Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation.

The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.

Ibrutinib-based therapy reinvigorates CD8+ T cells compared to chemoimmunotherapy: immune monitoring from the E1912 trial.

ABSTRACT: Bruton tyrosine kinase inhibitors (BTKis) that target B-cell receptor signaling have led to a paradigm shift in chronic lymphocytic leukemia (CLL) treatment. BTKis have been shown to reduce abnormally high CLL-associated T-cell counts and the expression of immune checkpoint receptors concomitantly with tumor reduction. However, the impact of BTKi therapy on T-cell function has not been fully characterized. Here, we performed longitudinal immunophenotypic and functional analysis of pretreatment and on-treatment (6 and 12 months) peripheral blood samples from patients in the phase 3 E1912 trial comparing ibrutinib-rituximab with fludarabine, cyclophosphamide, and rituximab (FCR). Intriguingly, we report that despite reduced overall T-cell counts; higher numbers of T cells, including effector CD8+ subsets at baseline and at the 6-month time point, associated with no infections; and favorable progression-free survival in the ibrutinib-rituximab arm. Assays demonstrated enhanced anti-CLL T-cell killing function during ibrutinib-rituximab treatment, including a switch from predominantly CD4+ T-cell:CLL immune synapses at baseline to increased CD8+ lytic synapses on-therapy. Conversely, in the FCR arm, higher T-cell numbers correlated with adverse clinical responses and showed no functional improvement. We further demonstrate the potential of exploiting rejuvenated T-cell cytotoxicity during ibrutinib-rituximab treatment, using the bispecific antibody glofitamab, supporting combination immunotherapy approaches.

Combined free-running four-dimensional anatomical and flow magnetic resonance imaging with native contrast using Synchronization of Neighboring Acquisitions by Physiological Signals.

BACKGROUND: Four-dimensional (4D) flow magnetic resonance imaging (MRI) often relies on the injection of gadolinium- or iron-oxide-based contrast agents to improve vessel delineation. In this work, a novel technique is developed to acquire and reconstruct 4D flow data with excellent dynamic visualization of blood vessels but without the need for contrast injection. Synchronization of Neighboring Acquisitions by Physiological Signals (SyNAPS) uses pilot tone (PT) navigation to retrospectively synchronize the reconstruction of two free-running three-dimensional radial acquisitions, to create co-registered anatomy and flow images. METHODS: Thirteen volunteers and two Marfan syndrome patients were scanned without contrast agent using one free-running fast interrupted steady-state (FISS) sequence and one free-running phase-contrast MRI (PC-MRI) sequence. PT signals spanning the two sequences were recorded for retrospective respiratory motion correction and cardiac binning. The magnitude and phase images reconstructed, respectively, from FISS and PC-MRI, were synchronized to create SyNAPS 4D flow datasets. Conventional two-dimensional (2D) flow data were acquired for reference in ascending (AAo) and descending aorta (DAo). The blood-to-myocardium contrast ratio, dynamic vessel area, net volume, and peak flow were used to compare SyNAPS 4D flow with Native 4D flow (without FISS information) and 2D flow. A score of 0-4 was given to each dataset by two blinded experts regarding the feasibility of performing vessel delineation. RESULTS: Blood-to-myocardium contrast ratio for SyNAPS 4D flow magnitude images (1.5 ± 0.3) was significantly higher than for Native 4D flow (0.7 ± 0.1, p < 0.01) and was comparable to 2D flow (2.3 ± 0.9, p = 0.02). Image quality scores of SyNAPS 4D flow from the experts (M.P.: 1.9 ± 0.3, E.T.: 2.5 ± 0.5) were overall significantly higher than the scores from Native 4D flow (M.P.: 1.6 ± 0.6, p = 0.03, E.T.: 0.8 ± 0.4, p < 0.01) but still significantly lower than the scores from the reference 2D flow datasets (M.P.: 2.8 ± 0.4, p < 0.01, E.T.: 3.5 ± 0.7, p < 0.01). The Pearson correlation coefficient between the dynamic vessel area measured on SyNAPS 4D flow and that from 2D flow was 0.69 ± 0.24 for the AAo and 0.83 ± 0.10 for the DAo, whereas the Pearson correlation between Native 4D flow and 2D flow measurements was 0.12 ± 0.48 for the AAo and 0.08 ± 0.39 for the DAo. Linear correlations between SyNAPS 4D flow and 2D flow measurements of net volume (r2 = 0.83) and peak flow (r2 = 0.87) were larger than the correlations between Native 4D flow and 2D flow measurements of net volume (r2 = 0.79) and peak flow (r2 = 0.76). CONCLUSION: The feasibility and utility of SyNAPS were demonstrated for joint whole-heart anatomical and flow MRI without requiring electrocardiography gating, respiratory navigators, or contrast agents. Using SyNAPS, a high-contrast anatomical imaging sequence can be used to improve 4D flow measurements that often suffer from poor delineation of vessel boundaries in the absence of contrast agents.

