Extracellular pectin-RALF phase separation mediates FERONIA global signaling function.

The FERONIA (FER)-LLG1 co-receptor and its peptide ligand RALF regulate myriad processes for plant growth and survival. Focusing on signal-induced cell surface responses, we discovered that intrinsically disordered RALF triggers clustering and endocytosis of its cognate receptors and FER- and LLG1-dependent endocytosis of non-cognate regulators of diverse processes, thus capable of broadly impacting downstream responses. RALF, however, remains extracellular. We demonstrate that RALF binds the cell wall polysaccharide pectin. They phase separate and recruit FER and LLG1 into pectin-RALF-FER-LLG1 condensates to initiate RALF-triggered cell surface responses. We show further that two frequently encountered environmental challenges, elevated salt and temperature, trigger RALF-pectin phase separation, promiscuous receptor clustering and massive endocytosis, and that this process is crucial for recovery from stress-induced growth attenuation. Our results support that RALF-pectin phase separation mediates an exoskeletal mechanism to broadly activate FER-LLG1-dependent cell surface responses to mediate the global role of FER in plant growth and survival.

Molecules from the Microbiome.

The human microbiome encodes a second genome that dwarfs the genetic capacity of the host. Microbiota-derived small molecules can directly target human cells and their receptors or indirectly modulate host responses through functional interactions with other microbes in their ecological niche. Their biochemical complexity has profound implications for nutrition, immune system development, disease progression, and drug metabolism, as well as the variation in these processes that exists between individuals. While the species composition of the human microbiome has been deeply explored, detailed mechanistic studies linking specific microbial molecules to host phenotypes are still nascent. In this review, we discuss challenges in decoding these interaction networks, which require interdisciplinary approaches that combine chemical biology, microbiology, immunology, genetics, analytical chemistry, bioinformatics, and synthetic biology. We highlight important classes of microbiota-derived small molecules and notable examples. An understanding of these molecular mechanisms is central to realizing the potential of precision microbiome editing in health, disease, and therapeutic responses.

Preparing Better Samples for Cryo-Electron Microscopy: Biochemical Challenges Do Not End with Isolation and Purification.

The preparation of extremely thin samples, which are required for high-resolution electron microscopy, poses extreme risk of damaging biological macromolecules due to interactions with the air-water interface. Although the rapid increase in the number of published structures initially gave little indication that this was a problem, the search for methods that substantially mitigate this hazard is now intensifying. The two main approaches under investigation are (a) immobilizing particles onto structure-friendly support films and (b) reducing the length of time during which such interactions may occur. While there is little possibility of outrunning diffusion to the interface, intentional passivation of the interface may slow the process of adsorption and denaturation. In addition, growing attention is being given to gaining more effective control of the thickness of the sample prior to vitrification.

Restoring the Sense of Touch Using a Sensorimotor Demultiplexing Neural Interface.

Paralyzed muscles can be reanimated following spinal cord injury (SCI) using a brain-computer interface (BCI) to enhance motor function alone. Importantly, the sense of touch is a key component of motor function. Here, we demonstrate that a human participant with a clinically complete SCI can use a BCI to simultaneously reanimate both motor function and the sense of touch, leveraging residual touch signaling from his own hand. In the primary motor cortex (M1), residual subperceptual hand touch signals are simultaneously demultiplexed from ongoing efferent motor intention, enabling intracortically controlled closed-loop sensory feedback. Using the closed-loop demultiplexing BCI almost fully restored the ability to detect object touch and significantly improved several sensorimotor functions. Afferent grip-intensity levels are also decoded from M1, enabling grip reanimation regulated by touch signaling. These results demonstrate that subperceptual neural signals can be decoded from the cortex and transformed into conscious perception, significantly augmenting function.

Hand Knob Area of Premotor Cortex Represents the Whole Body in a Compositional Way.

Decades after the motor homunculus was first proposed, it is still unknown how different body parts are intermixed and interrelated in human motor cortical areas at single-neuron resolution. Using multi-unit recordings, we studied how face, head, arm, and leg movements are represented in the hand knob area of premotor cortex (precentral gyrus) in people with tetraplegia. Contrary to traditional expectations, we found strong representation of all movements and a partially "compositional" neural code that linked together all four limbs. The code consisted of (1) a limb-coding component representing the limb to be moved and (2) a movement-coding component where analogous movements from each limb (e.g., hand grasp and toe curl) were represented similarly. Compositional coding might facilitate skill transfer across limbs, and it provides a useful framework for thinking about how the motor system constructs movement. Finally, we leveraged these results to create a whole-body intracortical brain-computer interface that spreads targets across all limbs.

Long-Term Culture Captures Injury-Repair Cycles of Colonic Stem Cells.

