The vital functions of cell membranes require their ability to quickly change shape to perform complex tasks such as motion, division, endocytosis, and apoptosis. Membrane curvature in cells is ...modulated by very complex processes such as changes in lipid composition, the oligomerization of curvature-scaffolding proteins, and the reversible insertion of protein regions that act like wedges in the membrane. But, could much simpler mechanisms support membrane shape transformation? In this work, we demonstrate how the change of amphiphile topology in the bilayer can drive shape transformations of cell membrane models. To tackle this, we have designed and synthesized new types of amphiphiles-Janus dendrimers-that self-assemble into uni-, multilamellar, or smectic-ordered vesicles, named dendrimersomes. We synthesized Janus dendrimers containing a photo-labile bond that upon UV-Vis irradiation cleavage lose a part of the hydrophilic dendron. This leads to a change from a cylindrically to a wedge-shaped amphiphile. The high mobility of these dendrimers allows for the concentration of the wedge-shaped amphiphiles and the generation of transmembrane asymmetries. The concentration of the wedges and their rate of segregation allowed control of the budding and generation of structures such as tubules and high genus vesicles.
Using cell-mimetic dendrimersomes we demonstrated how changes in the molecular topology of the amphiphilic Janus dendrimers forming the bilayer lead to the evolution of shape without the need for any active cellular machinery.
The accurate spatial segregation into distinct phases within cell membranes coordinates vital biochemical processes and functionalities in living organisms. One of nature’s strategies to localize ...reactivity is the formation of dynamic raft domains. Most raft models rely on liquid-ordered L 0 phases in a liquid-disordered L d phase lacking correlation and remaining static, often necessitating external agents for phase separation. Here, we introduce a synthetic system of bicomponent glycodendrimersomes coassembled from Janus dendrimers and Janus glycodendrimers (JGDs), where lactose–lactose interactions exclusively drive lateral organization. This mechanism results in modulated phases across two length scales, yielding raft-like microdomains featuring nanoarrays at the nanoscale. By varying the density of lactose and molecular architecture of JGDs, the nanoarray type and size, shape, and spacing of the domains were controlled. Our findings offer insight into the potential primordial origins of rudimentary raft domains and highlight the crucial role of glycans within the glycocalyx.
The construction of biomembranes that faithfully capture the properties and dynamic functions of cell membranes remains a challenge in the development of synthetic cells and their application. Here a ...new concept for synthetic cell membranes based on the self‐assembly of amphiphilic comb polymers into vesicles, termed ionic combisomes (i‐combisomes) is introduced. These combs consist of a polyzwitterionic backbone to which hydrophobic tails are linked by electrostatic interactions. Using a range of microscopies and molecular simulations, the self‐assembly of a library of combs in water is screened. It is discovered that the hydrophobic tails form the membrane's core and force the backbone into a rod conformation with nematic‐like ordering confined to the interface with water. This particular organization resulted in membranes that combine the stability of classic polymersomes with the biomimetic thickness, flexibility, and lateral mobility of liposomes. Such unparalleled matching of biophysical properties and the ability to locally reconfigure the molecular topology of its constituents enable the harboring of functional components of natural membranes and fusion with living bacteria to “hijack” their periphery. This provides an almost inexhaustible palette to design the chemical and biological makeup of the i‐combisomes membrane resulting in a powerful platform for fundamental studies and technological applications.
Comb polymers with a zwitterionic backbone and ionically‐linked side chains are self‐assembled into a new class of vesicles that amalgamates the high stability of polymersomes with the biomimetic thickness, flexibility, and lateral mobility of liposomes. The faithful biomimicry enables to integrate functional components and hijack the complex periphery of living cells by fusion.
A series of
N-substituted acridone-4-carboxamides have been synthesized and their anti-HCV and anti-T7 polymerase activity tested. Two compounds were efficient inhibitors of HCV RNA replication in a ...human hepatoma cell line.
A new class of compounds—acridone derivatives—was tested using the direct fluorometric helicase activity assay to determine the inhibitory properties of the derivatives towards the NS3 helicase of
Hepatitis C virus (HCV). The compounds were also tested as putative transcription inhibitors of in vitro transcription based on the DNA-dependent T7 RNA polymerase. Most of the acridone derivatives tested were transcription inhibitors; however, only four of them inhibited the NS3 helicase at low concentrations (IC
50 from 3
μM to 20
μM) and were therefore selected for further studies on the mechanism of inhibition. The acridone derivatives probably act via intercalation into double-stranded nucleic acids but they may also interact directly with viral enzymes. Selected carboxamides were tested in the subgenomic HCV replicon system. Two of the compounds:
N-(pyridin-4-yl)-amide and
N-(pyridin-2-yl)-amide of acridone-4-carboxylic acid are efficient RNA replication inhibitors with selectivity indexes of 19.4 and 40.5, respectively, proving that the acridone derivatives may be regarded as potential antiviral agents.