The Role of Narrow Aortic Bifurcation in Affecting EVAR Treatment and Outcomes.

BACKGROUND: The narrow aortic bifurcation (NAB) is considered a risk factor for endograft thrombosis after aorto-biiliac endovascular aneurysm repair (EVAR) for aortic or iliac aneurysm. Nowadays, no consensus on the threshold diameter for the definition of NAB is reached and other aortic bifurcation features are rarely considered. The aim of the study is to assess the EVAR outcomes using bifurcated endograft according to anatomical characteristics of aortic bifurcation. METHODS: The study included patients treated with primary EVAR from 2016 to 2022. A retrospective analysis of single-center prospectively collected database was performed. Patients were classified in standard aortic bifurcation (SAB) (aortic bifurcation diameter >20 mm), NAB (≤20 mm and >16 mm), and extremely NAB (eNAB) (≤16 mm). The 3 groups were compared in terms of patient demographics, risk factors, procedure setting (elective or urgent/emergent), and type of deployed endograft. In NAB and eNAB groups, severe calcification (SC) and length of stenotic aortic bifurcation >10 mm (long-NAB) were assessed from preoperative imaging. In SAB, NAB, and eNAB groups, following outcomes were evaluated: rate of intraoperative iliac endograft stenting (unilateral or kissing stenting), primary patency (PP), freedom from endograft-related reintervention, and overall survival during follow-up. RESULTS: The total number of deployed aorto-biiliac endografts was 365 (mean age: 76.6 ± 7.4 years; male 89.3%): SAB 298 (81.6%), NAB 57 (15.6%), and eNAB 10 (2.7%) cases. Female gender, chronic obstructive pulmonary disease patients, and active smokers were more frequent in patients with smaller aortic bifurcation diameter (P = 0.002, 0.039, and 0.010, respectively). In NAB and eNAB groups, SC was reported in 18/67 cases (26.9%) and long-NAB in 15/67 cases (25.4%). Patients with eNAB have more frequent SC of aortic bifurcation (60% vs. NAB 21.1%, P = 0.018) and long-NAB (50% vs. NAB 17.5%, P = 0.023). In SAB, NAB, and eNAB, intraoperative iliac endograft stenting was performed in 34/298 (11.4%), 9/57 (15.8%), and 5/10 (50%), respectively (P = 0.001). Kissing stenting was performed more frequently in groups with smaller aortic bifurcation diameter (P = 0.010). Mean follow-up was 30.2 ± 21.5 months. At 1, 3, and 5 years, PP was 98.5%, 96.6%, and 95.6%, respectively. eNAB had lower rate of PP compared to NAB group (P = 0.030). Long-NAB had lower rate of PP (P = 0.035). At 1, 3, and 5 years, endograft-related reintervention was 96.8%, 86.7%, and 76.7%, respectively, with no differences between 3 groups (P = 0.423). At 1, 3, and 5 years, survival was 92.5%, 77.6%, and 58.1%, respectively, with no difference between SAB, NAB, and eNAB (P = 0.673). CONCLUSIONS: Female gender, chronic obstructive pulmonary disease patients, and active smokers have more frequently smaller aortic bifurcation diameter. eNAB patients have more challenging anatomical characteristics compared with NAB group, requiring higher rate of intraoperative stenting, especially kissing stenting. Mid-term PP seems to be negatively influenced by aortic bifurcation ≤16 mm and long-NAB.

