Human LMNA gene mutations result in laminopathies that include Emery-Dreifuss muscular dystrophy (AD-EDMD) and Hutchinson-Gilford progeria, the premature aging syndrome (HGPS). The Lmna null ...(Lmna−/−) and progeroid LmnaΔ9 mutant mice are models for AD-EDMD and HGPS, respectively. Both animals develop severe tissue pathologies with abbreviated life spans. Like HGPS cells, Lmna−/− and LmnaΔ9 fibroblasts have typically misshapen nuclei. Unexpectedly, Lmna−/− or LmnaΔ9 mice that are also deficient for the inner nuclear membrane protein Sun1 show markedly reduced tissue pathologies and enhanced longevity. Concordantly, reduction of SUN1 overaccumulation in LMNA mutant fibroblasts and in cells derived from HGPS patients corrected nuclear defects and cellular senescence. Collectively, these findings implicate Sun1 protein accumulation as a common pathogenic event in Lmna−/−, LmnaΔ9, and HGPS disorders.
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▸ Premature death of progeric and dystrophic mice is ameliorated by removal of Sun1 ▸ LMNA mutations cause Sun1 overaccumulation in the Golgi ▸ Sun1 overaccumulation in the Golgi is pathogenic ▸ Cellular senescence of HGPS fibroblasts is corrected by depletion of SUN1
Reduced levels of SUN1 protein ameliorate the symptoms and cell biological hallmarks of laminopathies resulting from LMNA mutations in mice and in patient cells. The findings suggest a new mechanism for the pathology underlying lamin-deficient premature aging and muscle dystrophy.
Background and Aims
Organoids provide a powerful system to study epithelia in vitro. Recently, this approach was applied successfully to the biliary tree, a series of ductular tissues responsible for ...the drainage of bile and pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (extrahepatic bile ducts; EHBDs) or inside the liver (intrahepatic bile ducts; IHBDs). These organoids share many characteristics, including expression of cholangiocyte markers such as keratin (KRT) 19. However, the relationship between these organoids and their tissues of origin, and to each other, is largely unknown.
Approach and Results
Organoids were derived from human gallbladder, common bile duct, pancreatic duct, and IHBDs using culture conditions promoting WNT signaling. The resulting IHBD and EHBD organoids expressed stem/progenitor markers leucine‐rich repeat–containing G‐protein‐coupled receptor 5/prominin 1 and ductal markers KRT19/KRT7. However, RNA sequencing revealed that organoids conserve only a limited number of regional‐specific markers corresponding to their location of origin. Of particular interest, down‐regulation of biliary markers and up‐regulation of cell‐cycle genes were observed in organoids. IHBD and EHBD organoids diverged in their response to WNT signaling, and only IHBDs were able to express a low level of hepatocyte markers under differentiation conditions.
Conclusions
Taken together, our results demonstrate that differences exist not only between extrahepatic biliary organoids and their tissue of origin, but also between IHBD and EHBD organoids. This information may help to understand the tissue specificity of cholangiopathies and also to identify targets for therapeutic development.
•A novel model for fluid extraction from a packed bed.•The first analytical solution, clearly showing role of operating parameters.•Perturbation and travelling waves employed to analyse ...advection-diffusion.•Verification against experimental data for lanolin removal from wool fibres.•Proof that to characterise experiments both early and late time data required.
A mathematical model describing the erosion or leaching of a solid material by a flowing fluid in a column is developed. This involves an advection-diffusion equation coupled to a linear kinetic reaction describing the mass transfer between the solid and fluid. Two specific cases are analysed, the first where the extracted material has the same saturation solubility and rate of mass transfer throughout the process, the second where the solubility switches after a certain amount of erosion. In the first case there are only two model unknowns, the solubility and mass transfer coefficient, in the second there is a third unknown, the second solubility. Exploiting the fact that erosion is a slow process (relative to the flow rate) a perturbation solution based on the smallness of the amount removed is developed to describe the concentration and radius throughout the column. From this an analytical expression for the extracted fraction is obtained. The extracted fraction has a large linear section which results in a simple calculation to estimate the initial solubility from a very few or even a single data point. The remaining unknowns may also be easily calculated from the formula and later data points. A numerical solution, using finite differences, is developed to verify the perturbation solution. The analytical solution is also verified against experimental data for the removal of lanolin from wool fibres with a supercritical CO2/ethanol solvent. Values for the mass transfer rate and two solubilities are obtained for different pressures and shown to provide excellent agreement with a series of experimental results for the extracted fraction.
To estimate 1-year mortality rates in elderly patients who undergo operative treatment for distal femur fractures and identify potential risk factors for mortality.
Retrospective chart review.
Level ...1 and Level 2 trauma centers.
Two hundred eighty-three elderly patients (average age 76.0 years ± 9.8) who sustained distal femur fractures between 2002 and 2012.