Aim.
To introduce the scientific community to the main results of the international scientific and practical conference “National Identity and Patriotism in States in the Conditions of International ...Crises” which was held on October 28, 2022 and organized by the Department of Comparative Political Science of the Faculty of Political Science of Lomonosov Moscow State University with the support of the electronic network publications “Bulletin of the Moscow Region State University”.
Methodology.
This article presents the abstracts of the speeches of the conference participants who devoted their reports to the problems of national identity and patriotism. The authors were researchers from Moscow State University named after M. V. Lomonosov, INION RAS, Institute of Sociology FNISTs RAS, Northern (Arctic) Federal University named after M. V. Lomonosov (Arkhangelsk), Eurasian National University named after L. N. Gumilyov (Republic of Kazakhstan), University of Mumbai (Republic of India), University of Tair Recep Tayyip Erdogan (Republic of Turkey).
Results.
Using materials from Russia, Kazakhstan, Turkmenistan, Georgia, Belarus, Latvia, China and the Republic of Korea, the speakers showed a wide range of problems of national identity and patriotism. The main attention was paid to the topical issues of the formation of national identity and patriotism, the specifics of national identity in Russia and post-Soviet countries, the impact of stigmatization that fragments national identity and marginalizes the discourse of patriotism.
Research implications.
The published materials are of significant theoretical and practical importance in ensuring the sovereignty of Russia and other states, preserving and developing national identity and patriotic education of citizens under the influence of destructive socio-political technologies. The conclusions and recommendations of the researchers can contribute to the solution of urgent political, educational and educational problems.
Ionic Combisomes
In article number 2200617, Cesar Rodriguez‐Emmenegger and co‐workers present a new family of biomimetic vesicles known to us as ionic combisomes that amalgamates the high stability ...of polymersomes with the biomimetic thickness, flexibility, and lateral mobility of liposomes. The faithful biomimicry enables to integrate functional components, hijack the complex periphery of living cells by fusion and bring us one step closer to hybrid synthetic cells.
Disturbed flow has been suggested to contribute to aneurysm susceptibility in bicuspid aortic valve (BAV) patients. Lately, flow has emerged as an important modulator of DNA methylation. Hear we ...combined global methylation analysis with in vitro studies of flow-sensitive methylation to identify biological processes associated with BAV-aortopathy and the potential contribution of flow. Biopsies from non-dilated and dilated ascending aortas were collected from BAV (n = 21) and tricuspid aortic valve (TAV) patients (n = 23). DNA methylation and gene expression was measured in aortic intima-media tissue samples, and in EA.hy926 and primary aortic endothelial cells (ECs) isolated from BAV and TAV exposed to oscillatory (±12 dynes/cm
) or laminar (12 dynes/cm
) flow. We show methylation changes related to epithelial-mesenchymal-transition (EMT) in the non-dilated BAV aorta, associated with oscillatory flow related to endocytosis. The results indicate that the flow-response in BAV ECs involves hypomethylation and increased expression of WNT/β-catenin genes, as opposed to an angiogenic profile in TAV ECs. The EMT-signature was exasperated in dilated BAV aortas. Aberrant EMT in BAV aortic walls could contribute to increased aneurysm susceptibility, and may be due to disturbed flow-exposure. Perturbations during the spatiotemporally related embryonic development of ascending aorta and semilunar valves can however not be excluded.
Bicuspid aortic valve is the most common congenital heart malformation and the reasons for the aortopathies associated with bicuspid aortic valve remain unclear. NOTCH1 mutations are associated with ...bicuspid aortic valve and have been found in individuals with various left ventricular outflow tract abnormalities. Notch is a key signaling during cardiac valve formation that promotes the endothelial-to-mesenchymal transition. We address the role of Notch signaling in human aortic endothelial cells from patients with bicuspid aortic valve and aortic aneurysm. Aortic endothelial cells were isolated from tissue fragments of bicuspid aortic valve-associated thoracic aortic aneurysm patients and from healthy donors. Endothelial-to-mesenchymal transition was induced by activation of Notch signaling. Effectiveness of the transition was estimated by loss of endothelial and gain of mesenchymal markers by immunocytochemistry and qPCR. We show that aortic endothelial cells from the patients with aortic aneurysm and bicuspid aortic valve have down regulated Notch signaling and fail to activate Notch-dependent endothelial-to-mesenchymal transition in response to its stimulation by different Notch ligands. Our findings support the idea that bicuspid aortic valve and associated aortic aneurysm is associated with dysregulation of the entire Notch signaling pathway independently on the specific gene mutation.