Cortisol enhances aerobic metabolism and locomotor performance during the transition to land in an amphibious fish.

Amphibious fishes on land encounter higher oxygen (O2) availability and novel energetic demands, which impacts metabolism. Previous work on the amphibious mangrove killifish (Kryptolebias marmoratus) has shown that cortisol becomes elevated in response to air exposure, suggesting a possible role in regulating metabolism as fish move into terrestrial environments. We tested the hypothesis that cortisol is the mechanism by which oxidative processes are upregulated during the transition to land in amphibious fishes. We used two groups of fish, treated fish (+metyrapone, a cortisol synthesis inhibitor) and control (-metyrapone), to determine the impact of cortisol during air exposure (0 and 1 h, 7 days) on O2 consumption, terrestrial locomotion, the phenotype of red skeletal muscle, and muscle lipid concentration. Metyrapone-treated fish had an attenuated elevation in O2 consumption rate during the water to air transition and an immediate reduction in terrestrial exercise performance relative to control fish. In contrast, we found no short- (0 h) or long-term (7 days) differences between treatments in the oxidative phenotype of red muscles, nor in muscle lipid concentrations. Our results suggest that cortisol stimulates the necessary increase in aerobic metabolism needed to fuel the physiological changes that amphibious fishes undergo during the acclimation to air, although further studies are required to determine specific mechanisms of cortisol regulation.

Reporting guidelines for terrestrial respirometry: Building openness, transparency of metabolic rate and evaporative water loss data.

Respirometry is an important tool for understanding whole-animal energy and water balance in relation to the environment. Consequently, the growing number of studies using respirometry over the last decade warrants reliable reporting and data sharing for effective dissemination and research synthesis. We provide a checklist guideline on five key sections to facilitate the transparency, reproducibility, and replicability of respirometry studies: 1) materials, set up, plumbing, 2) subject conditions/maintenance, 3) measurement conditions, 4) data processing, and 5) data reporting and statistics, each with explanations and example studies. Transparency in reporting and data availability has benefits on multiple fronts. Authors can use this checklist to design and report on their study, and reviewers and editors can use the checklist to assess the reporting quality of the manuscripts they review. Improved standards for reporting will enhance the value of primary studies and will greatly facilitate the ability to carry out higher quality research syntheses to address ecological and evolutionary theories.

Cholesterol-Containing Liposomes Decorated With Au Nanoparticles as Minimal Tunable Fusion Machinery.

Membrane fusion is essential for the basal functionality of eukaryotic cells. In physiological conditions, fusion events are regulated by a wide range of specialized proteins, operating with finely tuned local lipid composition and ionic environment. Fusogenic proteins, assisted by membrane cholesterol and calcium ions, provide the mechanical energy necessary to achieve vesicle fusion in neuromediator release. Similar cooperative effects must be explored when considering synthetic approaches for controlled membrane fusion. We show that liposomes decorated with amphiphilic Au nanoparticles (AuLips) can act as minimal tunable fusion machinery. AuLips fusion is triggered by divalent ions, while the number of fusion events dramatically changes with, and can be finely tuned by, the liposome cholesterol content. We combine quartz-crystal-microbalance with dissipation monitoring (QCM-D), fluorescence assays, and small-angle X-ray scattering (SAXS) with molecular dynamics (MD) at coarse-grained (CG) resolution, revealing new mechanistic details on the fusogenic activity of amphiphilic Au nanoparticles (AuNPs) and demonstrating the ability of these synthetic nanomaterials to induce fusion regardless of the divalent ion used (Ca2+ or Mg2+ ). The results provide a novel contribution to developing new artificial fusogenic agents for next-generation biomedical applications that require tight control of the rate of fusion events (e.g., targeted drug delivery).