The colonic epithelium can undergo multiple rounds of damage and repair, often in response to excessive inflammation. The responsive stem cell that mediates this process is unclear, in part because of a lack of in vitro models that recapitulate key epithelial changes that occur in vivo during damage and repair. Here, we identify a Hopx+ colitis-associated regenerative stem cell (CARSC) population that functionally contributes to mucosal repair in mouse models of colitis. Hopx+ CARSCs, enriched for fetal-like markers, transiently arose from hypertrophic crypts known to facilitate regeneration. Importantly, we established a long-term, self-organizing two-dimensional (2D) epithelial monolayer system to model the regenerative properties and responses of Hopx+ CARSCs. This system can reenact the "homeostasis-injury-regeneration" cycles of epithelial alterations that occur in vivo. Using this system, we found that hypoxia and endoplasmic reticulum stress, insults commonly present in inflammatory bowel diseases, mediated the cyclic switch of cellular status in this process.

WNK1 is an assembly factor for the human ER membrane protein complex.

The assembly of nascent proteins into multi-subunit complexes is a tightly regulated process that must occur at high fidelity to maintain cellular homeostasis. The ER membrane protein complex (EMC) is an essential insertase that requires seven membrane-spanning and two soluble cytosolic subunits to function. Here, we show that the kinase with no lysine 1 (WNK1), known for its role in hypertension and neuropathy, functions as an assembly factor for the human EMC. WNK1 uses a conserved amphipathic helix to stabilize the soluble subunit, EMC2, by binding to the EMC2-8 interface. Shielding this hydrophobic surface prevents promiscuous interactions of unassembled EMC2 and directly competes for binding of E3 ubiquitin ligases, permitting assembly. Depletion of WNK1 thus destabilizes both the EMC and its membrane protein clients. This work describes an unexpected role for WNK1 in protein biogenesis and defines the general requirements of an assembly factor that will apply across the proteome.

The Anatomy and Physiology of Claustrum-Cortex Interactions.

The claustrum is one of the most widely connected regions of the forebrain, yet its function has remained obscure, largely due to the experimentally challenging nature of targeting this small, thin, and elongated brain area. However, recent advances in molecular techniques have enabled the anatomy and physiology of the claustrum to be studied with the spatiotemporal and cell type-specific precision required to eventually converge on what this area does. Here we review early anatomical and electrophysiological results from cats and primates, as well as recent work in the rodent, identifying the connectivity, cell types, and physiological circuit mechanisms underlying the communication between the claustrum and the cortex. The emerging picture is one in which the rodent claustrum is closely tied to frontal/limbic regions and plays a role in processes, such as attention, that are associated with these areas.

Conditionally mutant animal model for investigating the invasive trophoblast cell lineage.

Placental development involves coordinated expansion and differentiation of trophoblast cell lineages possessing specialized functions. Among the differentiated trophoblast cell lineages are invasive trophoblast cells, which exit the placenta and invade the uterus, where they restructure the uterine parenchyma and facilitate remodeling of uterine spiral arteries. The rat exhibits deep intrauterine trophoblast cell invasion, a feature shared with human placentation, and is also amenable to gene manipulation using genome-editing techniques. In this investigation, we generated a conditional rat model targeting the invasive trophoblast cell lineage. Prolactin family 7, subfamily b, member 1 (Prl7b1) is uniquely and abundantly expressed in the rat invasive trophoblast cell lineage. Disruption of Prl7b1 did not adversely affect placental development. We demonstrated that the Prl7b1 locus could be effectively used to drive the expression of Cre recombinase in invasive trophoblast cells. Our rat model represents a new tool for investigating candidate genes contributing to the regulation of invasive trophoblast cells and their roles in trophoblast-guided uterine spiral artery remodeling.

Molecular basis for curvature formation in SepF polymerization.

The self-assembly of proteins into curved structures plays an important role in many cellular processes. One good example of this phenomenon is observed in the septum-forming protein (SepF), which forms polymerized structures with uniform curvatures. SepF is essential for regulating the thickness of the septum during bacteria cell division. In Bacillus subtilis, SepF polymerization involves two distinct interfaces, the ß-ß and α-α interfaces, which define the assembly unit and contact interfaces, respectively. However, the mechanism of curvature formation in this step is not yet fully understood. In this study, we employed solid-state NMR (SSNMR) to compare the structures of cyclic wild-type SepF assemblies with linear assemblies resulting from a mutation of G137 on the ß-ß interface. Our results demonstrate that while the sequence differences arise from the internal assembly unit, the dramatic changes in the shape of the assemblies depend on the α-α interface between the units. We further provide atomic-level insights into how the angular variation of the α2 helix on the α-α interface affects the curvature of the assemblies, using a combination of SSNMR, cryo-electron microscopy, and simulation methods. Our findings shed light on the shape control of protein assemblies and emphasize the importance of interhelical contacts in retaining curvature.

