Tubular structures exist broadly in biological systems and exhibit important functions including mediating cellular communications. The construction of artificial analogues in living cells would provide a new strategy for chemotherapy. In this report, a kind of supramolecular channel has been constructed within intercellular gaps by mimicking the assembly process and structure of natural gap junctional channels, which consist of hydrophobic tubular modules located in the adjacent cell membranes and hydrophilic modules within the extracellular space. The assembly of the channels was driven by electrostatic interactions. The channels could inhibit tumor cell invasion by preventing cell migration.

BACKGROUND: Atrial fibrillation (AF) is associated with increased risk of stroke and mortality. It has been reported that the process of atrial fibrosis was regulated by β-catenin in rats with AF. However, pathophysiological mechanisms of this process in human with AF remain unclear. This study aims to investigate the possible mechanisms of β-catenin in participating in the atrial fibrosis using human right atrial appendage (hRAA) tissues .
METHODS: We compared the difference of β-catenin expression in hRAA tissues between the patients with AF and sinus rhythm (SR). The possible function of β-catenin in the development of AF was also explored in mice and primary cells.
RESULTS: Firstly, the space between the membrane of the gap junctions of cardiomyocytes was wider in the AF group. Secondly, the expression of the gap junction function related proteins, Connexin40 and Connexin43, was decreased, while the expression of β-catenin and its binding partner E-cadherin was increased in hRAA and cardiomyocytes of the AF group. Thirdly, β-catenin colocalized with E-cadherin on the plasma membrane of cardiomyocytes in the SR group, while they were dissociated and accumulated intracellularly in the AF group. Furthermore, the expression of glycogen synthase kinase 3β (GSK-3β) and Adenomatous Polyposis Coli (APC), which participated in the degradation of β-catenin, was decreased in hRAA tissues and cardiomyocytes of the AF group. Finally, the development of atrial fibrosis and AF were proved to be prevented after inhibiting β-catenin expression in the AF model mice.
CONCLUSIONS: Based on human atrial pathological and molecular analyses, our findings provided evidence that β-catenin was associated with atrial fibrosis and AF progression.

Gap junctions are channels that allow for direct transmission of electrical signals between cells. However, the ability of one cell to be impacted or controlled by other cells through gap junctions remains unclear. In this study, heterocellular coupling between ON α retinal ganglion cells (α-RGCs) and displaced amacrine cells (ACs) in the mouse retina was used as a model. The impact of the extent of coupling of interconnected ACs on the synchronized firing between coupled ON α-RGC-AC pair was investigated using the dopamine 1 receptor (D1R) antagonist-SCH23390 and agonist-SKF38393. It was observed that the synchronized firing between the ON α-RGC-ACs pairs was increased by the D1R antagonist SCH23390, whereas it was eradicated by the agonist SKF38393. Subsequently, the signaling drive was investigated by infecting coupled ON α-RGC-AC pairs with the channelrhodopsin-2(ChR2) mutation L132C engineered to enhance light sensitivities. The results demonstrated that the spikes of ON α-RGCs (without ChR2) could be triggered by ACs (with ChR2) through the gap junction, and vice versa. Furthermore, it was observed that ON α-RGCs stimulated with 3-10 Hz currents by whole cell patch could elicit synchronous spikes in the coupled ACs, and vice versa. This provided direct evidence that the firing of one cell could be influenced by another cell through gap junctions. However, this phenomenon was not observed between OFF α-RGC pairs. The study implied that the synchronized firing between ON α-RGC-AC pairs could potentially be affected by the coupling of interconnected ACs. Additionally, one cell type could selectively control the firing of another cell type, thereby forcefully transmitting information. The key role of gap junctions in synchronizing firing and driving cells between α-RGCs and coupled ACs in the mouse retina was highlighted.NEW & NOTEWORTHY This study investigates the role of gap junctions in transmitting electrical signals between cells and their potential for cell control. Using ON α retinal ganglion cells (α-RGCs) and amacrine cells (ACs) in the mouse retina, the researchers find that the extent of coupling between ACs affects synchronized firing. Bidirectional signaling occurs between ACs and ON α-RGCs through gap junctions.

In order to investigate the effectiveness and safety of miR-23b-3p in anti-seizure activity and to elucidate the regulatory relationship between miR-23b-3p and Cx43 in the nervous system, we have established a lithium chloride-pilocarpine (PILO) status epilepticus (SE) model. Rats were randomly divided into the following groups: seizure control (PILO), valproate sodium (VPA+PILO), recombinant miR-23b-3p overexpression (miR+PILO), miR-23b-3p sponges (Sponges+PILO), and scramble sequence negative control (Scramble+PILO) (n = 6/group). After experiments, we got the following results. In the acute phase, the time required for rats to reach stage IV after PILO injection was significantly longer in VPA+PILO and miR+PILO. In the chronic phase after SE, the frequency of spontaneous recurrent seizures (SRSs) in VPA+PILO and miR+PILO was significantly reduced. At 10 min before seizure cessation, the average energy expression of fast ripples (FRs) in VPA+PILO and miR+PILO was significantly lower than in PILO. After 28 days of seizure, Cx43 expression in PILO was significantly increased, and Beclin1expression in all groups was significantly increased. After 28 days of SE,the number of synapses in the CA1 region of the hippocampus was significantly higher in the VPA+PILO and miR+PILO groups compared to that in the PILO group. After 28 days of SE ,hippocampal necrotic cells in the CA3 region were significantly lower in the VPA+PILO and miR+PILO groups compared to those in the PILO group. There were no significant differences in biochemical indicators among the experimental group rats 28 days after SE compared to the seizure control group. Based on the previous facts, we can reach the conclusion that MiR-23b-3p targets and blocks the expression of hippocampal Cx43 which can reduce the formation of pathological FRs, thereby alleviating the severity of seizures, improving seizure-induced brain damage.