SPARCQ: A new approach for fat fraction mapping using asymmetries in the phase-cycled balanced SSFP signal profile.

PURPOSE: To develop SPARCQ (Signal Profile Asymmetries for Rapid Compartment Quantification), a novel approach to quantify fat fraction (FF) using asymmetries in the phase-cycled balanced SSFP (bSSFP) profile. METHODS: SPARCQ uses phase-cycling to obtain bSSFP frequency profiles, which display asymmetries in the presence of fat and water at certain TRs. For each voxel, the measured signal profile is decomposed into a weighted sum of simulated profiles via multi-compartment dictionary matching. Each dictionary entry represents a single-compartment bSSFP profile with a specific off-resonance frequency and relaxation time ratio. Using the results of dictionary matching, the fractions of the different off-resonance components are extracted for each voxel, generating quantitative maps of water and FF and banding-artifact-free images for the entire image volume. SPARCQ was validated using simulations, experiments in a water-fat phantom and in knees of healthy volunteers. Experimental results were compared with reference proton density FFs obtained with 1 H-MRS (phantoms) and with multiecho gradient-echo MRI (phantoms and volunteers). SPARCQ repeatability was evaluated in six scan-rescan experiments. RESULTS: Simulations showed that FF quantification is accurate and robust for SNRs greater than 20. Phantom experiments demonstrated good agreement between SPARCQ and gold standard FFs. In volunteers, banding-artifact-free quantitative maps and water-fat-separated images obtained with SPARCQ and ME-GRE demonstrated the expected contrast between fatty and non-fatty tissues. The coefficient of repeatability of SPARCQ FF was 0.0512. CONCLUSION: SPARCQ demonstrates potential for fat quantification using asymmetries in bSSFP profiles and may be a promising alternative to conventional FF quantification techniques.

Focused navigation for respiratory-motion-corrected free-running radial 4D flow MRI.

PURPOSE: To validate a respiratory motion correction method called focused navigation (fNAV) for free-running radial whole-heart 4D flow MRI. METHODS: Using fNAV, respiratory signals derived from radial readouts are converted into three orthogonal displacements, which are then used to correct respiratory motion in 4D flow datasets. Hundred 4D flow acquisitions were simulated with non-rigid respiratory motion and used for validation. The difference between generated and fNAV displacement coefficients was calculated. Vessel area and flow measurements from 4D flow reconstructions with (fNAV) and without (uncorrected) motion correction were compared to the motion-free ground-truth. In 25 patients, the same measurements were compared between fNAV 4D flow, 2D flow, navigator-gated Cartesian 4D flow, and uncorrected 4D flow datasets. RESULTS: For simulated data, the average difference between generated and fNAV displacement coefficients was 0.04 ± $$ \pm $$ 0.32 mm and 0.31 ± $$ \pm $$ 0.35 mm in the x and y directions, respectively. In the z direction, this difference was region-dependent (0.02 ± $$ \pm $$ 0.51 mm up to 5.85 ± $$ \pm $$ 3.41 mm). For all measurements (vessel area, net volume, and peak flow), the average difference from ground truth was higher for uncorrected 4D flow datasets (0.32 ± $$ \pm $$ 0.11 cm2 , 11.1 ± $$ \pm $$ 3.5 mL, and 22.3 ± $$ \pm $$ 6.0 mL/s) than for fNAV 4D flow datasets (0.10 ± $$ \pm $$ 0.03 cm2 , 2.6 ± $$ \pm $$ 0.7 mL, and 5.1 ± 0 $$ \pm 0 $$ .9 mL/s, p < 0.05). In vivo, average vessel area measurements were 4.92 ± $$ \pm $$ 2.95 cm2 , 5.06 ± $$ \pm $$ 2.64 cm2 , 4.87 ± $$ \pm $$ 2.57 cm2 , 4.87 ± $$ \pm $$ 2.69 cm2 , for 2D flow and fNAV, navigator-gated and uncorrected 4D flow datasets, respectively. In the ascending aorta, all 4D flow datasets except for the fNAV reconstruction had significantly different vessel area measurements from 2D flow. Overall, 2D flow datasets demonstrated the strongest correlation to fNAV 4D flow for both net volume (r2  = 0.92) and peak flow (r2  = 0.94), followed by navigator-gated 4D flow (r2  = 0.83 and r2  = 0.86, respectively), and uncorrected 4D flow (r2  = 0.69 and r2  = 0.86, respectively). CONCLUSION: fNAV corrected respiratory motion in vitro and in vivo, resulting in fNAV 4D flow measurements that are comparable to those derived from 2D flow and navigator-gated Cartesian 4D flow datasets, with improvements over those from uncorrected 4D flow.

