediction of the flow properties of bi- and polydisperse mixtures of ideal rods at least for moderate polydispersity.
Emerging therapeutic treatments based on the production of proteins by delivering mRNA have become increasingly important in recent times. While lipid nanoparticles (LNPs) are approved vehicles for ...small interfering RNA delivery, there are still challenges to use this formulation for mRNA delivery. LNPs are typically a mixture of a cationic lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and a PEG-lipid. The structural characterization of mRNA-containing LNPs (mRNA-LNPs) is crucial for a full understanding of the way in which they function, but this information alone is not enough to predict their fate upon entering the bloodstream. The biodistribution and cellular uptake of LNPs are affected by their surface composition as well as by the extracellular proteins present at the site of LNP administration, e.g., apolipoproteinE (ApoE). ApoE, being responsible for fat transport in the body, plays a key role in the LNP’s plasma circulation time. In this work, we use small-angle neutron scattering, together with selective lipid, cholesterol, and solvent deuteration, to elucidate the structure of the LNP and the distribution of the lipid components in the absence and the presence of ApoE. While DSPC and cholesterol are found to be enriched at the surface of the LNPs in buffer, binding of ApoE induces a redistribution of the lipids at the shell and the core, which also impacts the LNP internal structure, causing release of mRNA. The rearrangement of LNP components upon ApoE incubation is discussed in terms of potential relevance to LNP endosomal escape.
Current therapy of KRAS-mutant lung cancer Ghimessy, Aron; Radeczky, Peter; Laszlo, Viktoria ...
Cancer and metastasis reviews,
12/2020, Letnik:
39, Številka:
4
Journal Article
Recenzirano
Odprti dostop
KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to ...target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRAS-related studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications.
Lung transplantation is a life-saving treatment for patients with end-stage lung disease; however, it is infrequently considered for patients with acute respiratory distress syndrome (ARDS) ...attributable to infectious causes. We aimed to describe the course of disease and early post-transplantation outcomes in critically ill patients with COVID-19 who failed to show lung recovery despite optimal medical management and were deemed to be at imminent risk of dying due to pulmonary complications.
We established a multi-institutional case series that included the first consecutive transplants for severe COVID-19-associated ARDS known to us in the USA, Italy, Austria, and India. De-identified data from participating centres-including information relating to patient demographics and pre-COVID-19 characteristics, pretransplantation disease course, perioperative challenges, pathology of explanted lungs, and post-transplantation outcomes-were collected by Northwestern University (Chicago, IL, USA) and analysed.
Between May 1 and Sept 30, 2020, 12 patients with COVID-19-associated ARDS underwent bilateral lung transplantation at six high-volume transplant centres in the USA (eight recipients at three centres), Italy (two recipients at one centre), Austria (one recipient), and India (one recipient). The median age of recipients was 48 years (IQR 41-51); three of the 12 patients were female. Chest imaging before transplantation showed severe lung damage that did not improve despite prolonged mechanical ventilation and extracorporeal membrane oxygenation. The lung transplant procedure was technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. Pathology of the explanted lungs showed extensive, ongoing acute lung injury with features of lung fibrosis. There was no recurrence of SARS-CoV-2 in the allografts. All patients with COVID-19 could be weaned off extracorporeal support and showed short-term survival similar to that of transplant recipients without COVID-19.
The findings from our report show that lung transplantation is the only option for survival in some patients with severe, unresolving COVID-19-associated ARDS, and that the procedure can be done successfully, with good early post-transplantation outcomes, in carefully selected patients.
National Institutes of Health. VIDEO ABSTRACT.
Gd-EOB-DTPA-enhanced liver MRI is frequently compromised by transient severe motion artifacts (TSM) in the arterial phase, which limits image interpretation for the detection and differentiation of ...focal liver lesions and for the recognition of the arterial vasculature before and after liver transplantation. The purpose of this study was to investigate which patient factors affect TSM in children who undergo Gd-EOB-DTPA-enhanced liver MRI and whether younger children are affected as much as adolescents.
One hundred and forty-eight patients (65 female, 83 male, 0.1-18.9 years old), who underwent 226 Gd-EOB-DTPA-enhanced MRIs were included retrospectively in this single-center study. The occurrence of TSM was assessed by three readers using a four-point Likert scale. The relation to age, gender, body mass index, indication for MRI, requirement for sedation, and MR repetition was investigated using uni- and multivariate logistic regression analysis.
In Gd-EOB-DTPA-enhanced MRIs, TSM occurred in 24 examinations (10.6%). Patients with TSM were significantly older than patients without TSM (median 14.3 years; range 10.1-18.1 vs. 12.4 years; range 0.1-18.9, p<0.001). TSM never appeared under sedation. Thirty of 50 scans in patients younger than 10 years were without sedation. TSM were not observed in non-sedated patients younger than 10 years of age (p = 0.028). In a logistic regression analysis, age remained the only cofactor independently associated with the occurrence of TSM (hazard ratio 9.152, p = 0.049).