Fracture fixation of the distal femur.
Survival up to 1 year after surgery.
The 1-year mortality rate for distal femur fractures in elderly patients was 13.4%. There were no statistically significant differences in overall mortality between native bone and periprosthetic fractures, intramedullary nail or open reduction internal fixation, or across Orthopaedic Trauma Association fracture classifications. Overall patient mortality was significantly higher at 30 days (P = 0.036), 6 months (P = 0.019), and 1 year (P = 0.018), when surgery occurred more than 2 days from the injury. Mean Charlson Comorbidity Index scores were significantly lower in survivors versus nonsurvivors at all time intervals (30 days, P = 0.023; 6 months, P = 0.001 and 1 year P ≤ 0.001). A time to surgery of more than 2 days, regardless of baseline illness, did not result in improved survivability at 1 year.
Overall mortality for distal femur fractures was 13.4% in the elderly population. A surgical treatment more than 2 days after injury was associated with increased patient mortality.
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
With the goal of determining strategies to maximise drug delivery to a specific site in the body, we developed a mathematical model for the transport of drug nanocarriers (nanoparticles) in the ...bloodstream under the influence of an external magnetic field. Under the assumption of long (compared to the radius) blood vessels the Navier-Stokes equations are reduced, to a simpler model consistently with lubrication theory. Under these assumptions, analytical results are compared for Newtonian, power-law, Carreau and Ellis fluids, and these clearly demonstrate the importance of shear thinning effects when modelling blood flow. Incorporating nanoparticles and a magnetic field to the model we develop a numerical scheme and study the particle motion for different field strengths. We demonstrate the importance of the non-Newtonian behaviour: for the flow regimes investigated in this work, consistent with those in blood micro vessels, we find that the field strength needed to absorb a certain amount of particles in a non-Newtonian fluid has to be larger than the one needed in a Newtonian fluid. Specifically, for one case examined, a two times larger magnetic force had to be applied in the Ellis fluid than in the Newtonian fluid for the same number of particles to be absorbed through the vessel wall. Consequently, models based on a Newtonian fluid can drastically overestimate the effect of a magnetic field. Finally, we evaluate the particle concentration at the vessel wall and compute the evolution of the particle flux through the wall for different permeability values, as that is important when assessing the efficacy of drug delivery applications. The insights from our work bring us a step closer to successfully transferring magnetic nanoparticle drug delivery to the clinic.
Pinecone shells are assessed as a cost-effective biosorbent for the removal of metal ions Pb(II), Cu(II), Cd(II), Ni(II), and Cr(VI) in a fixed-bed column. Influent concentration, bed height, and ...flowrate are studied to improve efficiency. The breakthrough data is well fitted by the Sips adsorption model, suggesting a surface complexation mechanism, with maximum adsorption capacities of 11.1 mg/g for Cu(II) and 66 mg/g for Pb(II).
In multimetal solutions, the uptake sequence at breakthrough and saturation is Pb(II) > Cu(II) > Cd(II). Characterization via FTIR and XRD reveals carboxyl and hydroxyl functional groups interacting with metal ions. Ca(II) does not compete with Pb(II), Cu(II), and Cd(II) adsorption, highlighting the ability of pinecone to adsorb heavy metals via surface complexation. Its application in the treatment of industrial effluents containing Cu(II), Ni(II), and Cr(VI) is explored.
The study investigates bed media regeneration via eluting adsorbed metal ions with hydrochloric acid solutions. The potential of pinecone shells as an efficient biosorbent for removing toxic metal ions from industrial wastewater is emphasized. These findings enhance our understanding of the adsorption mechanism and underscore the fixed-bed column system's applicability in real-world scenarios, addressing environmental concerns related to heavy metal contamination of industrial effluents.
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•Adsorption capacities of 65 and 11 mg·g−1 for Pb(II) and Cu(II) were obtained.•When Pb(II) competed with Cu(II) and Cd(II) the adsorption capacity was 23.8 mg·g−1.•High correlation of the model with experimental data suggests surface complexation.•FTIR and XRD confirm the functional groups' active involvement in metal adsorption.•Robust column model gives valuable insights into adsorption kinetics and mechanisms.
Infection by malaria parasites triggers dynamic immune responses leading to diverse symptoms and pathologies; however, the molecular mechanisms responsible for these reactions are largely unknown. We ...performed Trans-species Expression Quantitative Trait Locus analysis to identify a large number of host genes that respond to malaria parasite infections. Here we functionally characterize one of the host genes called receptor transporter protein 4 (RTP4) in responses to malaria parasite and virus infections. RTP4 is induced by type I IFN (IFN-I) and binds to the TANK-binding kinase (TBK1) complex where it negatively regulates TBK1 signaling by interfering with expression and phosphorylation of both TBK1 and IFN regulatory factor 3. Rtp4−/− mice were generated and infected with malaria parasite Plasmodiun berghei ANKA. Significantly higher levels of IFN-I response in microglia, lower parasitemia, fewer neurologic symptoms, and better survival rateswere observed in Rtp4−/− than in wild-type mice. Similarly, RTP4 deficiency significantly reduced West Nile virus titers in the brain, but not in the heart and the spleen, of infected mice, suggesting a specific role for RTP4 in brain infection and pathology. This study reveals functions of RTP4 in IFN-I response and a potential target for therapy in diseases with neuropathology.