Carotid endarterectomy in asymptomatic octogenarians: Outcomes at 30 days and 5 years.

BACKGROUND: The following study investigated the 30-day and 5-year relative survival rate and freedom from neurological events in asymptomatic carotid stenosis (ACS) octogenarians who had undergone elective carotid endarterectomy (CEA). METHODS: Between January 2008 and June 2014, a retrospective review was conducted on ACS patients who had undergone elective CEA. The patients' sample was divided into two groups: Group A (GA) included octogenarians and Group B (GB) included younger patients. The GA patients were subjected to a risk-scoring system and follow-up. The two groups were compared analysing the following primary endpoints: 30-day mortality, stroke, stroke/death and acute myocardial infarction (AMI); GA patients' survival rate and freedom from neurological events at 5 years. The 30-day secondary endpoints included carotid shunting, redo surgical, need for general anaesthesia with preserved consciousness (GAPC) conversion and length of hospital stay. RESULTS: We identified 620 patients with ACS, of them 144 (23.2%) belonged to the GA and 476 (76.8%) belonged to the GB. No statistical difference between the two groups was found regarding the primary and secondary endpoints. One hundred nineteen of 144 GA patients (82.6%) underwent the follow-up; the median follow-up was 78.3 months. The GA patients' 5-year survival rate was 62%, while freedom from cerebral events was 94.9%. Analysis regarding GA patients' 5-year survival rate revealed a significantly lower percentage among the patients with a severe risk score compared with those with a moderate risk score (respectively, 29.5% vs 67.7%; p = .005). The multivariate analysis showed that chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) were independently associated with lower survival. CONCLUSIONS: The 30-day outcomes of CEA in octogenarians are comparable to those in younger patients. Comprehensive life expectancy and preoperative score, rather than age alone, should be taken into account before performing CEA on octogenarian patients, considering the short- and long-term efficacy in stroke prevention.

More than Breathing Air: Evolutionary Drivers and Physiological Implications of an Amphibious Lifestyle in Fishes.

Amphibious and aquatic air-breathing fishes both exchange respiratory gasses with the atmosphere, but these fishes differ in physiology, ecology, and possibly evolutionary origins. We introduce a scoring system to characterize interspecific variation in amphibiousness and use this system to highlight important unanswered questions about the evolutionary physiology of amphibious fishes.

LRG1: an emerging player in disease pathogenesis.

The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1-/- mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFß signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFß signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.

Context-dependent relationships between swimming, terrestrial jumping and body composition in the amphibious fish Kryptolebias marmoratus.

