Phospholipid membranes form cellular barriers but need to be flexible enough to divide by fission. Phospholipids generally contain a saturated fatty acid (FA) at position
whereas the
-FA is ...saturated, monounsaturated or polyunsaturated. Our understanding of the impact of phospholipid unsaturation on membrane flexibility and fission is fragmentary. Here, we provide a comprehensive view of the effects of the FA profile of phospholipids on membrane vesiculation by dynamin and endophilin. Coupled to simulations, this analysis indicates that: (i) phospholipids with two polyunsaturated FAs make membranes prone to vesiculation but highly permeable; (ii) asymmetric
-saturated-
-polyunsaturated phospholipids provide a tradeoff between efficient membrane vesiculation and low membrane permeability; (iii) When incorporated into phospholipids, docosahexaenoic acid (DHA; omega-3) makes membranes more deformable than arachidonic acid (omega-6). These results suggest an explanation for the abundance of
-saturated-
-DHA phospholipids in synaptic membranes and for the importance of the omega-6/omega-3 ratio on neuronal functions.
How proteins are targeted to lipid droplets (LDs) and distinguish the LD surface from the surfaces of other organelles is poorly understood, but many contain predicted amphipathic helices (AHs) that ...are involved in targeting. We have focused on human perilipin 4 (Plin4), which contains an AH that is exceptional in terms of length and repetitiveness. Using model cellular systems, we show that AH length, hydrophobicity, and charge are important for AH targeting to LDs and that these properties can compensate for one another, albeit at a loss of targeting specificity. Using synthetic lipids, we show that purified Plin4 AH binds poorly to lipid bilayers but strongly interacts with pure triglycerides, acting as a coat and forming small oil droplets. Because Plin4 overexpression alleviates LD instability under conditions where their coverage by phospholipids is limiting, we propose that the Plin4 AH replaces the LD lipid monolayer, for example during LD growth.
Autophagy involves engulfment of cytoplasmic contents by double-membraned autophagosomes, which ultimately fuse with lysosomes to enable degradation of their substrates. We recently proposed that the ...tubular-vesicular recycling endosome membranes were a core platform on which the critical early events of autophagosome formation occurred, including LC3-membrane conjugation to autophagic precursors. Here, we report that the release of autophagosome precursors from recycling endosomes is mediated by DNM2-dependent scission of these tubules. This process is regulated by DNM2 binding to LC3 and is increased by autophagy-inducing stimuli. This scission is defective in cells expressing a centronuclear-myopathy-causing DNM2 mutant. This mutant has an unusual mechanism as it depletes normal-functioning DNM2 from autophagosome formation sites on recycling endosomes by causing increased binding to an alternative plasma membrane partner, ITSN1. This “scission” step is, thus, critical for autophagosome formation, is defective in a human disease, and influences the way we consider how autophagosomes are formed.
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•Autophagosome release from recycling endosomes requires DNM2-dependent scission•Recycling endosome scission is regulated by DNM2 binding to LC3•Recycling endosome scission is impaired by a DNM2 centronuclear myopathy mutant•This DNM2 mutant is sequestered from autophagosome formation sites by binding ITSN1
Puri et al. show that autophagosome release from recycling endosomes requires DNM2-dependent scission. This process is enabled by DNM2 binding the core autophagy protein LC3 and is impaired by a DNM2 centronuclear myopathy mutant that is sequestered away from autophagosome formation sites by enhanced binding to plasma membrane ITSN1.
The factors regulating cellular identity are critical for understanding the transition from health to disease and responses to therapies. Recent literature suggests that autophagy compromise may ...cause opposite effects in different contexts by either activating or inhibiting YAP/TAZ co-transcriptional regulators of the Hippo pathway via unrelated mechanisms. Here, we confirm that autophagy perturbation in different cell types can cause opposite responses in growth-promoting oncogenic YAP/TAZ transcriptional signalling. These apparently contradictory responses can be resolved by a feedback loop where autophagy negatively regulates the levels of α-catenins, LC3-interacting proteins that inhibit YAP/TAZ, which, in turn, positively regulate autophagy. High basal levels of α-catenins enable autophagy induction to positively regulate YAP/TAZ, while low α-catenins cause YAP/TAZ activation upon autophagy inhibition. These data reveal how feedback loops enable post-transcriptional determination of cell identity and how levels of a single intermediary protein can dictate the direction of response to external or internal perturbations.
