Glycan-Driven Formation of Raft-Like Domains with Hierarchical Periodic Nanoarrays on Dendrimersome Synthetic Cells.

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 L0 phases in a liquid-disordered Ld 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.

Zwitterionic Dendrimersomes: A Closer Xenobiotic Mimic of Cell Membranes.

Building functional mimics of cell membranes is an important task toward the development of synthetic cells. So far, lipid and amphiphilic block copolymers are the most widely used amphiphiles with the bilayers by the former lacking stability while membranes by the latter are typically characterized by very slow dynamics. Herein, a new type of Janus dendrimer containing a zwitterionic phosphocholine hydrophilic headgroup (JDPC ) and a 3,5-substituted dihydrobenzoate-based hydrophobic dendron is introduced. JDPC self-assembles in water into zwitterionic dendrimersomes (z-DSs) that faithfully recapitulate the cell membrane in thickness, flexibility, and fluidity, while being resilient to harsh conditions and displaying faster pore closing dynamics in the event of membrane rupture. This enables the fabrication of hybrid DSs with components of natural membranes, including pore-forming peptides, structure-directing lipids, and glycans to create raft-like domains or onion vesicles. Moreover, z-DSs can be used to create active synthetic cells with life-like features that mimic vesicle fusion and motility as well as environmental sensing. Despite their fully synthetic nature, z-DSs are minimal cell mimics that can integrate and interact with living matter with the programmability to imitate life-like features and beyond.

Dendrimersome Synthetic Cells Harbor Cell Division Machinery of Bacteria.

The integration of active cell machinery with synthetic building blocks is the bridge toward developing synthetic cells with biological functions and beyond. Self-replication is one of the most important tasks of living systems, and various complex machineries exist to execute it. In Escherichia coli, a contractile division ring is positioned to mid-cell by concentration oscillations of self-organizing proteins (MinCDE), where it severs membrane and cell wall. So far, the reconstitution of any cell division machinery has exclusively been tied to liposomes. Here, the reconstitution of a rudimentary bacterial divisome in fully synthetic bicomponent dendrimersomes is shown. By tuning the membrane composition, the interaction of biological machinery with synthetic membranes can be tailored to reproduce its dynamic behavior. This constitutes an important breakthrough in the assembly of synthetic cells with biological elements, as tuning of membrane-divisome interactions is the key to engineering emergent biological behavior from the bottom-up.

Ionic Combisomes: A New Class of Biomimetic Vesicles to Fuse with Life.

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.

Unraveling topology-induced shape transformations in dendrimersomes.

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.

Permafrost Degradation and Subsidence Observations during a Controlled Warming Experiment.

Global climate change has resulted in a warmer Arctic, with projections indicating accelerated modifications to permafrost in the near future. The thermal, hydrological, and mechanical physics of permafrost thaw have been hypothesized to couple in a complex fashion but data collection efforts to study these feedbacks in the field have been limited. As a result, laboratory and numerical models have largely outpaced field calibration datasets. We present the design, execution, and initial results from the first decameter-scale controlled thawing experiment, targeting coupled thermal/mechanical response, particularly the temporal sequence of surface subsidence relative to permafrost degradation at depth. The warming test was conducted in Fairbanks, AK, and utilized an array of in-ground heaters to induce thaw of a ~11 × 13 × 1.5 m soil volume over 63 days. The 4-D temperature evolution demonstrated that the depth to permafrost lowered 1 m during the experiment. The resulting thaw-induced surface deformation was ~10 cm as observed using a combination of measurement techniques. Surface deformation occurred over a smaller spatial domain than the full thawed volume, suggesting that gradients in cryotexture and ice content were significant. Our experiment provides the first large field calibration dataset for multiphysics thaw models.

Distributed Acoustic Sensing for Seismic Monitoring of The Near Surface: A Traffic-Noise Interferometry Case Study.

Ambient-noise-based seismic monitoring of the near surface often has limited spatiotemporal resolutions because dense seismic arrays are rarely sufficiently affordable for such applications. In recent years, however, distributed acoustic sensing (DAS) techniques have emerged to transform telecommunication fiber-optic cables into dense seismic arrays that are cost effective. With DAS enabling both high sensor counts ("large N") and long-term operations ("large T"), time-lapse imaging of shear-wave velocity (V S ) structures is now possible by combining ambient noise interferometry and multichannel analysis of surface waves (MASW). Here we report the first end-to-end study of time-lapse V S imaging that uses traffic noise continuously recorded on linear DAS arrays over a three-week period. Our results illustrate that for the top 20 meters the V S models that is well constrained by the data, we obtain time-lapse repeatability of about 2% in the model domain-a threshold that is low enough for observing subtle near-surface changes such as water content variations and permafrost alteration. This study demonstrates the efficacy of near-surface seismic monitoring using DAS-recorded ambient noise.