Understanding the mechanisms that create phenotypic variation within and among populations is a major goal of physiological ecology. Variation may be a consequence of functional trade-offs (i.e. improvement in one trait comes at the expense of another trait) or alternatively may reflect the intrinsic quality of an organism (i.e. some individuals are simply better overall performers than others). There is evidence for both ideas in the literature, suggesting that environmental context may mediate whether variation results from trade-offs or differences in individual quality. We tested this overarching 'context dependence' hypothesis by comparing the aquatic and terrestrial athletic performance of the amphibious fish Kryptolebias marmoratus captured from two contrasting habitats, a large pond and small burrows. Overall, pond fish were superior terrestrial athletes but burrow fish were better burst swimmers, suggestive of a performance trade-off at the population level. Within each population, however, there was no evidence of a performance trade-off. In burrow fish, athletic performance was positively correlated with muscle content and body condition, consistent with the individual quality hypothesis. In pond fish, there was only a relationship between glycolytic white muscle and aquatic burst performance. Notably, pond fish were in better body condition, which may mask relationships between condition and athletic performance. Overall, our data highlight that population-level trends are insufficient evidence for the existence of phenotypic trade-offs in the absence of similar within-population patterns. Furthermore, we only found evidence for the individual quality hypothesis in one population, suggesting that patterns of phenotypic covariance are context dependent.

Physiological and behavioural strategies of aquatic animals living in fluctuating environments.

Shallow or near-shore environments, such as ponds, estuaries and intertidal zones, are among the most physiologically challenging of all aquatic settings. Animals inhabiting these environments experience conditions that fluctuate markedly over relatively short temporal and spatial scales. Living in these habitats requires the ability to tolerate the physiological disturbances incurred by these environmental fluctuations. This tolerance is achieved through a suite of physiological and behavioural responses that allow animals to maintain homeostasis, including the ability to dynamically modulate their physiology through reversible phenotypic plasticity. However, maintaining the plasticity to adjust to some stresses in a dynamic environment may trade off with the capacity to deal with other stressors. This paper will explore studies on select fishes and invertebrates exposed to fluctuations in dissolved oxygen, salinity and pH. We assess the physiological mechanisms these species employ to achieve homeostasis, with a focus on the plasticity of their responses, and consider the resulting physiological trade-offs in function. Finally, we discuss additional factors that may influence organismal responses to fluctuating environments, such as the presence of multiple stressors, including parasites. We echo recent calls from experimental biologists to consider physiological responses to life in naturally fluctuating environments, not only because they are interesting in their own right but also because they can reveal mechanisms that may be crucial for living with increasing environmental instability as a consequence of climate change.

Correction: Development of a transferable coarse-grained model of polydimethylsiloxane.

Correction for 'Development of a transferable coarse-grained model of polydimethylsiloxane' by Sonia Cambiaso et al., Soft Matter, 2022, https://doi.org/10.1039/d2sm00939k.

Development of a transferable coarse-grained model of polydimethylsiloxane.

Polydimethylsiloxane (PDMS) is a popular silicon-based polymer with advanced applications in microfluidics and nanocomposites. The slow dynamics of polymer chains in such complex systems hinders molecular dynamics investigations based on all atom force fields. This limitation can be overcome by exploiting finely tuned coarse-grained (CG) models. This paper develops a transferable CG model of PDMS, compatible with the recent Martini 3 force field, using structural and thermodynamic properties as targets in the parametrization, including a vast set of experimental free energies of transfer. We validate the model transferability by reproducing the correct scaling laws for the PDMS gyration radius in the melt and good and bad solvents. We successfully test the model by reproducing the wetting behavior of water and acetonitrile on PDMS and the phase behavior of a PDMS-peptide triblock copolymer system. This work sets the stage for computational studies involving the interaction between PDMS and many synthetic and biological molecules modeled within the Martini framework.

Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization.

[Figure: see text].

Habitat choice promotes and constrains phenotypic plasticity.

Habitat choice can either speed up or slow rates of phenotypic evolution, depending on which trait is measured. We suggest that habitat choice plays an analogous, and generally overlooked, role in shaping patterns of phenotypic plasticity. Using our work with an amphibious fish, we discuss two case studies that demonstrate how habitat choice can both promote and constrain expression of plasticity. First, habitat choice during the dry season accentuates adaptive metabolic plasticity and minimizes maladaptive changes to muscle, ultimately increasing survival time out of water. Second, a trade-off between water- and air-breathing drives matching habitat choice, resulting in positive feedback that reinforces respiratory specialization and environmental preference. Overall, these case studies demonstrate that we must consider the interactions between plasticity and habitat choice to fully understand how animals survive in the face of environmental change. Without considering both processes simultaneously, the performance of animals in challenging conditions can be either under- or over-estimated. Finally, because habitat choice shapes the frequency and predictability of environmental changes that animals experience, feedback between habitat choice and expressions of phenotypic plasticity may be an important factor that influences how plasticity evolves.