TSM in Gd-EOB-DTPA-enhanced liver MRI do not appear in children under the age of 10 years.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Complex fluids containing low concentrations of slender colloidal rods can display a high viscosity, while little flow is needed to thin the fluid. This feature makes slender rods essential ...constituents in industrial applications and biology. Though this behavior strongly depends on the rod-length, so far no direct relation could be identified. We employ a library of filamentous viruses to study the effect of rod size and flexibility on the zero-shear viscosity and shear-thinning behavior. Rheology and small-angle neutron scattering data are compared to a revised version of the standard theory for ideally stiff rods, which incorporates a complete shear-induced dilation of the confinement. While the earlier predicted length-independent prefactor of the restricted rotational diffusion coefficient is confirmed by varying the length and concentration of the rods, the revised theory correctly predicts the shear-thinning behavior as well as the underlying orientational order. These results can be directly applied to understand the manifold systems based on rodlike colloids and design new materials.
Current treatment guidelines refer to small cell lung cancer (SCLC), one of the deadliest human malignancies, as a homogeneous disease. Accordingly, SCLC therapy comprises chemoradiation with or ...without immunotherapy. Meanwhile, recent studies have made significant advances in subclassifying SCLC based on the elevated expression of the transcription factors ASCL1, NEUROD1, and POU2F3, as well as on certain inflammatory characteristics. The role of the transcription regulator YAP1 in defining a unique SCLC subset remains to be established. Although preclinical analyses have described numerous subtype-specific characteristics and vulnerabilities, the so far non-existing clinical subtype distinction may be a contributor to negative clinical trial outcomes. This comprehensive review aims to provide a framework for the development of novel personalized therapeutic approaches by compiling the most recent discoveries achieved by preclinical SCLC research. We highlight the challenges faced due to limited access to patient material as well as the advances accomplished by implementing state-of-the-art models and methodologies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The rapid development of image-based phenotyping methods based on ground-operating devices or unmanned aerial vehicles (UAV) has increased our ability to evaluate traits of interest for crop breeding ...in the field. A field site infested with beet cyst nematode (BCN) and planted with four nematode susceptible cultivars and five tolerant cultivars was investigated at different times during the growing season. We compared the ability of spectral, hyperspectral, canopy height- and temperature information derived from handheld and UAV-borne sensors to discriminate susceptible and tolerant cultivars and to predict the final sugar beet yield. Spectral indices (SIs) related to chlorophyll, nitrogen or water allowed differentiating nematode susceptible and tolerant cultivars (cultivar type) from the same genetic background (breeder). Discrimination between the cultivar types was easier at advanced stages when the nematode pressure was stronger and the plants and canopies further developed. The canopy height (CH) allowed differentiating cultivar type as well but was much more efficient from the UAV compared to manual field assessment. Canopy temperatures also allowed ranking cultivars according to their nematode tolerance level. Combinations of SIs in multivariate analysis and decision trees improved differentiation of cultivar type and classification of genetic background. Thereby, SIs and canopy temperature proved to be suitable proxies for sugar yield prediction. The spectral information derived from handheld and the UAV-borne sensor did not match perfectly, but both analysis procedures allowed for discrimination between susceptible and tolerant cultivars. This was possible due to successful detection of traits related to BCN tolerance like chlorophyll, nitrogen and water content, which were reduced in cultivars with a low tolerance to BCN. The high correlation between SIs and final sugar beet yield makes the UAV hyperspectral imaging approach very suitable to improve farming practice via maps of yield potential or diseases. Moreover, the study shows the high potential of multi- sensor and parameter combinations for plant phenotyping purposes, in particular for data from UAV-borne sensors that allow for standardized and automated high-throughput data extraction procedures.
The linear and nonlinear rheological behavior of two rod-like particle suspensions as a function of concentration is studied using small amplitude oscillatory shear, steady shear and capillary ...breakup extensional rheometry. The rod-like suspensions are composed of fd virus and its mutant fdY21M, which are perfectly monodisperse, with a length on the order of 900 nm. The particles are semiflexible yet differ in their persistence length. The effect of stiffness on the rheological behavior in both, shear and extensional flow, is investigated experimentally. The linear viscoelastic shear data is compared in detail with theoretical predictions for worm-like chains. The extensional properties are compared to Batchelor's theory, generalized for the shear thinning nature of the suspensions. Theoretical predictions agree well with the measured complex moduli at low concentrations as well as the nonlinear shear and elongational viscosities at high flow rates. The results in this work provide guidelines for enhancing the elongational viscosity based on purely frictional effects in the absence of strong normal forces which are characteristic for high molecular weight polymers.
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