Interface-confined intermediate phase in TiO2 enables efficient photocatalysis.

As a prototypical photocatalyst, TiO[Formula: see text] has been extensively studied. An interesting yet puzzling experimental fact was that P25-a mixture of anatase and rutile TiO[Formula: see text]-outperforms the individual phases; the origin of this mysterious fact, however, remains elusive. Employing rigorous first-principles calculations, here we uncover a metastable intermediate structure (MIS), which is formed due to confinement at the anatase/rutile interface. The MIS has a high conduction-band minimum level and thus substantially enhances the overpotential of the hydrogen evolution reaction. Also, the corresponding band alignment at the interface leads to efficient separation of electrons and holes. The interfacial confinement additionally creates a wide distribution of the band gap in the vicinity of the interface, which in turn improves optical absorption. These factors all contribute to the enhanced photocatalytic efficiency in P25. Our insights provide a rationale to the puzzling superior photocatalytic performance of P25 and enable a strategy to achieve highly efficient photocatalysis via interface engineering.

Elucidating the behavior of the SARS-CoV-2 virus surface at vapor-liquid interfaces using molecular dynamics simulation.

Aerosols play a major role in the transmission of the SARS-CoV-2 virus. The behavior of the virus within aerosols is therefore of fundamental importance. On the surface of a SARS-CoV-2 virus, there are about 40 spike proteins, which each have a length of about 20 nm. They are glycosylated trimers, which are highly flexible, due to their structure. These spike proteins play a central role in the intrusion of the virus into human host cells and are, therefore, a focus of vaccine development. In this work, we have studied the behavior of spike proteins of the SARS-CoV-2 virus in the presence of a vapor-liquid interface by molecular dynamics (MD) simulations. Systematically, the behavior of the spike protein at different distances to a vapor-liquid interface were studied. The results reveal that the spike protein of the SARS-CoV-2 virus is repelled from the vapor-liquid interface and has a strong affinity to stay inside the bulk liquid phase. Therefore, the spike protein bends when a vapor-liquid interface approaches the top of the protein. This has important consequences for understanding the behavior of the virus during the dry-out of aerosol droplets.

Membrane nanotubes transform into double-membrane sheets at condensate droplets.

Cellular membranes exhibit a multitude of highly curved morphologies such as buds, nanotubes, cisterna-like sheets defining the outlines of organelles. Here, we mimic cell compartmentation using an aqueous two-phase system of dextran and poly(ethylene glycol) encapsulated in giant vesicles. Upon osmotic deflation, the vesicle membrane forms nanotubes, which undergo surprising morphological transformations at the liquid-liquid interfaces inside the vesicles. At these interfaces, the nanotubes transform into cisterna-like double-membrane sheets (DMS) connected to the mother vesicle via short membrane necks. Using super-resolution (stimulated emission depletion) microscopy and theoretical considerations, we construct a morphology diagram predicting the tube-to-sheet transformation, which is driven by a decrease in the free energy. Nanotube knots can prohibit the tube-to-sheet transformation by blocking water influx into the tubes. Because both nanotubes and DMSs are frequently formed by cellular membranes, understanding the formation and transformation between these membrane morphologies provides insight into the origin and evolution of cellular organelles.

Proprioception: A New Era Set in Motion by Emerging Genetic and Bionic Strategies?

The generation of an internal body model and its continuous update is essential in sensorimotor control. Although known to rely on proprioceptive sensory feedback, the underlying mechanism that transforms this sensory feedback into a dynamic body percept remains poorly understood. However, advances in the development of genetic tools for proprioceptive circuit elements, including the sensory receptors, are beginning to offer new and unprecedented leverage to dissect the central pathways responsible for proprioceptive encoding. Simultaneously, new data derived through emerging bionic neural machine-interface technologies reveal clues regarding the relative importance of kinesthetic sensory feedback and insights into the functional proprioceptive substrates that underlie natural motor behaviors.

Natural Killer Cells Promote Fetal Development through the Secretion of Growth-Promoting Factors.

Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49a+Eomes+ subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF-secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49a+Eomes+ NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy.

Principles of organelle positioning in motile and non-motile cells.

Cells are equipped with asymmetrically localised and functionally specialised components, including cytoskeletal structures and organelles. Positioning these components to specific intracellular locations in an asymmetric manner is critical for their functionality and affects processes like immune responses, tissue maintenance, muscle functionality, and neurobiology. Here, we provide an overview of strategies to actively move, position, and anchor organelles to specific locations. By conceptualizing the cytoskeletal forces and the organelle-to-cytoskeleton connectivity, we present a framework of active positioning of both membrane-enclosed and membrane-less organelles. Using this framework, we discuss how different principles of force generation and organelle anchorage are utilised by different cells, such as mesenchymal and amoeboid cells, and how the microenvironment influences the plasticity of organelle positioning. Given that motile cells face the challenge of coordinating the positioning of their content with cellular motion, we particularly focus on principles of organelle positioning during migration. In this context, we discuss novel findings on organelle positioning by anchorage-independent mechanisms and their advantages and disadvantages in motile as well as stationary cells.