•Patients with bicuspid aortic valve and dilated aortas have attenuated Notch signaling•Endothelial cells derived from aortas of BAV/AoA patients have impaired Notch-dependent EMT induction•Notch pathway defect in BAV-associated aortic aneurysm is not obligatory associated with mutation in NOTCH1
Aortic valve calcification is an active proliferative process, where interstitial cells of the valve transform into either myofibroblasts or osteoblast-like cells causing valve deformation, ...thickening of cusps and finally stenosis. This process may be triggered by several factors including inflammation, mechanical stress or interaction of cells with certain components of extracellular matrix. The matrix is different on the two sides of the valve leaflets. We hypothesize that inflammation and mechanical stress stimulate osteogenic differentiation of human aortic valve interstitial cells (VICs) and this may depend on the side of the leaflet.
Interstitial cells isolated from healthy and calcified human aortic valves were cultured on collagen or elastin coated plates with flexible bottoms, simulating the matrix on the aortic and ventricular side of the valve leaflets, respectively. The cells were subjected to 10% stretch at 1 Hz (FlexCell bioreactor) or treated with 0.1 μg/ml lipopolysaccharide, or both during 24 h. Gene expression of myofibroblast- and osteoblast-specific genes was analyzed by qPCR. VICs cultured in presence of osteogenic medium together with lipopolysaccharide, 10% stretch or both for 14 days were stained for calcification using Alizarin Red.
Treatment with lipopolysaccharide increased expression of osteogenic gene bone morphogenetic protein 2
(5-fold increase from control;
= 0.02) and decreased expression of mRNA of myofibroblastic markers: α-smooth muscle actin
(50% reduction from control;
= 0.0006) and calponin
(80% reduction from control;
= 0.0001) when cells from calcified valves were cultured on collagen, but not on elastin. Mechanical stretch of VICs cultured on collagen augmented the effect of lipopolysaccharide. Expression of periostin
was inhibited in cells from calcified donors after treatment with lipopolysaccharide on collagen (70% reduction from control,
= 0.001), but not on elastin. Lipopolysaccharide and stretch both enhanced the pro-calcific effect of osteogenic medium, further increasing the effect when combined for cells cultured on collagen, but not on elastin.
Inflammation and mechanical stress trigger expression of osteogenic genes in VICs in a side-specific manner, while inhibiting the myofibroblastic pathway. Stretch and lipopolysaccharide synergistically increase calcification.
Members of the genus
Populus
L. play an important role in the formation of forests in the northern hemisphere and are used in urban landscaping and timber production.
Populus
species of closely ...related sections show extensive hybridization. Therefore, the systematics of the genus is rather complicated, especially for poplars of hybrid origin. We aimed to assess the efficiency of application of the sex-determining region (SDR) in addition to the nuclear and chloroplast genome loci traditionally used in phylogenetic studies of poplars to investigate relationships in sections
Aigeiros
Duby and
Tacamahaca
Spach. Targeted deep sequencing of NTS 5S rDNA, ITS,
DSH 2
,
DSH 5
,
DSH 8
,
DSH 12
,
DSH 29
,
6
,
15
,
16
,
X18
,
trnG-psbK-psbI
,
rps2-rpoC2
,
rpoC2-rpoC1
, as well as SDR and
ARR17
gene was performed for 379 poplars. The SDR and
ARR17
gene together with traditionally used multicopy and single-copy loci of nuclear and chloroplast DNA allowed us to obtain a clustering that is most consistent with poplar systematics based on morphological data and to shed light on several controversial hypotheses about the origin of the studied taxa (for example, the inexpediency of separating
P. koreana
,
P. maximowiczii
, and
P. suaveolens
into different species). We present a scheme of relationships between species and hybrids of sections
Aigeiros
and
Tacamahaca
based on molecular genetic, morphological, and geographical data. The geographical proximity of species and, therefore, the possibility of hybridization between them appear to be more important than the affiliation of species to the same section. We speculate that sections
Aigeiros
and
Tacamahaca
are distinguished primarily on an ecological principle (plain and mountain poplars) rather than on a genetic basis. Joint analysis of sequencing data for the SDR and chloroplast genome loci allowed us to determine the ancestors of
P.
×
petrovskoe
–
P. laurifolia
(female tree) ×
P.
×
canadensis
(male tree), and
P.
×
rasumovskoe
–
P. nigra
(female tree) ×
P. suaveolens
(male tree). Thus, the efficiency of using the SDR for the study of poplars of sections
Aigeiros
and
Tacamahaca
and the prospects of its use for the investigation of species of the genus
Populus
were shown.
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