Chemical Synthesis and Self-Assembly of a Ladderane Phospholipid.

Ladderane lipids produced by anammox bacteria constitute some of the most structurally fascinating yet poorly studied molecules among biological membrane lipids. Slow growth of the producing organism and the inherent difficulty of purifying complex lipid mixtures have prohibited isolation of useful amounts of natural ladderane lipids. We have devised a highly selective total synthesis of ladderane lipid tails and a full phosphatidylcholine to enable biophysical studies on chemically homogeneous samples of these molecules. Additionally, we report the first proof of absolute configuration of a natural ladderane.

Transition-metal-free acid-mediated synthesis of aryl sulfides from thiols and thioethers.

The preparation of diaryl and alkyl aryl sulfides via acid-mediated coupling of thiols and thioethers with diaryliodonium salts is reported. The scope, limitations, and mechanism of the transformation are discussed.

Platinum-catalyzed C-H arylation of simple arenes.

This report describes the Na2PtCl4 catalyzed C-H arylation of arene substrates with diaryliodonium salts. The site selectivity of these reactions is predominantly controlled by steric factors. Remarkably, Na2PtCl4-catalyzed naphthalene arylation proceeds with opposite site selectivity compared to that obtained with Na2PdCl4 as the catalyst. Preliminary mechanistic studies provide evidence for a Pt(II)/Pt(IV) catalytic cycle involving rate-limiting C-C bond-forming reductive elimination.

Palladium-catalyzed C-H arylation of 2,5-substituted pyrroles.

The palladium-catalyzed direct arylation of 2,5-substituted pyrrole derivatives with diaryliodonium salts to generate tri-, tetra-, and penta-substituted pyrrole products is described. The scope and limitations of these transformations are also reported.

Fetal gene therapy: opportunities and risks.

Advances in human prenatal medicine and molecular genetics have allowed the diagnosis of many genetic diseases early in gestation. In-utero transplantation of allogeneic hematopoietic stem cells (HSC) has been successfully used as a therapy in different animal models and recently also in human fetuses. Unfortunately, clinical success of this novel treatment is limited by the lack of donor cell engraftment in non-immunocompromised hosts and is thus restricted to diseases where the fetus is affected by severe immunodeficiency. Gene therapy using genetically modified autologous HSC circumvents allogeneic HLA barriers and constitutes one of the most promising new approaches to correct genetic deficits in the fetus. Recent developments of strategies to overcome failure of efficient transduction of quiescent hematopoietic cells include the use of new vector constructs and transduction protocols. These improvements open new perspectives for gene therapy in general and for prenatal gene transfer in particular. The fetus may be especially susceptible for successful gene therapy due to the immunologic naiveté of the immature hematopoietic system during gestation, precluding an immune reaction towards the transgene. Ethical issues, in particular those regarding treatment safety, must be taken into account before clinical trials with fetal gene therapy in human pregnancies can be initiated.

"Exterritorial" lymphocytic hypophysitis within an ovarian teratoma during pregnancy: a possible sentinel lesion?

Pituitary tissue is rarely to be found among the constituents of ovarian teratomas (dermoid cysts). In some exceptional cases, however, such ectopic pituitary anlagen may even give rise to secondary organ-specific pathologies. Akin to those of the pituitary in its natural location, these tend to be adenomas. We describe a unique example of lymphocytic hypophysitis incidentally encountered in a mature left ovarian teratoma from a 30-year-old woman in the 19th week of pregnancy. Amidst various fully differentiated derivatives of all three embryonic layers, the cyst wall also included a miniature replica of the anterior pituitary lobe 0.5 cm in diameter. While a full set of adenohypophyseal hormone-producing cell types could be identified, there was characteristic pregnancy-related hyperplasia of lactotrophs. This was further overlaid by prominent mononuclear inflammation, including infiltration by T lymphocytes, follicular aggregates of B cells, and attendant destruction of parenchyma. There was no significant inflammatory reaction elsewhere. Discounting the non-standard location, the ensemble of the clinical setting and histology were felt to be indistinguishable from the classical paradigm of lymphocytic hypophysitis complicating pregnancy. To date, lymphocytic thyroiditis is the sole form of organ-specific inflammatory process within an ovarian teratoma on record. By analogy, we hypothesize that this ectopic manifestation of immune-mediated inflammation of pituitary parenchyma may possibly be read as a preclinical sentinel lesion of lymphocytic hypophysitis.