The bone turnover capability influences the acquisition and maintenance of osseointegration. The architectures of osteocyte three-dimensional (3D) networks determine the direction and activity of bone turnover through osteocyte intercellular crosstalk, which exchanges prostaglandins through gap junctions in response to mechanical loading. Titanium nanosurfaces with anisotropically patterned dense nanospikes promote the development of osteocyte lacunar-canalicular networks. We investigated the effects of titanium nanosurfaces on intercellular network development and regulatory capabilities of bone turnover in osteocytes under cyclic compressive loading. MLO-Y4 mouse osteocyte-like cell lines embedded in type I collagen 3D gels on titanium nanosurfaces promoted the formation of intercellular networks and gap junctions even under static culture conditions, in contrast to the poor intercellular connectivity in machined titanium surfaces. The osteocyte 3D network on the titanium nanosurfaces further enhanced gap junction formation after additional culturing under cyclic compressive loading simulating masticatory loading, beyond the degree observed on machined titanium surfaces. A prostaglandin synthesis inhibitor cancelled the dual effects of titanium nanosurfaces and cyclic compressive loading on the upregulation of gap junction-related genes in the osteocyte 3D culture. Supernatants from osteocyte monolayer culture on titanium nanosurfaces promoted osteocyte maturation and intercellular connections with gap junctions. With cyclic loading, titanium nanosurfaces induced expression of the regulatory factors of bone turnover in osteocyte 3D cultures, toward higher osteoblast activation than that observed on machined surfaces. Titanium nanosurfaces with anisotropically patterned dense nanospikes promoted intercellular 3D network development and regulatory function toward osteoblast activation in osteocytes activated by cyclic compressive loading, through intercellular crosstalk by prostaglandin.

Noncoding RNAs (ncRNAs) are a class of nucleotide sequences that cannot be translated into peptides. ncRNAs can function post-transcriptionally by splicing complementary sequences of mRNAs or other ncRNAs or by directly engaging in protein interactions. Over the past few decades, the pervasiveness of ncRNAs in cell physiology and their pivotal roles in various diseases have been identified. One target regulated by ncRNAs is connexin (Cx), a protein that forms gap junctions and hemichannels and facilitates intercellular molecule exchange. The aberrant expression and misdistribution of connexins have been implicated in central nervous system diseases, cardiovascular diseases, bone diseases, and cancer. Current databases and technologies have enabled researchers to identify the direct or indirect relationships between ncRNAs and connexins, thereby elucidating their correlation with diseases. In this review, we selected the literature published in the past five years concerning disorders regulated by ncRNAs via corresponding connexins. Among it, microRNAs that regulate the expression of Cx43 play a crucial role in disease development and are predominantly reviewed. The distinctive perspective of the ncRNA-Cx axis interprets pathology in an epigenetic manner and is expected to motivate research for the development of biomarkers and therapeutics.

Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.

Animals can learn in real-life scenarios where rewards are often only available when a goal is achieved. This \'distal\' or \'sparse\' reward problem remains a challenge for conventional reinforcement learning algorithms. Here we investigate an algorithm for learning in such scenarios, inspired by the possibility that axo-axonal gap junction connections, observed in neural circuits with parallel fibres such as the insect mushroom body, could form a resistive network. In such a network, an active node represents the task state, connections between nodes represent state transitions and their connection to actions, and current flow to a target state can guide decision making. Building on evidence that gap junction weights are adaptive, we propose that experience of a task can modulate the connections to form a graph encoding the task structure. We demonstrate that the approach can be used for efficient reinforcement learning under sparse rewards, and discuss whether it is plausible as an account of the insect mushroom body.

Natural gap junctions are a type of channel protein responsible for intercellular signalling and mass communication. However, the scope of applications for these proteins is limited as they cannot be prepared at a large scale and are unable to spontaneously insert into cell membranes in vitro. The construction of artificial gap junctions may provide an alternative strategy for preparing analogues of the natural proteins and bottom-up building blocks necessary for the synthesis of artificial cells. Here we show the construction of artificial gap junction channels from unimolecular tubular molecules consisting of alternately arranged positively and negatively charged pillar[5]arene motifs. These molecules feature a hydrophobic-hydrophilic-hydrophobic triblock structure that allows them to efficiently insert into two adjacent plasma membranes and stretch across the gap between the two membranes to form gap junctions. Similar to natural gap junction channels, the synthetic channels could mediate intercellular signal coupling and reactive oxygen species transmission, leading to cellular activity.

The in situ generation of H2O2 in cells in response to external stimulation has exceptional advantages in modulating intracellular Ca2+ dynamics, including high controllability and biological safety, but has been rarely explored. Here, we develop photocatalyst-based metal-organic frameworks (DCSA-MOFs) to modulate Ca2+ responses in cells, multicellular spheroids, and organs. By virtue of the efficient photocatalytic oxygen reduction to H2O2 without sacrificial agents, photoexcited DCSA-MOFs can rapidly trigger Ca2+ outflow from the endoplasmic reticulum with single-cell precision in a repeatable and controllable manner, enabling the propagation of intercellular Ca2+ waves (ICW) over long distances in two-dimensional and three-dimensional cell cultures. After photoexcitation, ICWs induced by DCSA-MOFs can activate neural activities in the optical tectum of tadpoles and thighs of spinal frogs, eliciting the corresponding motor behaviors. Our study offers a versatile optical nongenetic modulation technique that enables remote, repeatable, and controlled manipulation of cellular and animal behaviors.