Asthma is a common respiratory disease affecting ∼300 million people worldwide. Airway inflammation is thought to contribute to asthma pathogenesis, but the direct relationship between inflammation ...and airway hyperresponsiveness (AHR) remains unclear. This study investigates the role of inflammation in a steroid-insensitive, severe allergic airway disease model and in severe asthmatics stratified by inflammatory profile. First, we used the T-helper (T(H))-17 cells adoptive transfer mouse model of asthma to induce pulmonary inflammation, which was lessened by tumor necrosis factor (TNF)-α neutralization or neutrophil depletion. Although decreased airspace inflammation following TNFα neutralization and neutrophil depletion rescued lung compliance, neither intervention improved AHR to methacholine, and tissue inflammation remained elevated when compared with control. Further, sputum samples were collected and analyzed from 41 severe asthmatics. In severe asthmatics with elevated levels of sputum neutrophils, but low levels of eosinophils, increased inflammatory markers did not correlate with worsened lung function. This subset of asthmatics also had significantly higher levels of T(H)17-related cytokines in their sputum compared with severe asthmatics with other inflammatory phenotypes. Overall, this work suggests that lung compliance may be linked with cellular inflammation in the airspace, whereas T-cell-driven AHR may be associated with tissue inflammation and other pulmonary factors.
Abstract
The accurate estimation of buildings’ solar potential contributes to boost the exploitation of solar energy at high latitudes. The decomposition of global irradiation into the direct and ...diffuse fractions is a fundamental step of the solar irradiance model chain. Diffuse and direct irradiation are, in fact, rarely measured. Previous works recommended Yang4 as the decomposition model with the best overall performance. However, in geographically limited applications, quasi-universal decomposition models such as Yang4 and Engerer4 can be outperformed by local models (i.e., models parametrized with climate-specific data) such as Skartveit3 and Starke3. This makes necessary to perform local validation studies to verify the findings from worldwide validation studies. In this study, the four decomposition models are implemented in Python and experimentally validated against one-minute solar irradiance data (i.e., direct and diffuse irradiance) of Trondheim (Lat. 63°26’ N, Norway). Two months representative of clear sky (August) and overcast (October) conditions are considered. The study confirms that the Yang4 model performed the best for high-latitude application: the nMBE ranged from -0.54% (August) to 0.65% (October), the nRMSE from 17.18% (August) to 22.29% (October), and the R
2
from 0.96 (August) to 0.97 (October). However, Skartveit3 combines a level of performance close to Yang4 with the lower number of input parameters.
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of haematological cancers with generally poor clinical outcomes. However, a subset of patients experience durable disease control, and ...little is known regarding long-term outcomes. The International T-cell Lymphoma Project (ITCLP) is the largest prospectively collected cohort of patients with PTCLs, providing insight into clinical outcomes at academic medical centres globally. We performed a long-term outcome analysis on patients from the ITCLP with available 10-year follow-up data (n = 735). The overall response rate to first-line therapy was 68%, while 5- and 10-year overall survival estimates were 49% and 40% respectively. Most deaths occurred prior to 5 years, and for patients alive at 5 years, the chance of surviving to 10 years was 84%. However, lymphoma remained the leading cause of death in the 5- to 10-year period (67%). Low-risk International Prognostic Index and Prognostic Index for T-cell lymphoma scores both identified patients with improved survival, while in multivariate analysis, age >60 years and Eastern Cooperative Oncology Group performance status 2-4 were associated with inferior outcomes. The favourable survival seen in patients achieving durable initial disease control emphasizes the unmet need for optimal front-line therapeutic approaches in PTCLs.
•Lipidomic data of Cer and SM species in 35 mammalian tissues/cells are provided.•The sphingoid base was predominantly d18-1 sphingosine in all cases.•The most abundant Cer species were those ...containing C24:0 and C24:1 acyl chains.•The main SM species was C16:0.•Brain was an exception, with Cer and SM C18:0 as the main species.