CD148 Deficiency in Fibroblasts Promotes the Development of Pulmonary Fibrosis.

Rationale: CD148/PTRJ (receptor-like protein tyrosine phosphatase η) exerts antifibrotic effects in experimental pulmonary fibrosis via interactions with its ligand syndecan-2; however, the role of CD148 in human pulmonary fibrosis remains incompletely characterized.Objectives: We investigated the role of CD148 in the profibrotic phenotype of fibroblasts in idiopathic pulmonary fibrosis (IPF).Methods: Conditional CD148 fibroblast-specific knockout mice were generated and exposed to bleomycin and then assessed for pulmonary fibrosis. Lung fibroblasts (mouse lung and human IPF lung), and precision-cut lung slices from human patients with IPF were isolated and subjected to experimental treatments. A CD148-activating 18-aa mimetic peptide (SDC2-pep) derived from syndecan-2 was evaluated for its therapeutic potential.Measurements and Main Results: CD148 expression was downregulated in IPF lungs and fibroblasts. In human IPF lung fibroblasts, silencing of CD148 increased extracellular matrix production and resistance to apoptosis, whereas overexpression of CD148 reversed the profibrotic phenotype. CD148 fibroblast-specific knockout mice displayed increased pulmonary fibrosis after bleomycin challenge compared with control mice. CD148-deficient fibroblasts exhibited hyperactivated PI3K/Akt/mTOR signaling, reduced autophagy, and increased p62 accumulation, which induced NF-κB activation and profibrotic gene expression. SDC2-pep reduced pulmonary fibrosis in vivo and inhibited IPF-derived fibroblast activation. In precision-cut lung slices from patients with IPF and control patients, SDC2-pep attenuated profibrotic gene expression in IPF and normal lungs stimulated with profibrotic stimuli.Conclusions: Lung fibroblast CD148 activation reduces p62 accumulation, which exerts antifibrotic effects by inhibiting NF-κB-mediated profibrotic gene expression. Targeting the CD148 phosphatase with activating ligands such as SDC2-pep may represent a potential therapeutic strategy in IPF.

A Modular Composite Device of Poly(Ethylene Oxide)/Poly(Butylene Terephthalate) (PEOT/PBT) Nanofibers and Gelatin as a Dual Drug Delivery System for Local Therapy of Soft Tissue Tumors.

In the clinical management of solid tumors, the possibility to successfully couple the regeneration of injured tissues with the elimination of residual tumor cells left after surgery could open doors to new therapeutic strategies. In this work, we present a composite hydrogel-electrospun nanofiber scaffold, showing a modular architecture for the delivery of two pharmaceutics with distinct release profiles, that is potentially suitable for local therapy and post-surgical treatment of solid soft tumors. The composite was obtained by coupling gelatin hydrogels to poly(ethylene oxide)/poly(butylene terephthalate) block copolymer nanofibers. Results of the scaffolds' characterization, together with the analysis of gelatin and drug release kinetics, displayed the possibility to modulate the device architecture to control the release kinetics of the drugs, also providing evidence of their activity. In vitro analyses were also performed using a human epithelioid sarcoma cell line. Furthermore, publicly available expression datasets were interrogated. Confocal imaging showcased the nontoxicity of these devices in vitro. ELISA assays confirmed a modulation of IL-10 inflammation-related cytokine supporting the role of this device in tissue repair. In silico analysis confirmed the role of IL-10 in solid tumors including 262 patients affected by sarcoma as a negative prognostic marker for overall survival. In conclusion, the developed modular composite device may provide a key-enabling technology for the treatment of soft tissue sarcoma.