Macrophages in infected tissues may sense microbial molecules that significantly alter their metabolism. In a seeming paradox, these critical host defense cells often respond by increasing glucose ...catabolism while simultaneously storing fatty acids (FA) as triglycerides (TAG) in lipid droplets. We used a load-chase strategy to study the mechanisms that promote long term retention of TAG in murine and human macrophages. Toll-like receptor (TLR)1/2, TLR3, and TLR4 agonists all induced the cells to retain TAG for ≥3 days. Prolonged TAG retention was accompanied by the following: (a) enhanced FA uptake and FA incorporation into TAG, with long lasting increases in acyl-CoA synthetase long 1 (ACSL1) and diacylglycerol acyltransferase-2 (DGAT2), and (b) decreases in lipolysis and FA β-oxidation that paralleled a prolonged drop in adipose triglyceride lipase (ATGL). TLR agonist-induced TAG storage is a multifaceted process that persists long after most early pro-inflammatory responses have subsided and may contribute to the formation of “lipid-laden” macrophages in infected tissues.
Background: How microbial agonists induce macrophages to store triglycerides (TAG) for prolonged periods was not known.
Results: Toll-like receptor (TLR)1/2, TLR3, and TLR4 agonists increased fatty acid uptake, increased TAG synthesis, and decreased lipolysis, augmenting TAG storage for ≥72 h.
Conclusion: TAG retention is an active, multifaceted, and long lasting response to sensing microbes.
Significance: Prolonged TAG storage contributes to foam cell formation.
Malaria transmission requires the production of male and female gametocytes in the human host followed by fertilization and sporogonic development in the mosquito midgut. Although essential for the ...spread of malaria through the population, little is known about the initiation of gametocytogenesis in vitro or in vivo. Using a gametocyte-defective parasite line and genetic complementation, we show that Plasmodium falciparumgametocyte development 1 gene (Pfgdv1), encoding a peri-nuclear protein, is critical for early sexual differentiation. Transcriptional analysis of Pfgdv1 negative and positive parasite lines identified a set of gametocytogenesis early genes (Pfge) that were significantly down-regulated (>10 fold) in the absence of Pfgdv1 and expression was restored after Pfgdv1 complementation. Progressive accumulation of Pfge transcripts during successive rounds of asexual replication in synchronized cultures suggests that gametocytes are induced continuously during asexual growth. Comparison of Pfge gene transcriptional profiles in patient samples divided the genes into two groups differing in their expression in mature circulating gametocytes and providing candidates to evaluate gametocyte induction and maturation separately in vivo. The expression profile of one of the early gametocyte specific genes, Pfge1, correlated significantly with asexual parasitemia, which is consistent with the ongoing induction of gametocytogenesis during asexual growth observed in vitro and reinforces the need for sustained transmission-blocking strategies to eliminate malaria.
•New models of nanoparticle melting based on the Maxwell–Cattaneo equation are proposed.•Consider temperature profiles that are continuous or have a jump across the solid–liquid interface.•The jump ...condition for the temperature is derived by taking a sharp-interface limit of a phase-field model.•The jump condition is the most suitable condition to use in phase-change models based on the Maxwell–Cattaneo equation.•Thermal relaxation is shown to substantially slow the melting process.
The role of thermal relaxation in nanoparticle melting is studied using a mathematical model based on the Maxwell–Cattaneo equation for heat conduction. The model is formulated in terms of a two-phase Stefan problem. We consider the cases of the temperature profile being continuous or having a jump across the solid–liquid interface. The jump conditions are derived from the sharp-interface limit of a phase-field model that accounts for variations in the thermal properties between the solid and liquid. The Stefan problem is solved using asymptotic and numerical methods. The analysis reveals that the Fourier-based solution can be recovered from the classical limit of zero relaxation time when either boundary condition is used. However, only the jump condition avoids the onset of unphysical “supersonic” melting, where the speed of the melt front exceeds the finite speed of heat propagation. These results conclusively demonstrate that the jump condition, not the continuity condition, is the most suitable for use in models of phase change based on the Maxwell–Cattaneo equation. Numerical investigations show that thermal relaxation can increase the time required to melt a nanoparticle by more than a factor of ten. Thus, thermal relaxation is an important process to include in models of nanoparticle melting and is expected to be relevant in other rapid phase-change processes.
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