Sphingolipids consist of a sphingoid base N-linked to a fatty acyl chain. Among them, sphingomyelins (SM) are major components of mammalian cells, while ceramide (Cer) plays an important role as a lipid second messenger. We have performed a quantitative lipidomic study of Cer and SM species in different mammalian tissues (adipose tissue, liver, brain and blood serum of human, mice, rat and dog), as well as in cell cultures of mammalian origin (primary hepatocytes, immortalized MDCK cells, mice melanoma b16 cells, and mice primary CD4 + T lymphocytes) using an ultra-high performance liquid chromatography coupled to time-of-flight mass spectrometry (UHPLC-ToF-MS)-based platform. The data have been compared with published, in general semi-quantitative, results from 20 other samples, with good agreement. The sphingoid base was predominantly d18-1 sphingosine (2-amino-4-octadecene-1,3-diol) in all cases. The fatty acid composition of SM was clearly different from that of Cer. In virtually all samples the most abundant Cer species were those containing C24:0 and C24:1 in their N-acyl chains, while the main species contained in SM was C16:0. Brain was the most divergent tissue, in which Cer and SM C18:0 were very abundant.
Primary refractory (PREF) follicular lymphoma (FL) has a completely different clinical course from that of FL that responds to front-line treatments. In addition to having poor responses to salvage ...therapies, it seems that patients with PREF are at increased risk of histological transformation (HT). The Aristotle consortium presented the opportunity of investigating the risk of HT in a very large series of cases. Thus, we investigated the risk of HT in patients with PREF FL compared with that of responding patients or in stable disease and ultimately their outcome.
Six thousand three hundred thirty-nine patients from the Aristotle database were included in the analysis. These patients had a histologically confirmed grade 1, 2 or 3a FL diagnosed between 1997 and 2013. The primary end-points were the cumulative incidence (CI) of HT at the first progression or relapse and the survival after transformation.
The 5-year CI of HT among patients with PREF was 34% (95% confidence interval (CI): 27–43), whilst it was 7.1% (95% CI: 6.0–8.5) in the group of patients with partial response (PR) or stable disease (SD) (PR + SD) and 3.5% (95% CI: 3.0–4.2) in the group of patients achieving complete response (CR). The 5-year survival after relapse (SAR) was 33% (95% CI: 28–39) for the PREF group, 57% (95% CI 54–61) in patients with PR, 51% (95% CI 43–58) in the SD group after first-line therapy and 63% (95% CI: 66–72) in patients with CR after initial treatment (p-value <0.001). The 5-year SAR for those patients with PREF who developed HT was 21% (95% CI: 12–31), clearly diminished when compared with those patients with PREF who did not experience HT (38% 95% CI: 31–44) (p-value = 0.001).
Patients with PREF FL have a dismal outcome and an associated very high rate of HT that further worsens their poor prognosis.
•Five per cent of patients with follicular lymphoma (FL) were primary refractory to initial treatment.•These patients have increased risk of developing histological transformation (HT).•HT in this group of patients worsens their already poor survival.•Hidden transformation at diagnosis should be investigated in this group of patients.
Abstract
This study presents a monitoring network for solar irradiation at high latitudes, called NTNU-SINTEF SolarNet. The network collects, with a time resolution ranging from seconds to hours, ...solar irradiance data, e.g. global horizontal irradiation, diffuse horizontal irradiation, direct normal irradiation, global tilted irradiation, solar energy generation, which are required in solar irradiation modelling in built environments. The network will be used for specific applications, such as (i) anomalies detection, (ii) influences of ground albedo, and (iii) ageing/degradation of solar modules, that are described in this paper. Some characteristics that make the NTNU-SINTEF SolarNet relevant for solar energy research at high latitudes are identified: short distances among the sensors, the ease of data accessibility, the use of the same sensor typologies, and different solar module technologies. The research holds the potential to boost the solar energy digitalization, impacting on several aspects such as predictive and adaptive control strategies for energy management, design of renewable energy system, multi-scale optimization and efficient exploitation of solar energy.
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