Silk-protein-based gradient hydrogels with multimode reprogrammable shape changes for biointegrated devices.

Biocompatible and morphable hydrogels capable of multimode reprogrammable, and adaptive shape changes are potentially useful for diverse biomedical applications. However, existing morphable systems often rely on complicated structural designs involving cumbersome and energy-intensive fabrication processes. Here, we report a simple electric-field-activated protein network migration strategy to reversibly program silk-protein hydrogels with controllable and reprogrammable complex shape transformations. The application of a low electric field enables the convergence of net negatively charged protein cross-linking networks toward the anode (isoelectric point plane) due to the pH gradient generated in the process, facilitating the formation of a gradient network structure and systems suitable for three-dimensional shape change. These tunable protein networks can be reprogrammed or permanently fixed by control of the polymorphic transitions. We show that these morphing hydrogels are capable of conformally interfacing with biological tissues by programming the shape changes and a bimorph structure consisting of aligned carbon nanotube multilayers and the silk hydrogels was assembled to illustrate utility as an implantable bioelectronic device for localized low-voltage electrical stimulation of the sciatic nerve in a rabbit.

Size-dependent charge transfer between water microdroplets.

Contact electrification (CE) in water has attracted much attention, owing to its potential impacts on the chemical reactions, such as the recent discovery of spontaneous generation of hydrogen peroxide (H2O2) in water microdroplets. However, current studies focus on the CE of bulk water, the measurement of CE between micrometer-size water droplets is a challenge and its mechanism still remains ambiguous. Here, a method for quantifying the amount of charge carried by the water microdroplets produced by ultrasonic atomization is proposed. In the method, the motions of water microdroplets in a uniform electric field are observed and the electrostatic forces on the microdroplets are calculated based on the moving speed of the microdroplets. It is revealed that the charge transfer between water microdroplets is size-dependent. The large microdroplets tend to be positively charged while the small microdroplets tend to receive negative charges, implying that the negative charges transfer from large microdroplets to the small microdroplets during ultrasonic atomization. Further, a theoretical model for microdroplets charging is proposed, in which the curvature-induced surface potential/energy difference is suggested to be responsible for the charge transfer between microdroplets. The findings show that the electric field strength between two microdroplets with opposite charges during separation is strong enough to convert OH‒ to OH*, providing evidence for the CE-induced spontaneous generation of H2O2 in water microdroplets.

Epidemiological connectivity between humans and animals across an urban landscape.

Urbanization is predicted to be a key driver of disease emergence through human exposure to novel, animal-borne pathogens. However, while we suspect that urban landscapes are primed to expose people to novel animal-borne diseases, evidence for the mechanisms by which this occurs is lacking. To address this, we studied how bacterial genes are shared between wild animals, livestock, and humans (n = 1,428) across Nairobi, Kenya-one of the world's most rapidly developing cities. Applying a multilayer network framework, we show that low biodiversity (of both natural habitat and vertebrate wildlife communities), coupled with livestock management practices and more densely populated urban environments, promotes sharing of Escherichia coli-borne bacterial mobile genetic elements between animals and humans. These results provide empirical support for hypotheses linking resource provision, the biological simplification of urban landscapes, and human and livestock demography to urban dynamics of cross-species pathogen transmission at a landscape scale. Urban areas where high densities of people and livestock live in close association with synanthropes (species such as rodents that are more competent reservoirs for zoonotic pathogens) should be prioritized for disease surveillance and control.

Ultrastrong spinodoid alloys enabled by electrochemical dealloying and refilling.

We present an extreme case of composition-modulated nanomaterial formed by selective etching (dealloying) and electrochemical refilling. The product is a coarse-grain polycrystal consisting of two interwoven nanophases, with identical crystal structures and a cube-on-cube relationship, separated by smoothly curved semicoherent interfaces with high-density misfit dislocations. This material resembles spinodal alloys structurally, but its synthesis and composition modulation are spinodal-independent. Our Cu/Au "spinodoid" alloy demonstrates superior mechanical properties such as near-theoretical strength and single-phase-like behavior, owing to its fine composition modulation, large-scale coherence of crystal lattice, and smoothly shaped three-dimensional (3D) interface morphology. As a unique extension of spinodal alloy, the spinodoid alloy reported here reveals a number of possibilities to modulate the material's structure and composition down to the nanoscale, such that further improved properties unmatchable by conventional materials can be achieved.